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FDA Advisory Panel: COVID Boosters, Video/Transcript (Sep. 17, 2021)

The following is a transcript (AI-generated) of the video, here.

Speaker1: [00:01:39] Good morning, and welcome to the 67th meeting of the Vaccines and Related Biological Products Advisory Committee. I’m Mike Kaczynski. I will be moderating today’s meeting. This is a live virtual meeting, so we do have participants from around the country and around the world. And because it is a virtual meeting of many of you have experienced in your own throat the last few years. Every once in a while, we may run into a technical glitch where we may cause us to have an unexpected pause just in order to make sure that we have our members and all that back in the meeting. So if that happens, don’t fret we’ll take care of it. But with that being said, I will have to jump in every once in a while just in case that does happen. So that being said, let’s get this meeting started, and I’d like to hand the meeting off to our chair, Dr. Arnold Monto, the acting chair. Arnold, are you there? Now, Arnold, let’s make sure we get you unmuted real quick. I gotcha. All right, Arnold Rosen, right after a while. All right. Take it away for all your technical help and backup in this challenging time in terms of organizing meetings. Let me add my welcome to the one hundred and sixty seventh meeting of the Vaccines and Related Biological Products Advisory Committee of the Center for Biologics Evaluation and Research. We have an important meeting to talk about to talk about a specific topic, and we are in open session to discuss Pfizer BioNTech. Supplemental Biologics Application for administration of a third dose or booster dose of the COVID 19 vaccine in individuals 16 months of age and older. Welcome again to all the members, the ad hoc members and to the public. Let’s get some of the housekeeping details out of the way first and also introduce our distinguished committee. I’d like to turn over to our designated federal officer from a trader who will do this activity. Thank you.

Speaker2: [00:04:19] Good morning, thank you, Dr. Monto. Good morning, everyone, this is Dr. Prabha trailer, and it is my great honor to serve as the designated federal officer that is DFO for two days. One hundred and sixty seven Vaccines and Related Biological Products Advisory Committee meeting on behalf of the FDA, the Center for Biologics Evaluation and Research and the Vaccines Advisory Committee, I would like to welcome everyone for today’s virtual meeting. The topic for today’s meeting is to discuss in open session Pfizer-BioNTech, some supplemental biologics license application for administration of a third dose or booster dose of the COVID 19 vaccine commonality in individuals 16 years of age and older. Today’s meeting and the topic were announced in the Federal Register notice that was published on September seven to twenty twenty one. I would like to introduce and acknowledge the excellent contributions of the staff in my division and the great team I have in preparing for this meeting. This Kathleen Vest is my code year for providing excellent support in all aspects of preparing for and conducting this meeting. Other staff who have contributed significantly on this molecule Dr.

Speaker2: [00:05:34] Jeanette Devine and MS. Christina Rad, who provided excellent administrative support. I would also like to express our sincere appreciation to Mike Kozinski in facilitating the meeting today. Also, our kudos to many FDA staff working hard behind the scenes every day, trying to ensure that today’s virtual meeting will also be a successful one. Like all the previous meetings on four key topics, please direct any press or media questions for today’s meeting to FDA’s Office of the Media Affairs, FDA OMB. One word that HHS sat down to discuss but meeting is that while we will begin today’s meeting by taking a formal roll call for the committee members and then temporary voting members, anything we will turn. Please turn on your video camera and mute your phone and then state your last name. And then when finished, you can turn off your camera so we can put it to the next person. Please see the committee roster slides in which we will begin with the chair. Mike, can we have the photo slide, please? Next slide, please. Somebody asked. Good morning. I’m not much of. The chair.

Speaker1: [00:07:04] Ok. This is Arnold Monto, I am professor of epidemiology and public health at the University of Michigan School of Public Health.

Speaker2: [00:07:13] Bravo. Thank you. That’s Dr Declan. Good morning, Dr. Amanda Cohen, pediatrician at the Centers for Disease Control and Prevention. Thank you, Dr. Chatterjee. Good morning, everyone, my name is Uchenna Chatterjee. I am the dean of Chicago Medical School and vice president for medical affairs at Rosalind Franklin University of Medicine and Science in Chicago. I am a pediatric infectious diseases specialist and happy to be here this morning. Thank you. Thank you, Dr. Meissner, Cody Meissner.

Speaker1: [00:07:53] Thank you, brother. My name is Dr. Cody Meissner. I’m professor of pediatrics at Tufts Children’s Hospital in Boston.

Speaker2: [00:08:05] Thank you, Dr. Meissner. Next, Dr Kelly. Good morning, Dr. Hayley Gans, pediatric infectious disease at Stanford University. Thank you. Next up to the Michael Gorilla.

Speaker1: [00:08:28] Thank you. Thank you. Good morning, Mike. I’m the director of the Division of Clinical Innovation at the National Center for Advancing Translational Science within NIH background in infectious disease product development and pathologist by training.

Speaker2: [00:08:46] Thank you, Dr. Paul Offit.

Speaker1: [00:08:52] Yes, good morning. I’m and I’m a professor of pediatrics at Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine.

Speaker2: [00:09:02] Thank you, Dr. Paula. Good morning, I’m Paula Annunciato I had vaccines, global clinical development at Merck, and today I am the industry representative, the non-voting industry representative for this meeting. Thank you. That’s Dr Stephen.

Speaker1: [00:09:22] Well, everybody, I’m Steve per game, I’m an associate professor in adult infectious disease at the Fred Hutchinson Cancer. Percy washing.

Speaker2: [00:09:33] Thank you, Dr.. That’s what we just love. The morning. Good morning, I’m Dr. Peter Fuller, I’m an associate professor of microbiology and immunology at the University of Michigan Medical Center and a member of the STEM initiative of the African Study Center. Thank you. Next, Dr. Rubin.

Speaker1: [00:10:02] Hi, Eric Rubin, I’m at the Harvard T.H. Chan School of Public Health, the Brigham and Women’s Hospital and the New England Journal of Medicine.

Speaker2: [00:10:11] Thank you. Next, Dr. James Hildreth.

Speaker1: [00:10:15] Good morning. I’m Dr. James Hildreth, I’m the president and CEO of Meharry Medical College and professor of Internal Medicine. Thank you.

Speaker2: [00:10:23] Thank you. Next, actor Jay Portnoy.

Speaker1: [00:10:26] I’m Dr. Jay Portnoy. I’m a professor of pediatrics at the University of Missouri, Kansas City School of Medicine, and I am an allergist, immunologist at Children’s Mercy Hospital in Kansas City, Missouri.

Speaker2: [00:10:39] Thank you. Next, Dr Janet me. Good morning, my name is Jeanette Lee.

Speaker1: [00:10:50] I’m a professor of biostatistics and a member of the Winthrop Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences.

Speaker2: [00:10:59] Thank you. Thank you. Next, Dr. Mark Sawyer. Dr. Sawyer.

Speaker1: [00:11:12] Good morning. This is actor Mark Sawyer. I’m a pediatric professor of pediatric infectious disease at the University of California, San Diego and Rady Children’s Hospital in San Diego.

Speaker2: [00:11:25] Thank you. Next, I would like to say that Dr. Peter Marks, center director, will say a few welcome remarks later after we start the session. And I would also like to acknowledge the presence of Dr. Celia Whitten, deputy director of Sieber, and Dr. Gruber, director of Office of Vaccines, and Dr. Philip Krauss, deputy director of the Office of Vaccines, at this meeting. Now I will proceed with reading the conflict of interest for Dr. Prabha.

Speaker1: [00:11:56] We forgot somebody. We have Dr. Horton.

Speaker2: [00:12:01] Well, I’m sorry, that’s Melinda Watts, and I’m very sorry. Can you can you introduce yourself? Good morning. I’m Melinda Gordon. I’m an adult infectious disease specialist and I’m at the Centers for Disease Control and Prevention. Thank you. Now we will read the conflict of interest statement for the public record.

Speaker1: [00:12:24] Probably still have some more temporary voting members.

Speaker2: [00:12:31] Ok, thank you, Doctor, hopefully we could you introduce yourself? We can’t hear you often don’t.

Speaker1: [00:12:42] Don’t forget to unmute. Good it go. Good morning, my name is Ofer Levy, and I’m director of the Precision Vaccines Program at Boston Children’s Hospital and professor of pediatrics at Harvard Medical School. Thank you.

Speaker2: [00:13:01] Next, Dr. Pamela McGinnis. Good morning, Pamela McKenna’s, past deputy director, National Center for Advancing Translational Sciences at the National Institutes of Health. Thank you. Thank you, Dr. Stanley Perlman.

Speaker1: [00:13:27] I. I’m Dr. Stanley Perlman, the Department of Microbiology and Immunology at the University of Iowa and a pediatric infectious diseases physician.

Speaker2: [00:13:40] Thank you. Ok, so let me. And the public record, this is a conflict of interest statement. The Food and Drug Administration is convening virtually today on September 17. Twenty twenty one. One hundred and sixty seven. The meeting of the Vaccines and Related Biological Products Advisory Committee under the Authority of the Federal Advisory Committee Act of 1970 to Dr. Arnold Monto, is serving as the acting chair for today’s meeting today on September 17. Twenty twenty one. The committee will meet in open session to discuss Pfizer BioNTech Supplemental Biologics License Application for administration of the third dose or booster dose of the COVID 19 vaccine COVID 19 in individuals 16 years of age and older. This topic is determined to be a particular matter involving specific parties, with the exception of the industry representative member all standing and temporary voting members of the past, or appointed special government employees, trustees or regular government employees from other agencies and are subjected to federal conflicts of interest laws and regulations. The following information on the status of the Committee’s compliance with the. Upregulated and conflicts of interest last including, but not limited to 18 United States code section to aid is being provided to participants in today’s meeting and to the public. Related to the discussions at this meeting, all members of G and C consultants of this committee have been screened for potential financial concepts of their own, as well as those imputed to them, including those of their spouse or minor children, and for the purpose of 18 years for two zero eight their employer.

Speaker2: [00:15:49] These interests may include investment consulting, expert witness testimony, contacts and grant cooperative research and development agreements for Canada teaching, speaking, writing, patents and royalties and primary employment. These may include interests that are current or under negotiation. Fda has determined that all members of this advisory committee, both regular and temporary members, are in compliance with the federal ethics and conflicts of interest laws under the 18 under 18 U.S. Code Section two zero eight. Congress have authorized the FDA to grant waiver to special government employees and regular government employees who have financial conflicts of interest when it is determined that the agency’s need for any special government employee services outweighs the potential for a conflict of interest created by financial interests involved, rather than the interests of the regular government employees. Not so substantial as to be deemed likely to affect the integrity of the services, which the government may expect from the employee. Based on today’s agenda and all financial interests supported by committee members and consultants, there have been one conflict of interest waiver issued under 18 U.S.

Speaker2: [00:17:15] Code two zero eight in connection with this meeting. We have the following consultants serving as temporary working members as you have seen before Dr. Robert Fuller, Dr. James Hildreth, Janet Leigh, Dr. Levy, Dr. Sam McGinnis, Dr. Arnold Monto. That’s Stanley Perlman, Dr. Eric Rubin, Dr. Mark Pryor and Dr. Melinda Wharton among these consultants. Dr. James Hildreth, especially government employee, has been issued a waiver for his participation in today’s meeting. The waiver was posted on the FDA website for public disclosure that will serve as the industry representative for today’s meeting. Industry representatives have not appointed as special government employees and serve as non-voting members of the committee. Industry Representatives act on behalf of all regulated industry and bring general industry perspective to the committee. Industry representatives on this committee is not screened, does not participate in any closed session itself and do not have the voting privileges. Dr. Jeff Portnoy is serving as the temporary consumer representative for this committee. Consumer representatives are appointed special government employees and are screened and cleared by a prior to their participation in the meeting. They are watching members of the committee. Today’s meeting has one external speaker from the Centers for the Centers for Disease Control and Prevention CDC, which is Dr.

Speaker2: [00:18:49] Dr. Sarah Oliver. All the guest speakers of this meeting are Dr. Sharon Alroy-Preis, who is the director of the Public Health Services Ministry of Health in Israel, and also Dr. Ron Mylo, a professor of plant and environmental sciences department. The Charles and Louise Gardener and chair of Weizmann Institute of Science in Israel. And Dr. Jonathan Stern, a professor of medical statistics and epidemiology within the medical school at University of Bristol, UK. Disclosure of financial conflicts of interest for speakers and guest speakers follows applicable federal laws, regulations and FDA guidance. Fda encourages all meeting participants, including open public hearing speakers, to advise the committee of any financial relationship that they may have with any affected from its product in its direct competitors. We would like to remind the standing and temporary members that these discussions involve any other products are not already on the agenda for which a participant has a personal, imputed financial interest. The participants need to inform the DFA and exclude themselves from such involvement and their disclosure. Then their exclusion will be noted, for the record. This concludes the reading of my conflict of interest statement for the public record. At this time, I would like to hand over the meeting to our chair, Dr. Arnold Monto, Dr. Monto. Take it away. Thank you.

Speaker1: [00:20:32] Dr. Monto, I think we have a muted right now. Hold on a second. And Dr. Monto, I’m going to get when we get a chance, we’re going to have you redo your camera. I think we have a little issue to camera, but not to worry. Go ahead. Ok. It’s my pleasure to introduce Dr. Peter Marks, the director of the Center for Biologics Evaluation and Research, who will give us his opening remarks. Thanks, Dr. Monto. Good morning and welcome to the committee members, FDA staff, the sponsor and the public viewing this meeting today. This committee advises the agency in discharging its responsibilities as they relate to helping ensure safe and effective vaccines. Over the past year, the committee has participated in some of the most important decisions made by the FDA in recent memory, contributing markedly to public health. Thank you so much for your continued service. Also, tremendous thanks go to all the FDA staff who have worked tirelessly through this pandemic to facilitate the availability of potentially life saving medical products. Today, the committee will consider the application from Pfizer for the administration of a third dose of their COVID 19 mRNA vaccine approximately six months following a primary vaccination series. In preparation for the discussion, there will be introductory presentations relevant to the potential need for additional vaccine doses. We know that there may be differing opinions as to the interpretation of the data regarding the potential need for additional doses.

Speaker1: [00:22:25] And we strongly encourage all the different viewpoints to be voiced and discussed regarding the data, which is complex. And evolving. And it also requires near real time analyses. We’re committed to focusing on the science and will drive our decision making, and we’ll carefully consider those data in the context of the clear and obvious public health need to continue slowing the spread of COVID 19, which at this time is leading to the deaths of close to two thousand Americans each day. That said, as we proceed, I would ask that we do our best to focus our deliberations on the science related to the application under consideration today and not on operational issues related to a booster campaign or on issues related to global vaccine equity. If we stray into those latter topics, the chair and I will gently bring us back into the scope of this advisory committee meeting. I’ll be present all day to assist as necessary and look forward to a very productive meeting. Thank you so much. Again, today we look forward to a very robust discussion. Thank you. Thank you, Dr. Marks. I would like to introduce Dr. Marion Gruber, director, Office of Vaccines Research and Review, who will introduce the topic. Dr. Gruber.

Speaker2: [00:24:08] Well, thank you very much, and good morning and welcome. My name is Cuba, and I’m the director of the Office of Vaccines Research and Review. This is my piece, my last meeting that I attend in my position as director of the Office of Vaccine. And retiring from federal government service on October 30, first after a very fulfilling and rewarding career as a public health servant at FDA. And for that, I’m grateful. I would like to take a few minutes to thank the members of the ballpark, both past and present, for lending their scientific expertise over the many years. That helped us to address many challenging and complex scientific and clinical issues pertaining to preventive vaccine development and to assure that the vaccines we license are safe and effective for their intended use. I also want to thank the American public. It has been a privilege to serve you. All of my actions and decisions over my 32 year FDA career have been grounded in science with you in mind and in the best interest of your health and safety. And I will continue to hold fast to these principles moving forward. And now to today’s topic, which is the application for licensure of a booster dose of community COVID 19 vaccine. My name and I have the next slide, please. On August 23rd of this year, the FDA approved Community for Active Immunization to Prevent Coronavirus Disease 2019, caused by severe acute respiratory

Speaker1: [00:25:59] Syndrome coronavirus

Speaker2: [00:26:00] Two in individuals 16 years of age and older when administered as a two dose series three weeks apart. On August 25, Pfizer BioNTech submitted a supplement to the Biologics License Application for community seeking approval for administration of a booster dose approximately six months after those two in individuals 16 years of age and older. The ballpark is convened today to determine whether the data submitted are sufficient to support approval of the booster dose of community when administered at least six months after completion of the primary series for use in individuals 16 years of age and older. Next slide, please. The emergence of the highly transmissible Delta variant of SARS-CoV-2 has led to considerations of the potential need for booster doses for fully vaccinated individuals. Data from post authorization effectiveness studies conducted suggests that the currently US authorized or licensed vaccines remain effective in protecting against severe disease. However, some data suggests that effectiveness may be waning. Concerns have also been raised that declining neutralizing antibody titers or reduced effectiveness against symptomatic disease may herald significant declines in effectiveness against severe disease, and you will be hearing an overview of some of these data in the next session. Next slide, please. For a licensed COVID 19 vaccine, it changed, and dosing regimen to include a booster dose will require the approval of a supplemental supplemental BLA. And the supplement must include data that demonstrate that the additional dose is safe and effective. There is an expectation that demonstration of effectiveness of the additional dose is based on adequate and well-controlled clinical trials. However, findings of effectiveness of the additional dose, while necessary, is not sufficient for an FDA approval, a determination that the additional dose is safe for the intended use is also required. Next slide, please. The evaluation, whether the additional dose is safe, involves weighing whether its benefits outweigh its risk.

Speaker2: [00:28:40] That means that available data should support the effectiveness of the booster dose specifically against currently circulating SARS-CoV-2 variants, and the benefit of the booster dose should be considered relative to the benefit already provided by previous vaccinations with the primary series. Considering risk available data should at a minimum, characterize the most common adverse reactions that are associated with the booster dose and the uncertainties regarding benefits and risks are also considered. Next slide, please. Most authorization data demonstrate an increased risks of myocarditis and pericarditis, particularly within seven days following the second dose of comunity, the observed risk is higher among males under 40 years of age than among females and older males. The observed risk is highest in males 16 to 17 years of age. It is not known whether there will be an increased risk of myocarditis, pericarditis or other adverse reactions after a booster dose of community, thus risk benefit considerations to determine whether to approve a booster dose will need to be informed by the known and the potential risks of the vaccine. Next slide. So to summarize, benefit risk evaluations should take into account whether the booster dose will prevent severe cases of COVID 19, including those caused by currently circulating variants. In addition to those prevented by the primary series, the safety profile of the additional dose will also be considered. Fda evaluation, supported by the pluck of the safety and effectiveness data of a booster dose of community in the age groups for which it is currently licensed is thus essential. And this concludes my introductory remarks, and I look forward to a robust and transparent and evidence based discussion. Thank you. I turn it back to you, Dr. Monto.

Speaker1: [00:30:57] Thank you so much, Dr. Gruber, and I want as an individual and representing the biomedical community to thank you for your years of service. They really are appreciated and have been extremely valuable. Next, I’d like to turn over four back further background to Dr. Ramachandra Naik from OVP over our. Dr Naik, thank you. Good morning, everyone. I am. My name is Ramachandra Nayak from the Division of Vaccines and Related Products Applications in the Office of Vaccines, and I am the Review Committee Chair for the Supplemental Bill. I’m going to provide background for today’s advisory committee meeting regarding Pfizer-BioNTech supplement to the BLA for the Moderna COVID 19 vaccine community for a booster dose in individuals 16 years of age and older. Oh, this is the outline of this back room talk. This provides a brief description of the licensed vaccine that is community overview of community supplemental bill and the clinical package and overview of today’s agenda. And finally, what in question to the committee? A community was licensed on August twenty three, twenty twenty one. This is the only approved COVID 19 vaccine in the US. The vaccine is indicated for prevention of COVID 19 caused by SARS-CoV-2 in the individual 16 years of age and older community is administered intramuscularly as a primary series of two doses three weeks apart. Eight zero point three Ml dose of community contains 30 micrograms of nucleoside modified messenger RNA encoding the viral spike glycoprotein of SARS-CoV-2. Oh, the topic for today’s advisory committee meeting, the booster dose supplement to the daily for the supplemental VLA was submitted on August 25.

Speaker1: [00:33:19] Twenty twenty one. A single dose single zero point three million dose of community containing 30 micrograms. Moderna is supposed to be administered approximately six months after the second dose in the individual 16 years of age and older. The clinical package includes safety and immunogenicity data from approximately three hundred and thirty participants who were re enrolled to receive a booster dose of humanity approximately six months after completing the primary series of two doses. Breakdown of these subjects and details of the data will be provided in later presentations by Pfizer and the FDA. This is the. Hmm. What would be of today’s agenda after this introduction and background, CDC Dr. Sarah Oliver is going to present the epidemiology of pandemic CDC, Delta variants and breakthrough infections, followed by Dr. Jonathan Stern’s presentation. He’s a professor at the University of Bristol. He’s going to present data on real world effectiveness of COVID 19 vaccines later. Dr. Sharon Alroy-Preis don’t see the slide. Oh, the doctor, Saddam. So Saddam and the director of Public Health Services, Ministry of Health Israel and Dr. Ron Mylo, professor at Weizmann Institute of Institute Israel. They’re going to present the data from Israel, boosted protection against confirmed infections and severe disease, followed by five minute breaks after the break. Dana Bash and Dr. Bill Gruber will provide the applicant presentation, followed by FDA presentation by Dr.

Speaker1: [00:35:24] Joe Healy, who is going to present the clinical data submitted to FDA by Pfizer. After that, there will be a lunch break after lunch. There will be open public hearing and followed by a short break. There will be a question and answer session regarding the applicant and FDA presentations, followed by committee discussion and voting before adjournment of the meeting. This is the question to the committee to the safety and effectiveness data from the clinical trial see four five nine one zero zero one support approval of a community booster dose administered at least six months after completion of the primary dose for use in individuals 16 years of age and older. Please vote yes or no. Thank you. But let’s. And of the federal. Thank you, Dr Knight. Next, I’d like to turn over to Dr Sarah Oliver of the Division of Viral Diseases CDC, who will update us on the epidemiology of pandemics. Cdc Delta variant breakthrough infections. I assume that CDC identified not at the CDC. I’d like to make sure that the speakers from now on will stick to time. We are going to have some real problems if we go over because we have a very important discussion at the end of the day. And that’s why I skipped the questions that are on the agenda for Dr. Knight. We’ll get to some of those later on. I believe we need very much to keep our focus on the next talks. Dr. Oliver, please.

Speaker2: [00:37:48] Thank you so much, and good morning. So today, I’ll look at COVID 19 cases and hospitalizations. Covid vaccines administered and COVID vaccine effectiveness. We’ll look at estimates for the over time we during times of the Delta variant and V for older adults. The first four COVID cases and hospitalizations. To date, over forty one million cases have been reported in the U.S.. This slide shows the trends in the number of COVID cases reported daily, with the seven day moving average in red as everyone is aware of or currently experiencing a surge in cases second only to the surge seen in the winter. The current seven day moving average is around one hundred and forty five thousand cases per day. This slide represents the daily trends in the number of COVID 19 deaths per day in the U.S., the seven day moving average around 13 hundred deaths per day. Then this slide shows the weekly trend in the COVID 19 associated hospitalization rates in the U.S. by age group rates has been increasing with this recent surge, but are somewhat less than what was noted this past winter. However, as we consider these rates, it’s important to see hospitalization rates among the vaccinated compared to the unvaccinated population. The figure on the left shows hospitalization rates among 18 to 40 nine year olds. The middle is 50 to 60 four year olds and the bottom is sixty five and over. Note for each of the graphics, the scale of the x axis is different.

Speaker2: [00:39:55] The Green Line at the bottom of each figure is the hospitalization rate among the fully vaccinated individuals, and the blue line is the hospitalization rate among those unvaccinated. Among adults 65 and over, the incidence was 13 times higher in unvaccinated, and for those less than sixty five, the hospitalization rates were twenty two to twenty three times higher in unvaccinated individuals. Typekit slide shows the various proportions among the sequenced lineages, the blue color on this figure represents the alpha variant and the orange color represents the Delta variant. You can see for recent weeks, Delta represents around ninety nine percent of sequenced lineages. Booster doses of COVID vaccines would only apply to those who had already received a primary series. I can highlight COVID vaccines already administered. So to date, there have been over three hundred and eighty million vaccine doses administered in the U.S.. The left shares the number of people fully vaccinated by vaccine series type, and on the right is the percent of fully vaccinated population by age. Sixty three percent of those 12 and over sixty five percent of those aged 18 and over and over eighty two percent of those 65 and over are fully vaccinated. So this figure shows the daily trends in doses administered over time. We hit a peak of around three to four million doses delivered per day in the spring with a decline into the summer.

Speaker2: [00:41:56] However, the average number of doses administered has increased since mid-July. This slide shows the proportion of the population receiving at least one dose among older adults in purple, those 65 and over at the top 90 percent or more have received at least one dose. And among younger adults and adolescents in yellow, around 50 to 60 percent have received at least one dose. So now to move to COVID victims first, we’ll look at data available over time. I want to highlight some recent publications that were pulling data from listed here. This slide shows the best estimates against hospitalisation from some studies listed on the previous slide, you can see the estimates have remained high over time. And Slide shows beat estimates against infection over time. We’ve seen some decreases in the estimates for the last one to two months. There are a variety of reasons where we could be noting this decline. One aspect could be waning of immunity due to time since primary series. However, there is another factor to consider as well. As we’ve described previously, since earlier this year, we’ve noticed increases of the Delta variant in late May. Delta was around seven percent of sequenced isolates. And by mid-July, this was up to ninety four percent of sequenced isolates. The impact of the Delta variant leaves this to this next aspect. What is we with the Delta variant? This slide shows results of studies that compare pre delta versus Delta estimates for the infection or symptomatic disease is on the left, and hospitalization or severe disease is on the right.

Speaker2: [00:44:14] In studies comparing pre. Delta and Delta time points, pre Delta V estimates are high. B against infection ranged from seventy two to ninety seven percent and against hospitalization for eighty four to ninety seven percent. Since the introduction of the Delta variant, the E against infection has ranged from thirty nine to eighty four percent and B against hospitalisation has remained high from seventy five to ninety five percent. This figure shows the best estimates by outcome for the alpha variant in blue compared to the Delta variant in orange. The outcomes range along the top, the E for any infection on the left, symptomatic infection in the middle and hospitalization or severe disease on the right. You can see that among global studies assessing infections with alpha versus delta. There was a mild decrease in Delta V. This may be due to a variety of factors that can impact these results and variation by country, including differences in study methods, different intervals between doses and timing with vaccination and the variant increases. This is a summary of the estimates since the introduction of the Delta variant. The colors correspond to the vaccine’s assessed in the study. This highlights that regardless of the vaccines evaluated, all vaccines have remained effective in preventing hospitalization and severe disease, but may be less effective in preventing infection or mild illness recently.

Speaker2: [00:46:09] The reasons for this lower effectiveness likely include both waning over time and the Delta variant. The next to address be for older adults. This slide shows unpublished COVID data with V against COVID 19 associated hospitalization among fully vaccinated patients 18 years of age and over by age group and month. Covid net conduct, hospitalisation surveillance with 14 states representing around 10 percent of the U.S. population. Patients must be a resident of the surveillance area and have a positive SARS-CoV-2 test within 14 days prior to or during the hospitalization. Chart reviews are conducted. Data presented at last month’s ACIP meeting showed a lower vs in those seventy five years and over. However, we’re constantly getting updates to the data with backfill for previous months with these updates. The COVID net data through July now show that the V against hospitalization in adults seventy five and over remains over eighty eight percent. Well, the be for this oldest age group has consistently been slightly lower than the over the older age group. The other age group, sorry, it has remained quite high and generally stable for the last several months. So then this slide shows data from the vision platform evaluating VE against hospitalisation as well as urgent care or ED visits the gets. Both outcomes was consistent at least eighty two percent or higher through at least 16 weeks after the second dose.

Speaker2: [00:48:04] Note this data is through June of twenty twenty one and may not represent the full picture with V with the Delta variant. This study highlights the four symptomatic infection with the Pfizer vaccine for several of the recent variants of concern. Adults 60 years of age and over are in the light blue V against symptomatic infection. In adults 60 and over is high, but some decreases are noted against variants of concern. However, it’s important to note that these differences were not significantly different. There were small numbers and very wide confidence intervals for several of these variants. These figures show V by age and time, since vaccination infection is on the left and severe disease is on the right. Um. Adults 60 and over are in light blue effectiveness against infection was over 60 percent in the first five to nine weeks after vaccination, with a gradual decline. Protection against severe disease has remained stable, with a decline noted in those 60 and over after twenty five weeks. However, also notes the very wide confidence confidence intervals for these later estimates. The slide highlights VE against hospitalization by time since vaccination in adult, sixty five years of age and over the years has decreased slightly over time, but remained high. And again, differences by time interval since vaccination were not significantly different. So next, we can consider long term care facility residents.

Speaker2: [00:50:05] There was some question initially for how these older, potentially medically frail adults may respond to the vaccine at all. However, this shows that initially v against infection with seventy four percent or higher by vaccine. However, as we look over time moving into the recent months where Delta was the primary variant, the E against infection has fallen to just over 50 percent. So then this is the same summary slide as before, but the other agent or grayed out, and we’ve added the estimates for adults 60 years of age and over to put these estimates for older adults into the overall context, lower body against infection was seen for older adults, particularly the long term care facility. Residents follow up is needed to monitor these V results over time. So in summary, COVID vaccines continue to maintain high protection against severe disease hospitalization and death protection against infection, which includes asymptomatic or mild infection, are lower in recent months. However, it’s difficult to distinguish the effects of increased time since primary series versus the impact of the Delta variant. And it’s important to monitor trends of effectiveness by severity of disease over time. Want to think the team of people that have helped pull this together, our ACIP team and the entire vaccine effectiveness team at CDC? I’ll highlight that the next two slides contain references that were listed and I’m happy to take questions. Thanks.

Speaker1: [00:52:00] Thank you so much, Dr Oliver, and thank you for keeping us to time. We do have time for a few questions before we move on to the next presentation, Dr. Gans.

Speaker2: [00:52:22] Thank you, Dr. Oliver. That was very helpful. I’m wondering if you could elaborate a little bit more because they seem to be lumped by Pfizer, Moderna and the breakthrough disease. Can you elaborate more in just the sense we’re thinking about Pfizer at the moment? Application, you give us more information about breakthrough disease and how it relates just to the Pfizer. Vaccine were the large majority of those Pfizer versus Moderna? So some of that has to be some of that has to do with the steady platform, several of them don’t have the power to split apart individual vaccines and still get stable estimates. So many of them had to kind of mRNA vaccines together. There were some and a few of the slides did look at kind of if you compared, if we had estimates for Pfizer and Moderna that are that are in there. But many of the the platforms had to kind of lump the RNA vaccines prior receipt together. I will say the vision platform is one of the larger ones and it it has been able to obtain product specific estimates. And so I can share those, those platforms, the estimates with you. I think compared to the Pfizer estimates were slightly lower than the Moderna estimates, but we’d have to kind of monitor that over time and look at it across various platforms.

Speaker1: [00:54:00] Dr Chatterjee.

Speaker2: [00:54:07] Thank you, definitely. Thank you for your presentation. My question is whether regard to mitigation measures in addition to vaccination. Obviously, these have an impact on risk of exposure. And I was curious whether any of these studies addressed that addressed those measures and the impact that they might have. Yeah, it’s difficult if you kind of overlay a lot on the time we know that sometimes Delta was taking over. There were also changes in how we were doing some of our social distancing and non-pharmaceutical interventions. I know several of the studies have have attempted to look at this. Unfortunately, it’s really difficult to look at to get kind of behavioural interventions and data on masks and behaviours in this. So we’ll continue to attempt to measure, but I know it’s been difficult for each of the platforms.

Speaker1: [00:55:11] Thank you. Dr. Corella. One more question after Dr Kurla before moving on. Thank you, Arnold. Sarah, it’s it’s convenient to divvy up the population into vaccinated and unvaccinated. But but there actually is a subgroup that is unvaccinated but private inspection and that has been increasing over time and failure to account for that would seem to actually underestimate vaccine efficacy going forward. So I’m wondering, have you have you attempted to take that into account in terms of actual calculation of vaccine efficacy?

Speaker2: [00:56:00] I know that, you know, the the platform, many of our broader, more robust platforms do a test negative design, but they’re not able to do serology screening on on everybody who would be admitted. So I don’t know that included into the specific they’re not like screening for serology prior to, including unvaccinated individuals. But I know that several of the platforms vision, I’ve attempt to account for this with their statistical, their statistical analysis.

Speaker1: [00:56:41] Ok, but but you haven’t done any attempts at sort of bounding what that given overall seroprevalence estimates are, you haven’t done any bounding of what that may be. How that may be impacting calculations of overall vaccine efficacy.

Speaker2: [00:56:59] I’ll tell you, I can get back, I can check with the specific site APIs and give back to you. Potentially this afternoon around exactly how how their analyses have have adjusted for that.

Speaker1: [00:57:12] Right. Dr. Meissner, final question. The Cody. Ok. My question is. The the charts and tables you showed us, some were for adults over 75. Some of the data were for adults over sixty five and some more for adults over 60. You how do you pull that? I mean, they’re fairly discrete groups in terms of the interval of time since they received a vaccine, for example. Do you look? How do you break down those the risk in those different age groups?

Speaker2: [00:58:11] Yeah, so, you know, essentially what we’ve reported is what has been published and was out there, so several of the studies we had to take, especially the ones not conducted at CDC, we had to take the the interval and age as as they reported them. There is absolutely kind of a different by age group. And so in some of the platforms where we have more people and could get stable estimates, so COVID, that is a larger system. So we tried to break out that sixty five to seventy four and seventy five over many of the platforms, though, that have, you know, smaller numbers just aren’t able to get that granular. So that’s why some of the platforms reported sixty five and over with an acknowledgement that there likely is, you know, an age kind of gradient and that a 64 60. I mean, a sixty five year old may not be exactly the same as an eighty five year old, but we can’t necessarily report Stable V estimates for each individual age group.

Speaker1: [00:59:21] Thank you. Ok. Thank you, Dr. Oliver. And as I’m going to mention to all of our speakers, we may well have more general questions later on, and I hope you can stay around with us during the entire day. Next, we go outside the US. Our next speaker is Dr. Jonathan Stern, Professor Professor Stern, who is at Bristol Medical School in the UK. Thanks very much, and I’m honored to be asked to present this important meeting, and the title of my talk is real world effectiveness of COVID 19 vaccines. And these are my declarations, I don’t have any financial interests with any of the firms or entities that are related to the meeting topic. And I’d like to acknowledge the authors listed here who have diligently assembled data on estimated effects of COVID 19 vaccines that I will present in the early part of my talk. You know, and the time are talking real world. I’m sorry. And the title of my talk is real world effectiveness of vaccines, and I want to emphasize that randomized trials provide the best estimates of effectiveness of any health care intervention in the real world. The issue that makes life difficult in the context of the sort of question that’s being addressed by the community today is that a host of urgent questions about COVID 19 vaccines have not been addressed in randomized trials, for example, for completely clear reasons, the randomized trials were almost exclusively conducted before the era of the Delta variant. The ongoing emergency The amazing success of the vaccines means that we have to make far reaching policy decisions, such as the one being considered today using observational data.

Speaker1: [01:01:34] And put a better title for my talk might be estimated effectiveness of vaccines in observational studies. And given that I’m going to spend my time talking about the potential biases in these studies and even better title might the estimated effectiveness of vaccines that is biased by an unknown amount and how to think about such biases. And now colleagues at the WHO and Cochrane are running an amazing systematic screening and data extraction process and published studies on vaccine effectiveness, and they are screening hundreds of studies per week classifying them. The published observational study is classified according to their peer reviewed or are available as a preprint and according to whether they’re prospective or retrospective or cross-sectional, and according to the underpinning study design. And there have been 178 such studies on vaccine effectiveness against variants of concern, as you can see here with a number of different study designs, but primarily cohorts and test negative case control designs and studies on plenty of studies on the Delta variant. 76 of them. And among those 76 studies on the Delta variant that has immunogenicity and of vaccine effectiveness, the number of studies are increasing weekly. There are 51 cohorts, nine tests, negative case controls. And if we look at the outcomes the outcome considered, our laboratory confirmed COVID 57 studies symptomatic confirmed COVID 34, severe or hospitalized, currently 37, and death from COVID 16.

Speaker1: [01:03:25] So and Dr. Oliver’s talk last time beautifully summarized the the data that’s out there, particularly as it relates to the question being considered by the committee today. And so those data were summarized in a paper in The Lancet published by these orphans, I was a minor contributor. It to it appeared on Monday and and that paper summarized efficacy overall, according to variant showing, as we’ve seen that efficacy against, well, firstly, the efficacy against severe disease is uniformly higher than efficacy against any infection. And secondly, the efficacy against Delta seems high and similar to efficacy against Alpha. And in a small number of studies, the efficacy for early vs. late to follow up appears similar for efficacy or effectiveness against severe disease, although somewhat lower for effectiveness against any infection. And this slide diligently put together by Dr. Anna Maria and our Restrepo and professor Sir Richard Peto just yesterday summarizes the current evidences as recorded in in the in this dataset of trier of studies and study results, the efficacy of messenger RNA vaccines against severe disease in settings where the Delta variant is circulating up to this week and as described in the previous talk, in most contexts. If you look at the middle column here, the right two columns show us the confidence interval efficacy remains high and full. For example, this study in Minnesota, where estimating the estimated efficacy was a little lower for both the Pfizer and Moderna vaccines, the confidence interval was rather wide in that study.

Speaker1: [01:05:26] I won’t spend time talking about this slide. The evidence was beautifully summarized in the previous talk. So I’m going to spend most of my time talking about methodological issues in estimating vaccine efficacy during the rollout, and I’m going to give some examples from analyses that let a large team of us have been doing in the UK based on the open safely analytics platform. And we’ve been fortunate or to establish in the UK near population coverage of detailed link to electronic health record data and Open Safely provides a trusted research environment within which those data can be securely accessed and analysed with appropriate disclosure controls. I want to emphasize that my example examples are different from from analyses of these data, but they’re not there to tell you about the results. They’re there to try to illustrate general issues in trying to estimate vaccine effectiveness from observational studies. So and here are the issues that I’m going to cover and the first and and obviously important one is the problem of confounding. I call it baseline confounding for reasons that I hope will become clear that the presence of characteristics of individuals that predict both vaccination and the outcome that we’re interested in. So confounding occurs when there’s a common cause of both vaccination and the outcome event, which might be symptomatic infection or hospitalization with COVID. And in that circumstance, the association that we estimate in our observational study may not equal the causal effect, the effectiveness of the vaccine.

Speaker1: [01:07:13] The reason that we randomized fundamentally is that randomization should remove confounding in a high quality randomized trial by ensuring by removing the link between prognostic factors factors that influence the outcome and vaccination because only the play of chance determines whether someone’s vaccinated. Now, here’s a graph of the rollout of vaccination in England from open safely in the over 80s in the in the upper panel that started on the 8th of December 2020 and rather later in the 70s. And 79 year old, which started in January and here vaccination with Oxford-AstraZeneca is in green. Vaccination with Pfizer-BioNTech is in purple and you can see what’s characteristic of those of countries that that achieve rapid rollout with high take up is that we see rapid rapid rapidly. We get to a point where where very high proportions of the population have been vaccinated, the light purple here is the receipt of second dose of Pfizer BioNTech, and that happened for only some people vaccinated with Pfizer and almost nobody vaccinated with AstraZeneca because the UK changed its vaccination schedule to 12 from three weeks in early in January 2020. So when we look at this, we can ask, well, what predicts the speed of Typekit speed of being vaccinated? What factors predict being vaccinated faster rather than slower? And that’s what’s shown on the next slide here, which shows estimated hazard ratios for people aged 80 years and over in the left, two columns of figures and people aged 70 to 79 years in the writing columns of figures separately.

Speaker1: [01:09:06] For Pfizer, the Bounty one seeks to be two or Oxford-AstraZeneca ChAdOx1, and I’m just highlighting two results. This is just to show you that patient characteristics that predict occurrence of COVID outcomes also predict whether you get vaccinated, even in a situation of rapid rollouts and publicly funded health care, such as in the UK. So even within these age groups, age influenced whether you got vaccinated and not necessarily in the same direction or consistently for the two vaccines because it depended on logistical issues. And even in the context of this publicly funded health care system, more or less deprived people in Group five were vaccinated faster than more of the more deprived people in Group one. And that was true for both vaccines and both age groups. And. It well documented that vaccine hesitancy is related to ethnicity in the UK and in other countries. And sure enough, white people got vaccinated faster than people of other ethnicities. Are people with learning disabilities got vaccinated slower? And and previous vaccination, which may be related to underlying underlying health care behaviors or vaccine hesitancy. So people who had received flu vaccine in the previous five years may also be related to co-morbidities who are more likely to be vaccinated with a COVID 19 vaccine. So there is every reason to say that estimates of vaccine efficacy will be subject to bias due to confounding. One way to address that is to adopt a test and negative design in which we don’t look at the whole population, we compare individuals with symptoms who test positive.

Speaker1: [01:11:00] The cases with individuals with symptoms who test negative for the control. Now that may reduce confounding, but as has been well documented, and here’s a pair of papers in the American Journal of Epidemiology published in 2016 discussing the test negative design in the context of flu vaccination. And there is. There is no reason to think that just by doing a test, the negative design you will remove confounding, and there are various consequences of testing negative designs that are discussed in detail in those paper. So I think that in the context of COVID 19 vaccination, careful evaluation of the potential for bias in estimates of vaccine effectiveness from test negative design seems warranted and indeed urgent. Now back to my graph of the cumulative incidence over time, because it tells us the next problem we have when we try to estimate vaccine vaccine effectiveness, which is that if I take somebody who’s unvaccinated on a particular date, for example, the 15th of January 2020, then that person, although they’re unvaccinated and they may serve as a competitor at that moment in time, is also likely rapidly to become vaccinated. And that gives us a problem in choosing a comparison group for our estimates of vaccine effectiveness. Because of the very rapidly rapid rollout of vaccination on the vaccinated, people rapidly become vaccinated. And there’s a solution to that which seems pretty obvious, which is to split the follow up time for each individual in our population into time, unvaccinated and time post-vaccination among the large majority of people who ultimately are vaccinated.

Speaker1: [01:12:40] The difficulty is that that gives us a new problem that hasn’t been extensively dealt with in studies of vaccine effectiveness, which is the problem of time varying confounding. So I’ve discussed already patient characteristics at the start of follow up, maybe confounders, because they predict both vaccination and COVID 19 outcomes. But as we move through follow up and people get vaccinated, there may also be vaccines by compounding after baseline, by time varying factors. And we call those time varying confounders. And here are some with under a difficulty here is that special methods such as, although not exclusively marginal structural models, are likely to be needed when there are time varying confounders. So here is here a further analysis from the same dataset that I showed you earlier, looking at time varying characteristics, predicting vaccination in those two age groups in England. And you can see that people who had recently tested positive for SARS-CoV-2 were hugely at least 90 percent less likely to be vaccinated. And in fact, there were almost nobody was vaccinated within a week of testing positive for SARS-CoV-2. So that and clearly that’s a confounder for being hospitalized with with COVID, so there’s every reason to think that time varying confounding is also a problem here. Why is it such a difficult problem analytically? Well, because it’s a confounder, because being positive, having a positive test predicts whether you get vaccinated and also predicts whether you’re hospitalized with COVID.

Speaker1: [01:14:36] But it’s also on the causal pathway from being vaccinated to being hospitalized, and that means that using standard modelling strategies may not work. So we tried to do analysis using marginal structural models to overcome this problem. And these are the results, and I’ll quickly take you through them. So the colors here relate to the degree of adjustment in green. We have basically just region adjusted, but no further adjustment. In orange, we have adjustment for baseline confounders. And in blue, we have additional adjustment for the time varying confounders. On the left hand graph, is any vaccine in the right hand graph is Pfizer only and the opposite of Graph sees the outcome positive test. The middle set of graphs is COVID 19 hospitalization and the bottom set of glasses all cause mortality. So firstly, you can see that adjusting to the time varying confounders makes a big difference and attenuate the apparent effects of the vaccines on all cause mortality. And it has some effects, although less dramatic for the other two outcomes. And and you can see, and this has been seen in a number of studies, that there is completely implausible protection immediately after vaccination. Even when we adjust for the time varying confounders, and I think that’s just unmeasured confounding, and I’ll say a bit more about that in the moment. So.

Speaker1: [01:16:13] The difficulty we have is that even with these details, our electronic health records and using probably the best method available and controlling for why for an extensive set of confounders, we get implausible levels of protection. Why implausible? Well, firstly, they weren’t seen in the trials. And secondly, most I think it would be broadly agreed that we expect we don’t expect huge protection against all cause mortality or hospitalization within a week of vaccination and with the first dose only. And what we’d like to do is we’d like to hope that that bias, which I think it plausibly plausible bias that we see very soon after vaccination goes away and that what we see later are good estimates of vaccine effectiveness. The worry we have is that, well, if it’s biased early, we don’t know when that bias goes away. But I think we should be particularly concerned about short follow up after vaccination for the reasons I’ve explained. We get similar results for the 70 to 79 year old. So I think there may be a problem with unmeasured confounding, particularly soon after vaccination. One plausible explanation is that if you show up for vaccination in the UK, there’s a big sign saying Please go away if you have symptoms of COVID, so people are likely to delay their vaccination if they have symptoms, and that’s not recorded anywhere in the health care record unless they subsequently test positive or show up for health care. And of course, that makes symptoms a time varying confounder, but is not measured.

Speaker1: [01:17:51] No big bonuses, because recent symptoms predict postponement of vaccination may wane with time. But it seems particularly hard to estimate short term effects of vaccination. Another couple of important issues, firstly, it’s vital to account for the fact the incidence of the outcome varies so dramatically over time is the incidence of hospitalisation in the last six months in the United States readily available on the web. And you can see that you don’t want to be comparing somebody on the 31st of August with somebody on the phone with somebody else on the 1st of July because things change so rapidly. So we have to deal with time since vaccination has one aspect of our analysis, but it’s vital that we also deal with calendar time in our analysis and people do that in a variety of different ways and the way that diversity makes the studies hard to appraise. But it will usually be important to carefully allow for both calendar time and time for vaccination in analysis. And finally, a word about persistently unvaccinated individuals, this is the other end because we’re most interested in people who’ve been vaccinated for some time and whether vaccination effectiveness is waning and in many highly vaccinated populations, perhaps less so in the U.S. That means we’re dealing with a highly selected set of individuals whose characteristics we need to understand. And a particular concern raised in a questionnaire before my talk is what proportion of those remained unvaccinated because of recent infection that conferred protection.

Speaker1: [01:19:39] So it’s hard to estimate vaccine effectiveness, and we need careful and critical evaluation. Here’s my final slide, and I will skip it because I’m out of time. We need to think carefully about confounding. We need to think about how our analyses need to allow for the stages of the rollout. We need to control for a wide range of potential confounders in studies of long term vaccination. We need to ask about what proportion of the unvaccinated were protected because of previous infection. We need we need critical appraisal of test negative designs, we should be very cautious of apparent short term benefits of vaccination because of the potential for confounding, for instance, delay to vaccination. But we need to deal with rapidly changing incidence of outcome events. And finally, ideally, there should be an analysis plan published before outcome data were available to reassure us that data won’t cherry predict. Thank you for your attention. Thank you so much, Professor Stern. As somebody who does test negative designs and knows the strengths and weaknesses of that design, I think you’ve covered it brilliantly. My first question because we’re going to be confronted with an issue of U.S. data versus outside the U.S. data. How did you handle the fact that with the mRNA vaccine, the Pfizer BioNTech vaccine in the UK, many people did not get the second dose in exactly three weeks, which was the protocol in the U.S., but the dose was delayed and therefore the immune response might be different.

Speaker1: [01:21:34] So the short answer is we didn’t, because the analyses I showed you just looked at first dose and didn’t account in any way. There are some incredibly interesting data coming soon. I believe in press from the Owners Community Infection Survey that we’ll speak to exactly that issue and that may indeed suggest the UK made a good call in extending the time between first and second doses. Right. That’s what I’m exactly, what I’m referring to, Dr. Carola. Thank you. You. I don’t know why my camera’s not working. You highlighted the still here issue. Ok, good. Thank you. You highlighted the issue of seeing an effect in in the in the immediate post vaccination period that would not be expected due to the due to the effect of the vaccine. But I’m wondering if if there is, do you think there could be a potential for a antigen independent vaccination enhancement in some degree of immunity and in shorter term, that period of time that wane very quickly that that may actually be overestimating short term estimates of vaccine efficacy that would then change over time. No, it’s possible, I mean, the difficulty for the committee is that you’re making incredibly important public policy decisions very rapidly in a situation of uncertainty, and there are very good reasons those decisions have to be made. And I do think that we can look to the trials for good and confounded suggestions of the likely short term. Dr. Gantz.

Speaker2: [01:23:42] Thank you for elaborating. Excuse me, elaborating, some of the things that we’ve all been very concerned about in a very well, very organized way. I’m wondering when you apply all of the founders and all of the considerations that you’ve made. What are the studies that filter out at the end that you would highlight for the committee? That would actually suggest that we have good, unbiased or at the best that we have in terms of how we should be. Vaccine.

Speaker1: [01:24:24] Now I’m going to. I’m not going to identify individual services, but I would identify. I tried to, on my last slide, identify characteristics, and they would include careful control of the confounders that we know are really important, such as age, age of vaccination, availability of vaccination. You know, as precisely as possible. And then, if possible, also other characteristics from detailed health care records and extremely close matching on on on current for calendar time. So that, broadly speaking, somebody who experiences an event should only be compared with somebody who is being followed up on the same day. And it’s perfectly possible to do that using setting up your survival analysis in the right way. And I’m not sure that all studies have done it, but I mean, I sympathize with you because it seems I find it incredibly hard to look at the very diverse set of descriptions of what’s been done in the individual studies and to know, well, did they do the things that I’ve just talked about? Thank you so much, Professor Stern. And again, we appreciate your keeping to time because we have a very busy day. Now we move to looking at booster protection against confirmed infection and severe disease data from Israel. We’re going to hear two speakers who will speak one after the other and then we will have the question period first and I’ll introduce both right now. Sharon Price, who is the director of public health services at the Ministry of Health and Jerusalem Israel, and then Professor Ron Mylo, who is at the Weitzman Institute in Israel. Dr. Elroy Price, please.

Speaker2: [01:26:35] Their chairman and honorable committee members, we were asked the Israeli Ministry of Health, we were asked by the FDA to present our data on waning and booster effect, and we are delighted to do so. We it’s important for us to start by emphasizing that we do not pretend to tell other authorities what to do in their setting. We are here to present the data from Israel and the decisions that we came up with in our setting, and we hope that this will help other countries or enable them other authorities to reach their decisions with the most advanced latest evidence that we have in Israel. Based on the multiple logos that you see on the screen, I would like to highlight that the work presented here was done by several leading academic institution in Israel in collaboration, knowing that the

Speaker1: [01:27:31] Evaluation of the booster

Speaker2: [01:27:33] Dose would be critical to Israel

Speaker1: [01:27:35] And the rest of the world.

Speaker2: [01:27:36] The analysis was done with extreme caution by different analysts from different institutions, by different analysis methods, as Ron will describe, and I would like to thank all these institutions coming together to do this work very diligently for several months. So we are both presenting Ron and myself, and we have no competing financial interest to disclose. I would like to say that Israel Ministry of Health and Pfizer have data sharing agreement on public health surveillance data. However, since the data that we are showing here was actually done by these academic institutions, only the final results

Speaker1: [01:28:19] Were shared with Pfizer.

Speaker2: [01:28:23] They would like to take you back in time to December 2020 in Israel. We started to see a third surge in cases our third wave, and this was actually after having two waves and two lockdowns. And when we were at the exit from the second wave, we had really pandemic fatigue in the country. And so we saw once we started opening the economy, we didn’t even were able to open everything up as we were starting to open places. We saw an increase in cases, both confirmed

Speaker1: [01:28:59] Cases, but also severe and critically ill.

Speaker2: [01:29:02] And there was a significant burden on the hospitals at that point in time. And we started, we decided on a lockdown. But as I said, that decision was not as the compliance of the public was not as it was in the previous two weeks. Um, thankfully, we had the ability to start a vaccination campaign in December, so Israel started vaccinating as soon as there was FDA approval for the Pfizer BioNTech vaccine. And there was a quick compliance and uptake of the vaccine. We open it in state in steps based on ages, and we reached a very high level of vaccine. And with that, the vaccine uptake, we started to see a decrease in cases over 100 fold decrease in cases following the vaccination campaign. And as I said, there was a partially effective lockdown at the time and the the main. The main thing was

Speaker1: [01:30:10] That when we opened the lockdown, we were able to open everything up, lift all restrictions

Speaker2: [01:30:16] Step by step and the cases did not go up again. And we saw in also the fact that we had reached high level of population wide immunity early on,

Speaker1: [01:30:32] Which was wonderful.

Speaker2: [01:30:33] But we also see that we were basically three

Speaker1: [01:30:37] Months ahead from other countries

Speaker2: [01:30:40] When we’re talking about now waning. So the very efficient vaccination campaign made Israel the leading country. But when we compare it to other countries, there is a time gap.

Speaker1: [01:30:53] So Israel reached about 40 percent of the population, covered

Speaker2: [01:30:57] Roughly three months ahead

Speaker1: [01:30:59] Of other countries that have five

Speaker2: [01:31:01] Million citizens or more. And that is important when we move ahead to explain why our data may be different than other things. Before we move ahead, it’s worth noting several things about Israel. First, all the residents are covered by four and those with comprehensive electronic medical record. The second point is that we have a large PCR testing capability in Israel, so we are basing all our data on PCR and not really rapid antigen testing. And two things that are allowing us to really monitor the effect of policy changes is that every COVID 19 test results, positive or negative is reported online to the Ministry of Health. So we know every day how many people are tested positive and negative, and all vaccines given in

Speaker1: [01:31:53] Israel are reported online to the Ministry of Health.

Speaker2: [01:31:56] So our capability of doing really online vaccine effectiveness is as comprehensive. So our third wave was mainly Alpha variant, as you see, and we started seeing or we started sequencing Delta variant sometime at the end of March, but it was really rare it was among people traveling abroad and it was one at a time. But there was steep increase in delta isolation, reaching over 98 percent of the cases in June. And at the same time, we started to see our fourth wave. We are now still in our fourth wave experience, the highest level of infection that we have seen so far in this pandemic. And this is despite widespread over 60 percent of vaccinated individuals and in the vulnerable population, over 85 percent there are vaccinated. And once we saw that, we were

Speaker1: [01:32:57] Trying to figure out what

Speaker2: [01:32:59] That tells us. We saw daily cases rose by more than tenfold in a month and a half. So from roughly 12 cases a day to about a thousand in a month and a half. And we what was more worrisome is that we saw severe active cases increased by more than tenfold in a month. And one of them was 60 percent vaccinated individuals, fully vaccinated individuals. So at that point, we had to stop and ask the question exactly, as the CDC officer said. Is that a Delta issue or is that waning immunity issue? We had some clue that it might not be the Delta variant, at least not alone with its effect, because we started vaccinating 12 to 15 years old with FDA approval and they actually had a fresh vaccine. And amongst them, we saw vaccine effectiveness of around 90 percent. So the majority of them were were protective. But still, you can’t really say because of the age difference and everything. So the other question we needed to figure

Speaker1: [01:34:08] Out

Speaker2: [01:34:08] Was what about the waning? And does that play a role? And as Ron described now the analysis we did, we think this is

Speaker1: [01:34:16] A major part of our picture in Israel, at least. Sorry. Okay, so good morning, everyone. They’ll be showing you the results of the observational analysis that we did in Israel, which is after a relatively short time since the vaccination campaign. In spite of the potential biases, as we described in the two papers that of our regarded the analysis, as well as the relatively short follow up time, we thought it was our responsibility to analyze the data is only as the crude and share it with the world through peer review. And this is what they’ll be presenting to the. So this is a bit of a heavy flight or complicated slide, it would be great if I also get a crater at the bottom. But I would say, let’s try and follow in the following way. Let’s start from the x axis. You can see three cohorts and will be focusing initially on the cohort on the right aged 60 and above. Or the y axis, you see the confirmed infection rate per 1000. We will be talking about traces of SARS-CoV-2 confirmed infection. This is both symptomatic and asymptomatic based on PCR results. Hmm. And I’ll be talking here about people with more concern in the month of July. So as Sharon was saying, this is vastly dominated by the Delta variant. And the different shades that you see here refers to what happens for people that are not vaccinated at different times, starting from the dark colors would be January, meaning the ones that vaccinated early in the campaign.

Speaker1: [01:36:15] Ok, great. I got a cursor. So you can see here this is in the beginning, and then you can see we’re proceeding here based on the mindful vaccination from six months prior to the study period, up to two or three months from the study period. And I think you can see that there is a change in the rate of confirmed infections per 1000 people. And this is both at the age of 60 and above, which is what you see here on the stock exchange. And you can also view what happened to the other age groups, the other age groups. I do want to mention you see the wasn’t vaccinated earlier tend to be health care workers or people, mostly severely immunodeficient people, and therefore this should be interpreted with caution. But you can see a signal of waning both at the other end of both other cohorts, which we interpret as the waning effect. You can also see here what happens in terms of waning immunity in relation to severe disease in the aged 60 and above. The y axis is again regarding race for 1000 individuals in the study period in the month of July. All of those or ninety nine or whatever percent of the Delta variant, because this is what by far the most dominant, you can see that the confidence intervals, these are 95 percent confidence intervals.

Speaker1: [01:37:54] We can see that they are larger now. This is because the number of cases is smaller. I would mention that we have here over a million people that are being analyzed. So I would say it’s not easy to get very small confidence intervals for these studies, even though the study group is very, very large. As you can see, the change in rate screen time. All of this, by the way, is publicly available. We made it available on the archive and it’s in the final stages of being published. Q also present what happens in the younger age groups, this is mostly preliminary data that you can see the ages 50 to 59, 40 to 49 in the younger age groups. The numbers are much smaller because the rate of severe disease is smaller, and therefore the statistical confidence is also not as strong. And one could see the general potential trend, but it is hard to conclusively interpret it, given the relatively small numbers. We do think what could be indications of the trend, but it depends heavily on how you want to also interpret what happened with the with the medical health care workers that were vaccinated in the month of January. There is an important point here that I want to mention. This was an issue in Israel in trying to think about this. We saw in the CDC presentation and the following presentation we were mentioning the issue of high degree of protection that you get from the vaccine for severe cases.

Speaker1: [01:39:40] And I want to just take a minute to show something that I found. It’s confusing and some of the discussion for us. There’s no doubt that the vaccine with good protection, meaning much better than not having the vaccine, and this has been shown in many different ways, and we observe it as at the same time you can have high protection of the 97 percent, so you can have high protection of 85 percent and 97 percent is what has been published. What is observed for against severe disease, 85 percent was mentioned in some of the previous slides and also concurs with what we seem to be seeing right now of the delta for those who are vaccinated relatively early, meaning half a year ago. And while 85 percent might still seem very high and this is only a small percentage point difference. I just want to point out that this translates the 97 percent vaccine efficacy is three percent relative risk, whereas 85 percent vaccine efficacy in 16 percent relative risk, meaning a five fold increase in relative risk. Which is a very large increase. A full change in the number of severe cases vaccinated, doubly vaccinated. So this has to be taken care of in the Israeli hospital system. This is in line with the values that Sharon was mentioning of what we saw, the sharp increase over half of these in vaccinated people.

Speaker1: [01:41:07] So based on the evidence of winning in Israel and their trajectory, excluding vessels hospitalization capacity, given the rapid rise in severe cases, Israel decided to begin a third vaccination campaign on July 30th, starting with the elderly. And I want to show you what we found regarding the the effect of those of the. So here is just the outline of the Temple campaign. So as I said, we started the end of July, beginning of August, and there’s been about one million doses given the ages 60 and above. And you can feel some of the other cohorts starting with the 50 plus two weeks later and then 40 plus, et cetera, all altogether, we close to three million booster doses, which were given to date. You can see it here is a fraction of the eligible population in each for the eligible are the ones that got two vaccines. They were eligible to take the third vaccine, assuming it was over five months in our case. And you can see that a significant fraction of the population, some people, you can see that it started mostly with the elderly and that made us do the analysis for that age cohort, which is where we have the most follow up type. You can also see here the fraction of those of those eligible that were vaccinated with a third dose to date. Overall, we’re talking in the age of 60 plus were included in the study.

Speaker1: [01:42:40] We’re talking about a million people altogether. They are in which you were about 13000 confirmed infection in the study period in August. We are still in the midst of a wave and therefore a lot of cases. Ok, just before I get to the results, I can show you what we might be expecting or the form of the results I’ll be showing you or the exact results show you the date for vaccination and on the y axis, I’ll show you the fold reduction in risk of the two doses. So throughout the study, for many reasons, for example, that were mentioned in the previous presentation, we are sure to compare between those that already to two doses and those who decided to also take the third and compare between the two groups and not the unvaccinated, which might contain potential confounders. In the beginning, also, as was mentioned before, this could be all sorts of possible channels and biases in the days just following the fate of those people usually and we have we see the signal. There’s a tendency to go and do less PCR tests for COVID 19. But then we see that decreasing. And then we’re looking at a time period of about 12 days onward, which is the timescale in which we’re expecting to see the effect because of two reasons. One is because we know that there is time until the neutralizing antibody response increases, that’s usually on the order a few days or a week.

Speaker1: [01:44:15] And then there’s also a time between whenever you are infected or get protection from infection and the time this is observed through a in PCR test of the average in Israel about five days, probably related to the incubation period for developing symptoms or just in general. Also, when you look at contact tracing, etc. that’s roughly seven days to five days or 12 days is roughly what you’re expecting to see the effect being observed. So here are the results. Again, this is on the x axis, you can see the tail section and on the y axis you can see, I think, yeah, sorry. And the y axis you see the fold reduction in the rate again compared to the two doses. All of this has also been publicly available, and now we gave the slide the requested three days ago, but by now also published in the Journal of Medicine, all the results are showing you are based on profound regression in order to take into account as many of the confounders as we could. It’s adjusted for age, for gender, for demographic group. For the time is your second dose was given and the calendar that just as was mentioned before, that these two temporal effects should be taken into account. And will be comparing what are we talking about protection in the main analysis we’re comparing between what happened was based on what this is, what happened with no booster, meaning only two doses.

Speaker1: [01:45:58] Here is a summary of the results we gave an estimated production of about 11000. You can give it the confidence intervals here are relatively slow of between 10 and 12 as the result of the many which basically go into the analysis, and the second is over 1000 infections in this group over those 10 million days and about five times 5000 infections from 4000 infections in the two only no booster group. The great difference is about eighty six point six, one hundred thousand person days. These are the results for the aged 60 and above. We also have preliminary results for the ages 50 to 59, and you can see a consistent picture where after about 12 days, we’re seeing about the 10 force protection. In the lead for the ages 40 to 49, we say again something like tenfold decrease, tenfold protection against doing the same kind of perform regression adjusted for all of those efforts. We understand the importance of doing this analysis as thoroughly as possible, and therefore we try to use different approaches. So what I showed you so far is based on the profound regression approach. We also use the matching approach, which is common in many of the studies for doing this. And when we’re doing matching between those that got three doses to two doses, we got the very similar results in terms of the reduction in the risk.

Speaker1: [01:47:42] Also did another kind of analysis being worried that maybe they are effective we should account for just in terms of the behavior of those the only decided to take three doses versus two doses and therefore we took only those three doses. And as you can see here, we compared with those that were 12 days on, weren’t very active. Now the control group would be people they decided to take the table. But we looking at what happened to them four to six days following the booster dose. And we think that even under this analysis, we think that we’re getting about five fold reduction, meaning significant protection also in this more stringent or conservative type of analysis. Let me move on to show you what we get for the severe results. He see what happens for the ages 60 and above in terms of severe COVID 19 for the same period, and we see again a very significant decrease in the rate of the order of 10 fold or higher and an absolute rate difference of 7.5 severe cases per 100000 person days. Going back to the to the issue of Delta versus Alpha and waning, I want to point out that overall what we’re seeing if we had the in terms of confirmed infections, if fact when we think something on the order of 50 percent. Versus the delta, which is also observed in different studies from around the world with a tenfold increase, which is roughly what we’re seeing.

Speaker1: [01:49:27] You get back to about 95 percent. Kimberly, if you start from about 80 percent vaccine efficacy against severe disease with a tenfold increase, you get to about 97 percent or higher. And these are similar to the reports of what happens in terms of protection against. They’re against the Alpha variant with the fresh vaccine. So overall, it seems like with the booster dose we are getting again the the protection that we originally brought against the Alpha variant. And I want to point out that it’s very hard to decompose. What is the net effect that only comes from the waning or only comes from this distance between the Alpha and the delta? But I’ve shown you enables us to do some of that. But overall, I would say, even if you decompose exactly the effect, what we’re seeing here is that in totality, the combination of both gives you the results that I’ve just presented. I want to finish by just seeing what happened at the national level. This is what was the reproduction number R that we observed in Israel. And as you can see throughout the month of of June, and even before that, we were at about 1.3 to 1.4, which translates a doubling every 10 days, which relates to what Sharon was saying about the fact that we had over 100 fold increase in the prevalence. This is what happens following the in the following weeks and months, we try to reinstate the green passport, but that did not have had the marked effect on the production number.

Speaker1: [01:51:02] And then with the boosted campaign with a delay, this is roughly in line with what we expect. We started to see the continued decrease in the reproduction number. You can see that this took a while and therefore we had to make a decision also for the other age groups where we still had an increase in the numbers and the R was still above one. It shows you again, the second at the national level, what you’re seeing here is a function of time is what is what will happen to the number of new daily cases and there’s no confirmation following the administration of the booster dose. This was for the aged 60 and above, and we see that with a delay of about two weeks. We’re seeing a decrease, whereas for the other ages where the booster dose was still not administered, we think a continuous rise. This is in terms of confirmation. You can see the picture in terms of what happened in terms of severe disease. We’re talking about daily severe cases. You can see the booster dose being administered. And you’re seeing that with a delay, you start to see a sharp decrease for those vaccinated versus those who are vaccinated, in which the right continues and did not go down significantly. Ok. Sharon. Share your news.

[01:52:43] Oh. Thank you.

Speaker2: [01:52:53] You can see. You can see here the projection that we were looking at, the pink projection was based on no booster at all. And looking at the reproduction number, as Ron said, we were doubling every 10 days

Speaker1: [01:53:11] And we got two places of thousands of cases

Speaker2: [01:53:14] Doubling every 10 days. It’s scary and the fact that we had roughly 1.5 percent of those confirmed cases turning into

Speaker1: [01:53:24] Severe and

Speaker2: [01:53:24] Critically ill patients. So you see here the. That pink line, which is the model we were looking at that was based on the reproductive number, the cases, number of cases, confirmed cases that we had each day and then how many of them would turn into being severe cases and then accumulating them over time? And you see the purple one looking at a model taking into consideration and boost your dose with 80 percent compliance rate and the black line is actually the line of our data. So if we only looked at the model at the end of August, if we had not started booster doses at the end of July, we would have come to the capacity of the Israel hospitalization capabilities and probably have gone beyond it. So 2000 active severe cases that are hospitalized in the in in hospitals in Israel is way beyond what we experienced in the third wave. Just to give a context, we were at 12 hundred cases and it was stretching. We had increasing mortality rates.

Speaker1: [01:54:39] It was it was a stretch.

Speaker2: [01:54:40] So this we were anticipating at the end of August 2000 cases active severe cases a day in the hospitalized. So what happened is with the booster dose, we were able to dampen that effect and our severe cases now that are hospitalized are roughly seven hundred or less and that has stayed stable, even though we still have days of 10000 confirmed cases a day. Go to the other point. Except for effectiveness and the and what we think is important enough to see with the vaccine. The other really important point is the safety. So I’m going to show you a few slides of the rate of events that are reported to the Israeli Ministry of Health. I want to emphasize from the get go that we are sure to have underreporting probably the same at every dose. But even if we have less under more

Speaker1: [01:55:43] Underreporting of the third dose,

Speaker2: [01:55:45] We still would think that serious adverse

Speaker1: [01:55:48] Event would be reported to us.

Speaker2: [01:55:51] And I will touch on myocarditis in a moment, but this is generally the the adverse event reporting to us from the first dose. Right. The first dose, the second dose and now the third dose in what we can clearly see is that for systemic adverse events, we didn’t see any new types of adverse events and the rate to be modest is at least the same, if not slower. And if we look at local adverse events, we would still see sort of the same trend. We don’t see any new adverse event. We know that there’s more lymphadenopathy, but we’re not seeing any new adverse events and the risk is smaller again. I say that with a caution that it’s probably underreporting when our HMOs are doing direct, calling people or sending them questionnaires, they get more than that. But I want to emphasize on the serious adverse

Speaker1: [01:56:55] Event because this is what is really

Speaker2: [01:56:57] Important to us. And we had 19 serious reports following

Speaker1: [01:57:02] The third dose for more than two

Speaker2: [01:57:04] Point eight million booster dose administered, and each one of them is being investigated by an independent clinical workgroup using all the data from the hospitals, from the HMOs to try to figure out if this is connected to the third dose or not. So what we have been getting is seven reports on on serious adverse events following the third dose between the ages

Speaker1: [01:57:32] 12 to 64.

Speaker2: [01:57:33] You see how many vaccines? It was over two million and we had two allergic reactions that are noted as connected to the third dose. We had a case of myocarditis in a male in his 30s who was

Speaker1: [01:57:52] Hospitalized for two days and discharged.

Speaker2: [01:57:55] And we had a case of Guillain-Barré and Bell’s palsy that is possibly connected to the dose. And then three cases of DVT PE, Tia Siva and VTE in a runner that happened during a routine stress test. All three of them was not deemed connected to the vaccine

Speaker1: [01:58:14] By the workgroup.

Speaker2: [01:58:17] And among 65 and above, you see over eight thousand eight hundred thousand vaccines. We had 12 cases of serious adverse event. The first was suspected encephalitis. The guy who came in with fever and confusion. And for him, it was the second time it happened. It happened to him after the first dose did not happen after their second dose, but did happen again after the third. And that’s a possible connection, a vigorous hemorrhage that is possibly connected, a fever that is still under investigation. A bulk of of cases. Four or five cases that are infection origin. Septic shock thrombocytopenia due to sepsis. Three cases of BTI and pneumonia that was deemed unconnected to the vaccine. And then three cases of mortality that was not connected. People with very multiple co-morbidities that had reason for their demise. That was not connected to the to the vaccine. And so the myocarditis focus, I want to I want to emphasize first on this sentence, most young vaccinees received a booster only in the last two weeks, so we don’t have a full follow up for them for 30 days. As we as we want, we continue to follow them. Another important point is in Israel, because of the myocarditis that was a signal. We saw it in the second dose of the vaccine. We saw increase in cases among young, mainly male, between the ages of 16 to 30.

Speaker2: [02:00:02] So you see here increasing cases after the second dose, and that was usually after the four day or during the fourth or fifth day after the second dose. So to some extent, we believe that some cases should have popped up in the two weeks follow up that we have so far for several of the vaccines. But still, we need to be very cautious. We had only one cases of said up to 30 30 something year old male in the myocarditis cases. We’re actually doing active surveillance. So it’s not just reporting to us. We are contacting each hospital every week to get all myocarditis cases, not just following vaccination. And so we feel here much more safe that it’s not just underreporting effect. And our life slide is really the summary, so the booster dose in Israel was effective and so far had safety profile similar to the other doses, we saw that the booster dose improves the protection by tenfold against confirmed infection and at least for elderly against severe COVID 19. What we saw is basically the post booster effect. Efficacy against Delta was similar to the waning efficacy against Alpha like a fresh vaccine, and the adverse event was not were not more acute than the first or second. And we didn’t see any new severe

Speaker1: [02:01:28] Cases of adverse event

Speaker2: [02:01:30] Based on the data that we continuously collect. We are presenting this to our vaccine safety and Effectiveness Committee, and they have approved by steps giving the booster dose after five months to people starting from 60 and then 50 and then 40. And so we are rolling now

Speaker1: [02:01:52] In the

Speaker2: [02:01:54] Vaccination campaign and administration of the booster

Speaker1: [02:01:57] Dose help Israel in severe cases in the fourth wave. Thank you for your attention. And thank you both so much for these valuable data. I was about to ask a two fold question, which I usually don’t like to allow, but first about myocarditis, but you presented very carefully information, including the fact that younger individuals really have not been heavily vaccinated as yet. So the age is there, the age cutoff is hard to determine. One point of information the second dose in Israel with the Pfizer BioNTech vaccine was typically given and after three weeks or delayed, yes.

Speaker2: [02:02:52] Yes. So we gave we started the vaccine campaign after the FDA approval, exactly by the protocol approved by the FDA with

Speaker1: [02:03:00] Three weeks apart. Ok. Thank you, Dr. Pergamon. Thank you very much. That’s a really thoughtful set of slides, and we really appreciate you sharing. I had a question specifically, it seems like you have an opportunity to look at demographic differences between individuals who were eligible to get vaccinated with the booster, but didn’t the group that only received two doses for. Received the three. Do you find any demographic differences, you have a really robust medical record. I’d be really curious to know, are there differences that might suggest maybe that the group that received the booster were either higher risk or did differential levels of protection in that? Ok. Yes. So I would say we definitely we definitely looked into this and there are differences which we account for in both the perform regression and confounders and in the matching approach also confounding. We see them, for example, in terms of the tendency to take the variables which is different and what will different demographic groups in Israeli society among different age groups? And this is all reported in the in the paper that was published. You can see the table there really significant differences, but all of those are supposed to be accounted for inherently in the way we’re doing the analysis. Dr. Corella. Thank you, I. Cameras actually work during this time.

Speaker1: [02:04:54] Nope. Ok, there we go. Yes, it is now. Thank you for the presentation. Very, very insightful. One of the one of the things that stands out for me from your data is that the waning of immunity, which seems to be more waning of immunity rather than a delta specific phenomenon, although there may be a small component. It would seem that one would have to conclude either that the mRNA vaccine in general, that that platform or else the shortened dosing interval is not really between the two doses does not lead to long term good durability of the immune response. And those individuals at risk, particularly for severe disease, don’t have a good cell mediated immune response and are relying entirely on their neutralizing titer and other serology, which is dropping off rather quickly. Your boots clearly does that. So my question to you is, is it’s actually twofold. One, although it’s very early, do you have any evidence that the six month boost is actually contributing with a better dosing interval to give you more long term durability in the immune response? And is there any change in the kinetics of the antibody response? Or do you anticipate that just every six months you’re going to have to keep boosting these people?

Speaker2: [02:06:17] So I’ll start with it with the end of your question, I think this is very early. We can’t really show we know from other viruses that sometimes like in hepatitis, you get a dose and after a month the dose and after six months, the booster and you have protection for many, many years. Whereas for influenza, we need to be vaccinated every year. And I think it’s not really clear where this is going. We definitely don’t have any plans at the moment. To boost every six months will be fit exactly as we did here. Based on the results, we will continue to monitor and see if there is again any waning, any waning effect. But it may be that we won’t see that

Speaker1: [02:07:00] That after the booster will have a higher protection for a longer period of time. I would add that that I think that the effect of the delta versus alpha is not very small. I think they’re both very significant both the alpha versus Delta and the waning and is also maybe an interaction, a synergistic effects from both of them together. I wouldn’t I wouldn’t think about it as a small effect. Thank you, Doctor. Dr. Lavie. And quick questions and quick answers, please, we’re going to have time to come back again later. Hello. I’d like to thank the presenters for a wonderful presentation and impressive progress. One question I had was related to the decision to give boosters to the younger individuals as well as we know there is some increased risk of myocarditis, particularly in younger males. And it seemed like there was relatively less data in the younger age group. So what were the considerations from a policy perspective of recommending a trigger for that youngest group? If, if Dr Alroy-Preis can say a few words, I’d really appreciate it. Thank you.

Speaker2: [02:08:20] Sure. So first of all, we know from research done by colleagues HMO in Israel that the risk of myocarditis from corona

Speaker1: [02:08:29] Itself is higher than the risk score from the

Speaker2: [02:08:33] Vaccine. And when you have really warring pandemic with a surge of thousands of cases and doubling every 10 days, the risk of people, even young people to be infected with corona and get get the myocarditis is higher than being vaccinated. And that risk, and I have to say that there is a work being published or in the in the review process from Israel about the myocarditis. Ninety five percent of the cases, the myocarditis was was not severe. And so we feel that when we weigh a pandemic roaring

Speaker1: [02:09:14] With, we saw reproductive number of over 1.3,

Speaker2: [02:09:21] Doubling every 10 days. The risk, even for the young adults, would be higher. And I have to say something about a mix of our population. So if we only vaccinated the 60 and above, this is roughly 60 percent of our population. Most of our population is younger. And when we looked at the at the cases confirmed cases that we had in the fourth wave, 15 percent of them were 60 and above. So the majority was not the 60 and above, and we believe we wouldn’t be able to control the pandemic just by vaccinating those 16 and above. When you have roaring pandemic and we know that the numbers are doubling, then we really have to make sure that we get to a reproductive

Speaker1: [02:10:10] Number of under one in order to control this,

Speaker2: [02:10:13] And we wouldn’t have been able to do this. We think just by vaccinating the 60 and above.

Speaker1: [02:10:18] And conflict with any sense of a. We’re going to have to move on. Ok, we’ve got a list of about eight people who want to ask questions Doctor Dance. So. Well. Go ahead, please. The advance. We’re going to have to go on, thank you, Dr. Rubin.

Speaker2: [02:10:59] Sorry, sorry. Ok, I’ll dance quickly. Thank you. This is wonderful and very provocative, given that you were ahead of us,

Speaker1: [02:11:09] And so foreseeing the

Speaker2: [02:11:10] Future, so thank you for sharing your data. I had a question because not only and as you suggested in your last answer, in order to really control a pandemic, we actually have to control secondary cases. So the ability to spread and what we are starting to see is in our vaccinated households. We are starting to see spread into our younger populations who are no longer seemingly protected by, you know, herd immunity around them. Were you able to look at the secondary cases within households? You have the opportunity to do that. People are getting tested. So what is the the lack of protection for children when you started seeing those surges? And then was there any control of that protection to those in our societies who haven’t been able to be vaccinated?

Speaker1: [02:12:05] We answer to a complicated question, please,

Speaker2: [02:12:09] We’ll do our best. So our fourth wave actually started with younger people coming from abroad and their and their kids, the older adults who were vaccinated, the kids obviously were not. And we see we saw a surge in cases among both. And that was the beginning of our fourth wave in kind of two spots and then spread in a community way. What we saw at the beginning of of June is that the ability of a vaccinated individual to to spread it to others

Speaker1: [02:12:47] Was

Speaker2: [02:12:48] Lower than the non-vaccinated. So roughly 80 percent of the people who were vaccinated at the beginning who were vaccinated did not infect others outside their household in their household. It was highly contagious, so vaccinees that became confirmed cases were infecting their household. And that actually led us to to a policy that said, if if you have a confirmed case at your household and you need to take care of him a child, you can’t really go in and out taking care of him because you’ll be infected and you’ll infect

Speaker1: [02:13:30] Others going to work.

Speaker2: [02:13:32] So we definitely see that cases that are vaccinated, vaccinated, doubly vaccinated, that are

Speaker1: [02:13:38] No longer fresh, what we call more than

Speaker2: [02:13:41] Six months from the second dose are infecting other people. It’s obviously less than non-vaccinated, but we’re seeing that, especially in their household.

Speaker1: [02:13:53] Dr. Rubin, the final question before we are forced to take a break. I think, Arnold, thank you very much for the presentation and for generously sharing the data, the Israeli data are very important for all of us making these decisions. So are in a great laboratory and you’ve done a very nice job of it. Dr. Gans just mentioned how one of the goals would be to prevent transmission and reduce the size of the epidemic, but of course, another goal is preventing severe disease. If you look at it through that lens, can you identify the people who are likely to get severe disease? Do they look like the people at high risk otherwise? In other words, could you focus the administration of a third dose of vaccine on particular groups to give a very high yield for preventing severe disease?

Speaker2: [02:14:49] The obvious question is those who are 60 and above and those who have comorbid conditions, especially morbid obesity, we see that as a very

Speaker1: [02:15:00] Clear

Speaker2: [02:15:02] Chronic disease that is a risk factor for COVID 19. However, as I said before, we having about 60 percent of the population over 60, it’s really very we can’t imagine just vaccinating those that group knowing that 85 percent of the confirmed infections are among the rest of the population and trying to get to a record number

Speaker1: [02:15:30] Of under under one so that

Speaker2: [02:15:32] This pandemic starts to shrink,

Speaker1: [02:15:34] This wave will start to fall.

Speaker2: [02:15:36] We have to, in our opinion, in Israel, we had to vaccinate more than just 16 percent of the population to get there. So we definitely see mortality among young people who are not vaccinated. Thirty twenty

Speaker1: [02:15:50] Five.

Speaker2: [02:15:51] Forty one really young people. And we started to see the same trend of severe, critically ill patients among those who are 40 to 60 and have been doubly vaccinated. And we just didn’t want to wait to see those results. And we knew that we needed to vaccinate a

Speaker1: [02:16:10] Larger proportion of the population in

Speaker2: [02:16:13] Order to get the numbers down quickly. And I have to add one more thing. We all we always look at the severe and critical disease status or mortality. I think there is also importance in COVID

Speaker1: [02:16:28] Among those who

Speaker2: [02:16:29] Are infected. And so we can’t really put this aside and say, you know, this is influenza. If, if, if you if you went through this, it’s fine to see that there is a high percentage of people, including young people who are left with symptoms for over months.

Speaker1: [02:16:45] So there are several reasons why we wanted to make sure that we overcome this fourth wave. Ok. Thank you so much. Very good and very informative presentations at a very vigorous discussion, which actually will be continued and the question and answer session which comes later. And I hope our speakers from Israel, especially where there’s a seven hour time difference, will be able to stay with us and from the UK as well for that discussion later on. So five minutes for a break and then we resume again. Thank you. Oh, welcome back to the 167 VRBPAC meeting we will get started with, that was a nice little short break, and I will hand it back to Dr. Monto. Take it away. Thank you, Mark. We’re about to move to the sponsor presentations. We’re going to be hearing about the effect of the booster shot. And we’re going to be listening to presentations from Donna Boyce, Senior Vice President, Global Regulatory Affairs, Pfizer, and from Dr. Bill Gruber, senior vice president at Pfizer. Take it away.

Speaker3: [02:26:47] Good morning, members of the committee, the FDA and ladies and gentlemen in the audience. It’s a pleasure to be here today. I’m Donna Boyce and I’m the senior vice president of global regulatory affairs for Pfizer. I would like to thank the FDA for organizing this very and the VRBPAC chair and members for their time. Pfizer and our partner BioNTech are pleased to be here today to discuss a revision to the dosing schedule for our mRNA COVID 19 vaccine. Our presentation today will follow this agenda after I provide a brief introduction. Dr. William Gruber, Senior Vice President, Vaccine Clinical R&D, will review the Booster Clinical Development Program, including the neutralisation data from Phase one, the Phase three immunogenicity and safety results. The pharmacovigilance plans real world evidence supporting the use of a booster and a benefit risk conclusion. After this, I will come back to provide conclusions for our presentation. The Pfizer-BioNTech COVID 19 vaccine, also known as BNT162b2, has been available for the prevention of COVID 19 disease in individuals greater than or equal to 16 years of age since December 2020 under an emergency use authorization and an individual’s greater than 12 years of age since May 2021. To date, one point seven billion doses have been distributed globally between February and May 2021 and in accordance with FDA guidance.

Speaker3: [02:28:21] We conducted a pivotal clinical study to evaluate the safety and effectiveness of a booster dose. Fda granted full VLA approval of BNT162b2, often known as community on August 23rd for the prevention of COVID 19 disease in individuals greater than 16 years of age as a tuto series given three weeks apart. The duration of protection following the two dose primary series is currently unknown, but available data suggests that efficacy wanes over time. Based on the positive results of the booster dose study available, real world evidence and in consultation with FDA on August 27, we submitted a supplemental biologics license application to seek approval of a single booster dose after the primary series. There are substantial randomized controlled trial data and real world evidence to support that vaccine efficacy wane over time. As you heard earlier, recent data from Israel and the United States in the context of the Delta variant of concern suggests that vaccine protection against COVID 19 infection wanes approximately six to eight months following the second dose. A retrospective Real-World Evidence Cohort study conducted at Kaiser Permanente Southern California suggests that the observed erosion in vaccine effectiveness is likely primarily due to waning effectiveness rather than due to delta escaping vaccine protection. Waning effectiveness over time is further supported by a recent FDA requested post hoc analysis of breakthrough cases in the pivotal phase three efficacy study.

Speaker3: [02:30:12] To demonstrate the safety and effectiveness of a booster dose against COVID 19. Pfizer and BioNTech conducted a substudy of the Phase three pivotal study that complies with the FDA guidance. The results of this study demonstrate that a booster dose of BNT162b2 has an acceptable safety profile and elicits robust immune responses. Finally, real world evidence from a recently initiated booster vaccination program in Israel that we just heard in the face of waning immunity and in the period when the delta is the dominant vaccine shows a booster dose has a reactogenicity profile similar to that seen after receipt of the second primary series dose and restores high levels of protection against COVID 19 outcomes. The booster study was conducted in individuals 18 to 55 years of age, as recommended in the FDA guidance. The study was conducted in two phases. Phase one demonstrated that a booster dose administered approximately six months after the second vaccination of our vaccine had an acceptable safety profile and elicited robust immune responses against the wild type, as well as the beta and Delta variants of concern. Phase three showed that the vaccine was as well-tolerated as the second primary dose and elicited immune responses against the wild type variant that were noninferior to the immune responses observed after the second primary dose meeting.

Speaker3: [02:31:43] The protocol specified immuno bridging success criteria for GMT and sera response rates. Moreover, and according to an FDA guidance, the safety and effectiveness of the booster dose in individuals 18 to 55 five years of age can be extrapolated to individuals 16 and 17 years of age and over 55 years of age. These data serve as the basis for the Supplemental Biologics License Application. During the remainder of our presentation, we will share data with you that demonstrate that the overall benefit risk of the booster dose is favorable. Specifically, that the demonstrated safety and effectiveness of the third dose support adding a booster dose to the vaccination schedule and the global real world evidence demonstrates that the reduction in vaccine efficacy is likely due to waning effectiveness and support that a booster dose can restore high levels of protection with an acceptable safety profile. Based on these, we’re requesting licensure of a single booster dose of BMT one six two v two administered intramuscularly at least six months after the primary series in individuals greater than 16 years of age. I will now turn our presentation over to Dr. William Gruber, who will present a clear and compelling data demonstrating the booster safety and immunogenicity and effectiveness bill.

Speaker4: [02:33:13] Thank you, Donna. It’s my pleasure to share with you today, the clinical program that supports the safety and effectiveness of a booster dose. I have three goals in my presentation this morning. First, I will speak to the public health need that could be well served by a booster. Second, I will describe the clinical trial in real world effectiveness data supporting the safety and effectiveness of the booster dose. Third, I will conclude with overall benefit risk of a booster dose. Let’s begin there is clear erosion of vaccine protection over time against COVID 19, and emerging data indicates loss of protection against hospitalization. We need to maintain high vaccine effectiveness against COVID 19 to contain the pandemic. A safe and effective Pfizer BMT vaccine booster dose for individuals 16 years of age and older would be expected to restore protection and reduce COVID 19 illness and spread. The BMT 160 to be two vaccine is highly protective against COVID 19, but the duration of protection wanes over time. Let’s talk about the lines of evidence supporting this claim. First, data from the pivotal Phase three clinical trial showed that two doses of the Pfizer-BioNTech vaccine administered three weeks apart confers protection against both symptomatic and severe COVID 19. That, of course, was the basis for the emergency use authorization and the recent licensure of the COVID 19 vaccine in individuals 16 years of age and older. The full duration of protection of the Pfizer BioNTech vaccine is currently unknown.

Speaker4: [02:35:13] And analysis of efficacy up to six months after dose two from the pivotal clinical trial shows that initial vaccine efficacy slightly wanes over time in the pre delta period from ninety six point two percent in the first two months after vaccination to ninety point one percent over four months, and is still sustained at eighty three point seven percent up to approximately six months. Further waning of immunity and protection over time has been observed across the world, coinciding with penetration of the Delta variant originally observed in Israel, as you heard. This is now being observed in the United States and elsewhere. As we all know, the Delta variant became widespread globally as of June and July of this year. Reports describing reduced effectiveness of the Pfizer vaccine and other COVID 19 vaccines against SA’s coronavirus two infections caused by Delta have surfaced from Israel, the United States and Qatar. As you’ve also heard earlier this morning, recently in Israel, reduction in vaccine effectiveness has been observed against hospitalization and severe infection over time after a two dose Pfizer vaccine primary series. And again, you heard details about this earlier today from the Israeli Ministry of Health. In addition, recent U.S. CDC data hint at reduced COVID 19 vaccine effectiveness over time against severe disease and hospitalization in the U.S.. This reduced vaccine effectiveness tracks with longer spans of time between two doses of vaccine and SARS coronavirus two exposure.

Speaker4: [02:37:00] Vaccine effectiveness studies to date have not adequately differentiated the impact of Delta from potential waning immunity on recent reductions of vaccine effectiveness. In collaboration with Kaiser Permanente and Southern California, Pfizer evaluated overall and variant specific real world effectiveness of the Pfizer vaccine against SARS coronavirus two infection and COVID 19 related hospitalizations by time since vaccination. This was done to further inform issues of waning immunity and protection. So let’s first take a look at the methods that were used in the Kiser trial that informed thinking the setting is the Kaiser Permanente Southern California group, which includes over three point four million members greater than 12 years of age, who would be potential vaccine recipients. The study period includes December of 2020 through August the 8th 2021. This encompasses both the period when, first the Alpha and later the Delta variants were present. Whole genome sequencing has been done on all samples obtained during this period. As part of this trial, a cohort approach was used using Cox models. And again, this looks for both outcomes of infection, as well as COVID 19 related hospitalization as defined in the footnotes shown at the bottom of the slide. The vaccine status was evaluated with those fully vaccinated, with two doses of vaccine at least seven days after the second dose. This also looked at attack rates in the unvaccinated as a comparator.

Speaker4: [02:38:48] Here’s the first key observation. Vaccine effectiveness waned over time against infections, but as of this summer had not yet waned against hospitalization. In the Kaiser Permanente study. So let me describe for you the data that supports these observations. If we start on the left hand side, you see the graph titled SARS coronavirus two infection on the x axis are represented months after full vaccination and on the y axis adjusted vaccine effectiveness. Each of the colored lines represents a different age group from 12 to 15 years of age, up to adults. Sixty five years of age and older. The Black Line represents all individuals 12 years of age and older vaccine effectiveness against circulating virus at each time point is shown as a corresponding number above the x axis. Vaccine effectiveness was eighty eight percent in individuals one month after two doses of the Pfizer vaccine in this study. As you can see, for all age groups 16 years of age and above, efficacy wanes over time, dropping to forty seven percent for those individuals out more than five months from completion of the two dose series for 12 to 15 year olds. Efficacy may be somewhat better sustained, perhaps consistent with higher virus neutralization levels achieved in this age bracket. However, follow up is of shorter duration due to the more recent approval of a vaccine for this age group. If we look on the right hand side, we see in contrast to effectiveness against infection, effectiveness against COVID 19 related hospitalization has been sustained over this period of time in all age groups, from 12 to 15 years of age, those over 65 years of age out to at least five months.

Speaker4: [02:40:41] You can see that the efficacy for those vaccinated at least at less than one month is eighty seven percent, and for those vaccinated at greater than five months is still around 88 percent. Now, please keep in mind what you’ve heard earlier from the Israeli Ministry of Health. Effectiveness against severe disease and hospitalization has begun to decline in Israel. The combination of early comprehensive immunization and a high proportion of the population more than six months post-vaccination in Israel may have contributed to this early signal in Israel. These results, along with recent CDC data, portend that effectiveness against COVID 19 hospitalization and severe disease are less likely to remain sustained in the future. In the U.S., we may we may see similar increases in hospitalizations and severe disease in weeks to months for those individuals vaccinated early in the U.S. campaign. If so, the time to restore protection with a safe and effective booster dose of BMT one six two v two is now. It’s important also to look at the relationship between vaccine effectiveness and the variants that are circulating. And a second key observation from the Kaiser study becomes clear vaccine effectiveness wanes over time, irrespective of the variant of concern.

Speaker4: [02:42:12] What is the evidence to support this claim? Again, the orientation of this slide is much the same as you saw previously. Months after full vaccination are shown on the x axis and adjusted vaccine efficacy is shown on the y axis. Whether we examine other sequences SARS coronavirus two variants represented by the Black Line or the Delta variant shown in the blue line, the vaccine effectiveness over time wanes. Point estimates of vaccine effectiveness are lower for the Delta variant after completion of a two dose vaccine series, but a number of the confidence intervals overlap most prominently. Comparative data shown here supports that declining immune response over time is the primary driver of vaccine effectiveness and not variants. Escape restoration or improved immune response by a booster BNT162b2 dose would be expected to restore the comparable high protection against Delta and other variants seen at the left end of the grass. We also have additional information gleaned from the pivotal clinical trial that informs this thinking this type of randomized control analysis was noted to be a best practice by Dr. Stern earlier today. It reveals waning protection between five and 10 months after two doses of the Pfizer vaccine, as shown in the top graphic. This evaluation was done in the pivotal phase three efficacy trial in individuals over 16 years of age who completed the two dose series early in the study.

Speaker4: [02:44:03] The original vaccinees to participants who are in the placebo group that crossed over to the vaccine after the vaccine received emergency use authorization. This permitted evaluation of the difference in incidence rate and relative protection against COVID 19 for those who receive vaccine proximate to the Delta Surge. The crossover group versus those who receive vaccine more remotely. The original vaccinees the text at the bottom beginning on the left describes the results. The mean time from dose two to July. The first is four point seven months for the crossover group and nine point eight months for the original vaccine group, providing a separation in time that allows one to differentiate a potential effect of this parameter on immune response and protection. Ninety percent of the crossover group received dose to less than six months prior to July. The first, and almost all in the original vaccine group received dose to more than eight months prior to July, the first. Relative vaccine efficacy comparing those immunized later compared to those immunized earlier was twenty six point three percent. If we assume for a moment that protection against COVID 19 falls below 70 percent, which is reasonable based on trial data as well as the Kaiser data I’ve shared with you, and that it falls below 70 percent at five months after vaccination. Efficacy by extrapolation would be expected to be below 60 percent at 10 months compared to those that were unvaccinated.

Speaker4: [02:45:49] Difference in incidence rates calculate as eighteen point six cases for one thousand person years of follow up, and the magnitude of this risk highlights the public health importance of time. When one extrapolates this to the millions of individuals who may remain at risk in the setting of Delta variant or other variant spread. Over a year’s time, one point eighty six million more cases might be expected to occur in one hundred million individuals similarly exposed over a year, who are 10 months out from a two dose series compared to those five months out from a two dose series. A safe and effective booster dose of the Pfizer-BioNTech vaccine would be expected to narrow this gap. So let me summarize then the public health need that leads us to conclude that a safe and effective booster would be beneficial. Israel and the United States real world evidence suggests that vaccine efficacy against COVID 19 infection wanes approximately six to eight months following the second dose, when the Delta variant is predominant. A retrospective Kaiser study suggests that vaccine efficacy reductions are primarily due to waning vaccine induced immunity rather than due to delta escaping vaccine protection. Waning vaccine effectiveness is further supported by the recent FDA requested post hoc analysis of breakthrough cases in the pivotal phase three clinical study. While waning vaccine efficacy against hospitalization was not observed in the United States, this should be carefully monitored as data from Israel suggests that reduced effectiveness against severe disease could eventually follow reductions in vaccine effectiveness against SARS coronavirus two infections the Israeli experience could portend for U.S.

Speaker4: [02:47:52] COVID 19 future and soon. So the information I presented to you speaks to the importance of waning protection and a compelling rationale to restore protection. What information do we have that reassures us about the safety and potential effectiveness of a booster dose to meet that need? I’m going to share that with you now. First, it is important to understand the nature of responses across not only the current variant of variants of concern, but variants that may be of concern in the future. As we contemplate the advantages of a booster dose for this, information that we have after two doses of the Pfizer BioNTech vaccine are reassuring. The vaccine elicited sera effectively neutralize a broad range of SARS coronavirus two spike variants after two doses of the Pfizer BioNTech mRNA vaccine. And you can see this is true whether we’re talking about the wild type variant, the previously prominent Alpha variant, the beta variant or the more recent Delta variants. I would highlight that even in a circumstance associated with the lowest response seen here, a GMT of one ninety four to the beta variant efficacy was observed in the South African cohort. From our pivotal trial, you will recall that we demonstrated a K split of zero nine vaccine versus placebo, eight of whom had a specimen successfully sequenced to reveal that the virus was the beta variant.

Speaker4: [02:49:27] So this provides the following reassurances so far immunologic escape from serum neutralization after two vaccine doses has not been demonstrated, given that a second Pfizer BioNTech vaccine dose is associated with robust antibody responses across variants of concern. Increased responses to vaccine virus What we reference is wild type virus after a third dose should also be associated with increased neutralization response to variants of concern. I will share with you evidence that supports this logic. First, I want to remind you about the original pivotal study design, which was used for us to examine a booster dose. This slide may look familiar to you because it’s similar to what was presented at the time of emergency use authorization. The vaccination period for the purposes of this trial for the two primary doses were twenty one days apart. As you can see, represented on the graph. Individuals had active surveillance performed. Look for COVID 19 illness in association with nucleic acid amplification test positive evidence of SARS coronavirus two infection. As you can see, the length of times that were used to follow up for reactogenicity shown in the green one month for non-serious, six months for serious ages and up to two years for deaths occurring in this population, including older adults and those with comorbid conditions.

Speaker4: [02:51:03] Now I want to share with you where we are today. This graphic represents the experimental design of a third dose of vaccine administered to individuals recruited from the phase one and phase three phase of the pivotal safety and efficacy trial. Again, we took the population who had received their original two doses 21 days apart for phase one. We went to the Sentinel cohorts who were first immunized as part of our trial in May of last year, which represented 23 individuals and administered a booster dose. Obtaining the safety information as well as serum samples to measure immune response over the time period shown lighter blue represents days, darker blue months after we gained sufficient information from phase one that reassured us about the safety and immune response to the vaccine. We then moved to the expanded group that recruited from the phase two three portion of the pivotal trial. So these individuals were now approximately seven months post dose two. There were three hundred and twelve of them in the group who were boosted, and again we tracked reactions, adverse events and obtained blood specimens as shown to monitor safety and immune response. So let me summarize for you first, the data from the phase one part of this trial. I’m going to begin with the immunologic responses post those three, the one six two to indicate a substantial boost and reduced gap between the wild type and beta neutralisation.

Speaker4: [02:52:41] With the boost, the beta variant was chosen at the time because of concern about potential for spread and as a surrogate for other variants. So let me now share with you the evidence that supports this statement. First, let’s examine the 18 to fifty five year old group on the left hand side of the slide. The x axis represents the time of dosing and measurement of antibody response, and the y axis represents 50 percent serum neutralizing titer to SARS coronavirus two. If we begin with those individuals who receive two doses of vaccine, the primary series, you can see that for both the wild type and the beta variant tested in this trial that there were robust antibody responses that were most prominent seven days after dose two. These began to decline as soon as one month after dose two and were still lower before dose three. If you then look at the response after administering the booster, there at least three important observations. Number one, there is a dramatic increase in the antibody response as measured by GMC’s for both the wild type virus, as well as the beta variant at seven days after dose three, as well as one month after dose three. Number two, the difference between the response to the wild type and the beta variant has narrowed, represented by the geometric mean ratio shown at the top.

Speaker4: [02:54:07] The ratio, one month after dose two is zero point two seven one month after dose three. This ratio is zero point seven three. So we see a narrowing of the geometric mean ratio and therefore narrowing of difference between immune response to the wild type vaccine virus and the beta variant after the third dose. Number three, in contrast to the decrease in antibody response seen seven days after dose two to one month after dose two, we actually see an increase in antibody response between seven days after those two and one month after dose three. So what does all this mean? Our interpretation is that we’re seeing a robust immune response that equals or greatly exceeds the response that we’ve seen after the second dose. This response continues to mature, as evidenced by a continuing increase in antibody response at one month and narrowing of the difference in geometric mean ratio between the response to the wild type and the beta variant. This bodes well for comparable and perhaps improved protection after a third Pfizer BioNTech vaccine dose. Again, on the right hand side of the graphs, these observations are recapitulated and perhaps even more important in the sixty five to eighty five year olds. Why responses after the second dose of vaccine tended to be lower and decayed more rapidly than in younger adults. But look what happens after the third dose. Higher antibody response or seen seven days and one month after dose three compared to those after the second dose and closely rival those seen in younger adults.

Speaker4: [02:55:48] There is again narrowing of the GMR between wild type and beta variant and an increase in response over time. This suggests a significant immunologic benefit of a booster dose of the vaccine that is likely to confer similar or perhaps better protection than that provided by the second dose. This information was published in the New England Journal of Medicine this week. Now, of course, it’s important to know, does this apply to the Delta variant, since that’s the variant of current concern. I’m pleased to report the post dose. Three Pfizer-BioNTech GM teas indicate a substantial boost to the Delta variant, similar to that seen with wild type. This information is also included in the New England Journal of Medicine publication. Here we’ve represented for you the responses one mean one month after dose two compared to one month after dose three with a similar scheme, as shown on the prior slide. Younger adults on the left and older adults on the right. We again see a dramatic increase in immune response after the third dose, as measured by virus neutralizing GMT to both wild type virus and the Delta variant, and a narrowing of the GMR point estimates, as shown at the top after the third dose. Note that this narrowing of response is most prominent in the older age group.

Speaker4: [02:57:18] This provides further reassurance that a third dose of vaccine is likely to provide immunologic benefit, restoring and perhaps improving protection against the Delta variant. Given the observations I shared with you earlier about lack of immunologic escape for variants tested to date after two doses, these observations inspire optimism about the potential for a high level of protection against current and future variants after a third vaccine dose. So what about reactions seen in phase one in the phase one cohorts of younger and older adults? The evidence was reassuring that local reactions by maximum severity within seven days of the third dose. The bottom panel were similar to those after dose two, the top panel. The local reactogenicity captured by E Diary revealed no redness or swelling and comparable pain. Also, systemic events by maximum severity within seven days after the third dose were similar after dose three compared to dose two. We have found fever and chills to be the most discriminating common reactions in the phase one cohorts. Comparable levels of fever and a comparable level of chills were seen after dose three compared to dose two. Other reactions were also comparable. This safety information, coupled with the preceding immune response data, gave us confidence that we could move forward into the expanded cohort. So let me now summarize for you, the phase three portion of this booster study to begin, I will describe for you how this Phase three study was designed by Pfizer and approved by the FDA to support a booster dose indication in individuals 16 years of age and older.

Speaker4: [02:59:11] This FDA approved approach is based on meeting predefined safety and immune response criteria in the 18 to fifty five year old age group. With extrapolation to the full age range, 16 years of age and above. So what is the basis for extrapolation of phase three third dose data to 16 to 17 and greater than fifty five year olds? The FDA immunogenicity requirement is outlined in the text shown and referenced by the footnote. It reads Studies may be conducted in a single age group, for example, adults 18 to fifty five years of age, with extrapolation of results to other age groups for which the prototype vaccine has been authorized, meaning this requirement was judged by Seaver as sufficient to submit immunologic data for a supplemental licensure of the Pfizer BioNTech vaccine third dose. Regarding extrapolation of safety to the full age range, a few observations are pertinent for 16 to 17 year olds. Similar reactions in this age group to 18 to fifty five year olds after two doses predicts that reaction would also be similar after the third dose for adults over 55 years of age. Local reactions and systemic events in participants greater than 55 years after dose two were lower than those seen in younger adults.

Speaker4: [03:00:39] This predicts slower reactions after the third dose in individuals greater than fifty five years of age based on the favorable or better reactogenicity profile seen after the third dose compared to the second dose in 18 to fifty five year olds. Data that I’ll be sharing with you shortly. Now, to interpret these results in the context of what we’re seeking today, it’s important to understand the FDA immunogenicity criteria for a booster dose. The FDA guidance specifies that the booster dose must be adequately powered to demonstrate that the immune responses induced by the booster dose serum neutralizing titers against SARS coronavirus two, as measured by sera response rates and gigantes are statistically noninferior compared to those elicited by the vaccine in the primary series. So how do we do that? The success criteria include demonstration of NONINFERIORITY margins of minus 10 percent for sera response rates and one and a half fold for GMT. Based on consultations with Sieber, these criteria are also considered sufficient to support licensure of a booster following full approval of the primary series. This table shows the demographics of subjects receiving the third dose. These demographics are representative of 18 to fifty five year olds in the parents study. Note that we have a balanced representation across gender, races and ethnicity. Over 50 percent of individuals had co-morbidities as measured by the Charlson Comorbidity Index. The age of vaccination was approximately forty one. The time from dose two to the booster was close to seven months, with

Speaker1: [03:02:31] A minimum of approximately

Speaker2: [03:02:32] Microphone has been turned on.

Speaker1: [03:02:39] You’re back connected.

Speaker4: [03:02:41] Ok, thank you. Let me maybe start a little bit back to make sure that everybody gets to hear what I had to say. So this table shows the demographics of subjects receiving the third dose. These demographics are representative of 18 to fifty five year olds in the parents study. Now that we have a balanced representation across gender races, note that we have a balanced representation across gender races and ethnicity. Over 50 percent of individuals had comorbidities, as measured by the Charlson Comorbidity Index. The age of vaccination was approximately forty one. The time from dose two to the booster was close to seven months, with a minimum of approximately five months and a maximum of eight months since the two dose series. So let’s look at the immune response data. Recall that the study needed to be to immunologic criteria for Noninferiority based on comparison, a geometric mean virus neutralization titers and sera response after the third dose to those responses seen after the second dose. The geometric mean ratio of neutralizing titers, NONINFERIORITY Criterion Host dose three compared to post dose two was met with titers after the third dose approximately three fold higher than those seen after the second dose. This table shows SARS-CoV-2 coronavirus two neutralization titers in two hundred and ten individuals looking at one month post dose to about three, compared to the GMC’s after dose two. The GMR is the ratio of these responses to declare success. The lower bound of the confidence interval for the GMT on the right side of the table needed to be above zero point six, seven or two thirds.

Speaker4: [03:04:35] We see that the lower bound greatly exceeds the success criteria at two point seventy six, with the GMR point estimate indicating responses were three fold higher after the booster dose compared to responses after dose two. Hence, this meets not only the NONINFERIORITY criteria, but indicates that the virus neutralization response is seen after the third dose are consistent with phase one results and greatly exceed and are statistically greater than those seen after the second dose. This figure demonstrates graphically the SARS coronavirus two neutralisation GMT with relationship to dose GMT shown are based on the number of subjects with valid results at each time point. While the NONINFERIORITY analysis for the GMT ratio shown on the prior slide are based on subjects who had valid results at both one month post dose two and one month post booster time and doses are shown on the x axis 50 percent neutralizing GMT on the y axis. Results are consistent with those seen in the phase one study. Neutralizing GMT rise to protective levels after the second dose, followed by a drop prior to the third dose. By seven days after those three observed virus neutralization gaps are nearly double and by one month are triple those achieved after the second dose. These results indicate that a third dose is likely to begin conferring benefit shortly after administration. Noninferiority of the booster dose was also demonstrated based on proportion of subjects with a sera response meeting the second immune response licensure criteria criterion, several response is defined as achieving a greater than or equal to four fold rise from baseline to four dose one in this population of one hundred and ninety eight individuals.

Speaker4: [03:06:37] The one month post booster response was ninety nine point five percent after dose three versus ninety eight percent after dose two, when both were compared to baseline. This yielded a one and a half fold greater response after the booster, with a lower bound of the confidence interval of minus zero point seven percent, well above the minus 10 percent required. Noninferiority was also confirmed based on an FDA defined alternative analysis. We were asked by the FDA in a post hoc analysis to compare booster versus post booster sera response, and you can see that with this analysis. In one hundred and seventy nine individuals, the sera response rate was ninety three point nine percent post 03 versus ninety seven point eight percent post dose two, again meeting the minus 10 percent NONINFERIORITY criteria, with a percentage of the lower confidence interval being minus eight point two percent. So both the pre-specified GMT and sera response results, as well as the post hoc alternative sera response rates, satisfied licensure criteria for a booster dose with neutralization GMT us greatly exceeding those seen after dose two. Now I want to share with you the safety data that supports a booster dose. Let’s follow up. Time for the booster dose study is shown here. Total exposure from booster vaccination to the data cut date

Speaker1: [03:08:11] With the mean. Could you please wrap up pretty soon where you’re running out of time?

Speaker4: [03:08:19] All right. Let me get through the safety information I thought we had. Forty five minutes, are we running close to that?

Speaker1: [03:08:27] You are

Speaker4: [03:08:29] Ok. Ok, well, we’ll move quickly through this. Ok, follow up time for the booster dose. A study has shown here. Total exposure from booster vaccination to the data cutoff date was a mean of two point seven months and a median of two point six months, with the ranges shown and the total exposure from dose two to the cutoff date. So including both exposure post-osama as well as that, both those three was a mean of nine point four months and a median of nine point five months. So let’s look at the reaction solicited by E Diary after the booster dose compared to reactions after dose two. Local reactions after those three were comparable to those seen after dose two reactions after dose three are in the bottom panel, those two in the top panel. And I think you can see these recapitulated results that we saw in phase in phase one. This provides reassurance of comparable local reactions with a booster dose. Likewise, systemic events by maximum severity within seven days of the third dose are similar to post dose two. Again, the same scheme those three in the bottom dose two in the top panel and again, draw your attention, particularly to fever and chills. Elsewhere in this larger data set, you can see that if anything, the fever point estimate is lower than that seen for fever after the second dose in this cohort of 18 to 55 year olds, reported shows are also lower in other reactions are comparable to those seen after the second dose.

Speaker4: [03:09:55] This provides reassurance that the diary reactogenicity profile after a third dose is similar or perhaps even better than that seen after the second dose. Adverse events by system organ class occurring greater than one percent of participants with one month post dose third dose were less than those post those two in the parents study. With the exception of lymphadenopathy, adverse events after dose three are shown in dark blue bars, adverse events after dose two light blue bars at the top of the graphic chart. Blood and lymphatic disorders at five four five point two percent is entirely represented by axillary lymphadenopathy. By comparison, after dose two point five percent of the zero point six percent in this category is also represented by lymphadenopathy. Generally, lymphadenopathy after dose three was mild, self-limited and resolved. Lymphadenopathy includes one individuals who’ve lymph node enlargement was judged severe by the investigator due to reported prevention of arm movement, it lasted for five days and resolved for reactions other than blood and lymphatic disorders. As shown on this graphic, the incidence of adverse events was typically lower or comparable after dose three. These findings are reassuring regarding the safety profile of the vaccine. There were no essays or withdrawals due to assays in the one month period after the third dose.

Speaker4: [03:11:15] Only one serious adverse event was observed in the median of two, two point six months of follow up at the time of data cutoff, which was assessed as unrelated to the vaccine. This was a myocardial infarction reported sixty two days after dose three by an individual in their 40s. The event was considered unrelated to study intervention by the investigator. This individual had a medical history pertinent to the etiology of the myocardial infarction, and the cardiac event was considered secondary to stimulant abuse. Myocardial infarction was reported as recovered or resolved without sequelae within one day of onset following treatment. Details of this case are included in the briefing document. You may recall a version of this slide from the Emergency Use Authorization, which has been annotated somewhat to reflect the ongoing work that is done. You can see the nature of the pharmacovigilance that we are conducting. Pharmacovigilance activities are a critical component of activities relating to the detection, assessment, understanding and prevention of risk. Pfizer has been conducting robust pharmacovigilance activities and collaborating with regulators and international groups. We will continue to look for rare adverse events such as myocarditis, anaphylaxis as well as other adverse events and special interests. The current approach to pharmacovigilance has been valuable in detecting and assessing rare events and risk, and we will

Speaker1: [03:12:39] Continue these in your time bill.

Speaker4: [03:12:43] All right. The evidence today supports a positive risk benefit for the Pfizer BMT vaccine. Let’s go to the next slide, please.

Speaker1: [03:12:56] Mr. We really just that you’re really over your time, FDA has to be able to speak.

Speaker4: [03:13:05] Right. I understand. So let me just recapitulate, you’ve already had the chance if we go to the next slide, please. Information has been shared with you earlier, you heard earlier from this morning, a third booster dose restored high level of effectiveness for preventing both infection and severe COVID 19. And this

Speaker3: [03:13:26] Table represents. All right.

Speaker4: [03:13:30] So I think that the point is that we obviously have seen a dramatic fold reduction by 11 fold for infection and 15 and a half fold for severe infection that we believe a booster dose can restore. And with that, I will turn this over to Donna Boyce to wrap up.

Speaker1: [03:13:50] Well, I think we we we already had a wrap up, so thank you both very much. We will have a Q&A session later on in which you all will be able to participate. Let’s go on now and here the FDA presentation from Dr. Eugene Lee after league plates.

Speaker2: [03:14:20] Good, good morning, everyone, I am Dr. Judy Lee and the medical officer at the Office of Vaccines and Research and Review within the Center for Biologics Evaluation and Research at the FDA. So here is an overview of the presentation today. I’d like to just mention that these slides are a collective effort of many members of the Office of Vaccines. So to quickly go through this on August twenty third, twenty twenty one FDA approved the BNT162b2 vaccine under the proprietary name of Community for Active Immunization to prevent coronavirus disease 2019 caused by SARS-CoV-2 in individuals 16 years of age and older. It’s currently the only vaccine or medical product that is FDA approved for the prevention of COVID 19, and the BLR supplement being discussed today is intended to support approval for booster administration of community approximately six months following the primary series. So I will start with the regulatory background with some key dates in April 20 20 starting on the left, the pivotal study three four five nine one one enrolled the first patient in December. Twenty twenty an neoessary was issued for the primary series in individuals 16 years of age and above. Uh, and on May twenty twenty one, which was extended to individuals 12 years of age and above. And on August 13, EUA was issued for a third primary series dose for immunocompromised individuals in August. As I previously mentioned on the 23rd, we licensed the primary series.

Speaker2: [03:16:18] A community and individual 16 years of age and above. So let me go through the booster study design, as previously mentioned, mention the start with the parents study, during which over forty four thousand individuals were randomized to receive community sailing placebo given to two doses given three weeks apart. Now, after serial unblinding, a number of individuals received a booster dose, both in phase one, where twenty three adults received their booster dose approximately eight point two to eight point four months after dose two and in 306 individuals from the phase two three portion who received it on a median of 6.8 months after those two safety data were collected uniformly, as shown in the boxes below, which solicited unsolicited serious adverse events and death from serious adverse events that were deemed related to be collected for up to two years after those two. Now, I’ll point out that the data to be discussed today will be from a subset of the forty four thousand and so. For the first two doses. Go with it. So just to give you an overview of the demographic profile for the booster dose participants. The phase one participants were very homogeneous and as you can see on the bottom bar or section below, none were obese and had co-morbidities or history of SARS-CoV-2 exposure per dose one. And the homogeneity is largely a function of the eligibility criteria for the study at phase one and development. And in the last column, you see, as we’ve seen before, the profile for participants in phase two and three.

Speaker2: [03:18:25] And you see some greater diversity in race, predominantly white at eighty one percent and some with history of SARS-CoV-2 exposure at three point six percent. Any of the comorbidities deemed to confer increased risk for severe COVID. Excluding obesity was at eighteen point three percent and approximately 40 percent with obesity. So we’ll move on to the immunogenicity results. So the primary and immunogenicity objective was to demonstrate noninferiority of neutralizing antibody geometric mean titers against the reference or the wild type SARS-CoV-2 strain. Usa. Washington one like Washington one, I’m sorry, which is unlike it was measured after the booster dose. And compared to after the two dose primary series and the same individuals and you can see in the pictorial above the four time points of interest that will be discussed in the subsequent slides. Another point to make is that the immunogenicity data were obtained using a validated virus micro neutralization assay. What? The qualified. So there are two primary immunogenicity end points for which Noninferiority was assessed. The first is the ratio of GMT of SARS-CoV-2 neutralizing titers against the wild type virus strain. And you can see here the ratio post booster dose over posters, too. And here on the right, the criteria for Noninferiority lower bound. The two sided ninety seven point five confidence interval sixteen point six seven and the point estimate of the GMT ratio was at least two point eight.

Speaker2: [03:20:36] For the second immunogenicity endpoint that was analyzed for NONINFERIORITY was the percentage difference of serial response at one month post booster dose and at one month post dose two responses defined as at least a fourfold rise, which depends on a baseline measurement that is under the lower limit of quantification and opposed to vaccination measure. That is at least four times that, to be considered a fair response. And so what was being evaluated here at pre-specified was the percentage of individuals with a fourfold rise from pre dose one to one month post both booster dose. Minus percentage of those with a fourfold rise from 3.1 to one month post those two and non-inferiority was declared based on the following criterion with a lower bound for the difference in the percentage of zero responders at these two times lows of being greater than negative 10 percent. So here are the immunogenicity analysis population. Let me see if I can get the. I. The little arrow starting at the top is the 306 end of the individuals who comprise the all available immunogenicity population, and those were those who received BNT162b2 at 30 micrograms. And in the process of reaching the valuable immunogenicity population, forty four were excluded, primarily due to important protocol deviations. And then the number further slightly decreased to two point thirty four because of the additional criteria of having no evidence of infection from dose one to one month after booster dose.

Speaker2: [03:22:37] And indeed, depending on the bottom, is a definition of what was considered without evidence of infection. Ok. So here the the slide shows the GNP is against the reference range in the dose three booster evaluable immunogenicity population without evidence of infection. And on the y axis on a large scale are the GMT and along. From left to right, you go from pre dose one one month post of to right to four post dose post right before booster dose. I’m sorry and then one month post booster dose. And so you can see the trend that has been previously pointed out with, with the titers increasing dramatically after post two, with some waning within the six months prior to the booster dose administration and a rise of significantly greater than that one month post booster dose. So here I show the NONINFERIORITY analysis based on the ratios against the reference strain and boxed in blue is the primary analysis population, which are the two hundred and ten individuals who are qualified to be a valuable immunogenicity population with no evidence of infection. And I’ll leave you to the right most column, which is the GMT ratio that we looked at comparing posters three to posters to the point estimate of three point two nine and the lower bound of two point seventy six was clearly above the Noninferiority criterion that was mentioned before, which is the estimate of being greater than or at least 0.8 and a lower bound of greater than point sixty seven.

Speaker2: [03:24:53] And here we are. You see the prespecified Noninferiority analysis based on terror response and the right most column shows the endpoint, the difference in response between one month after booster and one month after those two and. The difference is at one point five percent with the lower bound of negative 0.7 percent. So this met the criteria set with respect to the lower bound of being greater than negative 10 percent. And as mentioned previously by Dr. Gruber, we did ask for an alternative or complementary analysis for which we ask them to define fear response using pre booster rather than pre dose one to define the zero responders or the difference in serum response between one month after booster dose and one month after dose two. And as you can see here, the numbers are different, but these findings do not challenge the previous the data from this previous slide, which shows that they’ve achieved noninferior immunogenicity for the two co-primary endpoints. Ok, so here we go through the exploratory phase one analysis of. A virus neutralization titers against the Delta variant, as well as against the wild type of reference strain, as previously mentioned, the assay that was used to produce these data confirm a 50 percent plaque reduction neutralization test, and this was done in twenty three participants against the reference U.S.

Speaker2: [03:26:54] strain and the Delta variant. And these titers were assessed in sera one month after those two and one month after those three and in the box. In the middle of the slide are some considerations that this is not the same as the validated micro neutralization assay for which we have immunogenicity data, which was presented in the preceding slides. It is well accepted and there was standardization, but it’s not validated and it was used for exploratory purposes and the relatively relative sensitivity for the two strains currently are unknown. So here are the results on the columns are divided. You see on the left column Delta variant GMT wildtype GMT with confidence intervals, I have presented the 11 18 to fifty five year olds on top of the older adults and you see posters to hear. Versus post booster dose, so these numbers have been presented in the previous presentation. This is just a range slightly differently, but you can see that neutralizing titers against the Delta variant and the wild type are present measurable in both populations or age groups. And they you see the difference between both those two both dose three uniformly. Across the two and across the age group as well. Now, another post hoc analysis that we requested from Pfizer had to do with breakthrough infections, particularly those that were detected during the delta surge. And so what we have to Pfizer was to provide numbers of protocol specified COVID 19 cases that were were accrued during the early July and end of August in participants 16 years of age and above.

Speaker2: [03:29:14] And. On the left, you see, we are looking at participants who completed the two dose vaccination series early in the study for the parents study. So these are two individuals who were originally randomized to be 91. And these almost 19000 individuals? There were. There were seventy point three cases per 1000 person years. That’s the incidence of calculation that Pfizer provided. Three were severe. This is collected over a period of nine point eight months post to. And on the right, you were considering the individuals who were who completed the two dose vaccination series later in the study. In other words, those who are originally randomized to placebo and then crossed over to active vaccination group among these almost 18000 individuals. There was an incidence rate of fifty one point six cases per 1000 years, person. I’m sorry, the mean duration was slightly less as expected at four point seven months post of two. So the data here suggests that the incident. Of breakthrough infections appears to be higher in those who completed the vaccination series early versus those who completed it later. So in order to contextualize this delta in incidents, we did the following we made the following calculation. And number one on the left, you see you see the ratio that we said at the incidence rate among vaccinated versus early vaccine and that came up to zero point seven three.

Speaker2: [03:31:19] And so the purpose of this calculation is try to translate the relative breakthrough rates to vaccine efficacy. So we took this ratio of zero point seven three and for each of the assumed efficacy values shown in the table below. Among the placebo crossover group, we calculated the impact of this differential in breakthrough cases on the corresponding efficacy among those who are vaccinated earlier. So let me take you through one if we assume that the efficacy of the vaccine likely for severe disease in placebo crossover recipients vaccinated later, then the differential in the incidence rate that was determined during the delta surge would translate to approximately a four point four percent reduction in vaccine efficacy in those vaccinated earlier. Now. Continuing on, so. This is this is not actually during the delicacies, but pre delta surge, if you look at the numbers, we consider the incidence of COVID 19 among early vaccinations from the evaluable efficacy population before the delta surge occurred. In the case rate, or the incident rate was at twelve point six cases per 1000 person years. And when you look at the later vitamins, the placebo crossovers, in this case, before Delta, the influenza was actually higher at forty three point four cases per 1000 person years. So the takeaway message is the data are complicated and the limitations of the analysis are as follows.

Speaker2: [03:33:12] The parents study was not designed to assess the relative vaccine efficacy of the crossover group versus the original vaccines, and therefore this analysis is exploratory nature. But still, we thought was would be quite informative or important to consider. In addition, the open label nature of the booster dose. More than just confounding factors that include behavioral changes that bias the results, and of course, as mentioned previously, there are confounders that we are just not aware of at this time. And. Well. Going on to defeat your results. As mentioned previously, here, I the mean length of safety follow up. All the booster recipients in the phase one portion and the phase two three portion were basically the same at two point seven months and two point six months, respectively. Here I am showing you the local reactogenicity data across doses, dose, one dose, two data coming from the reactogenicity subset of vaccines from the blinded portion or blinded phase of the study, with an end of twenty eight, ninety nine and twenty six eighty two. And comparing this with the reactogenicity of those who received Booster the these two three participants in phase one. And you can see here those that injection pain site pain continues to be the most common. Local reaction and severity tended to be low with only one case, for instance, in the booster recipient. Overall, the data suggest that local reactogenicity does not appear to be enhanced following a dose the booster dose relative to dose two.

Speaker2: [03:35:30] You know, this is a busy slide, but so here are the systemic, reactive, just genetically preferred terms that were recorded by you during seven days after each dose. So along here, I’ve ordered the specific adverse reactions in descending order of frequency, so fatigue is the most common. And here you see the phase two, three dose one recipients. To treat those two recipients and the booster dose in. We said those recipients from the same faith and fatigue continues to be the most common and severity does not, the severity of fatigue does not appear to vary significantly from that observed after post after dose two. And a similar relationship between all these other commonly reported systemic adverse reactions. Can be seen between those two and the three. Frequency of fever. But we did after the third dose. And use of antibiotics and pain medication were comparable after those two. That’s compared to after the booster dose. Ok, so here we’re looking at the systemic reactogenicity profile by age strata. So the two hundred and eighty nine individuals who submitted diary data for eighteen to fifty five. And here this table only includes the individuals in their sixty five to eighty five year old age strata and there are 12. And so if you look. Overall. The order of frequency of systemic reactogenicity. About the same and. It’s worth. It’s worth pointing out that severe reactions of any kind in terms of systemic reactogenicity were not reported among these 12 recipients.

Speaker2: [03:37:55] Peter was also not reported. And the use of antibiotics or pain medication was also less. Now going on to unsolicited adverse events that were monitored one month post Booster. So here presented in this table are the most common events that occurred in more than two participants or two or more participants, I should say. And the one worth pointing out is lymphadenopathy. It occurred in 16 participants with the corresponding frequency of five point two percent. The majority were mild to moderate, and they did resolve. About one is reported to be ongoing at this time. One, as mentioned previously, was deemed severe due to impact on activity. This occurred two days after the booster dose and resolved over five days. Considering the time period of booster dose, the data cutoff, which is at least two months of post of three follow up in the three hundred and six participants, there was one additional A.E. of acute myocardial infarction reported as an unrelated see. This occurred on day sixty two post booster dose and we recovered an adult. More participants were withdrawn due to adverse events, and among the three hundred and six participants evaluated, there are no cases of anaphylaxis, hypersensitivity, Bell’s palsy, appendicitis or myocarditis pericarditis. And among the twenty three phase one booster recipients, there were no eight use that were reported one month after booster dose.

Speaker2: [03:39:44] So finally, I come to my last slide, which is a summary of the data that we reviewed that were submitted to this supplement. So in terms of immunogenicity, success criteria against the reference strain were met for both prespecified co-primary immunogenicity endpoints, which were the GMT ratio and the difference in terror response rates among study participants with no evidence of SARS-CoV-2 infection prior to one month after the booster dose. The immunogenicity data to support effectiveness of the booster dose against the Delta variant are limited to exploratory analysis in a small number of participants using an assay while standardized and with a with, the reference control is not validated to date. In terms of the safety data from the three hundred and six phase two three booster recipients, there’s no evidence that there is increased reactogenicity relative to those two. Difficult to reach conclusions about relative reactogenicity by age, or it is difficult to reach any conclusions about the relative reactogenicity by age, as there are only 12 participants and in the age strata of sixty five to eighty five, the minimum and maximum age range was sixty five to seventy five. Lymphadenopathy was observed more frequently following the booster dose than after the primary series doses. That’s worth mentioning there were no deaths, vaccine related serious adverse events or events of myocarditis, pericarditis, anaphylaxis, appendicitis or Bell’s palsy among the three hundred and twenty five booster recipients. And so. I am done with my my portion.

Speaker1: [03:41:59] Thank you very much. It’s time for our break, we will break until the open public hearing begins at. 12:30 Eastern, so we’ve got a long, 13 or seven minute break until the open public hearing. See you back then. And Peter, I’m here. All right, well, welcome back to the one hundred and sixty seventh meeting of the Vaccines and Related Biological Products Advisory Committee meeting. We will now get started and I will hand it back over to our acting chair, Dr. Monto. Welcome to the open public hearing session. Please note that both the FDA and the public believe in a transparent process for information gathering and decision making to ensure such transparency during the open public hearing session of the Advisory Committee meeting. Fda believes that it is important to understand the context of an individual’s presentation. For this reason, FDA encourages you the open public hearing speaker at the beginning of your written or oral statement to advise the committee of any financial relationship that you may have with a sponsor, its product and, if known, its direct competitors. For example, this financial information may include the sponsor’s payment of expenses in connection with your participation in this meeting. Likewise, FDA encourages you at the beginning of your statement to advise the committee if you do have or do not have any such financial relationships. If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.

Speaker2: [04:02:49] Okay, good afternoon, everyone. This is the at the designated central officers for this session who is going to conduct the open public hearings and the next speaker. The first speaker for this session is Dr. Rajesh Gupta. Dr. Gupta, could you please start your presentation, please? You have three minutes to go.

Speaker1: [04:03:12] My name is Rajesh, I do consulting for the pharmaceutical industry, including vaccine manufacturers. I have more than 40 years experience in development, manufacture, quality control and regulation of vaccines, both in the industry and regulatory agencies, including FDA, where I was a deputy division director. And let’s. Today, I’m going to present my views on some aspects about the need for a booster dose of COVID 19 vaccine based on my experience and understanding of science while working with other vaccines. Next slide, please. Maybe a justification for a booster dose have been waning circulating at neutralizing antibodies and incidence of COVID 19 infections in vaccinated individuals a few months after vaccination. Let’s slide a few facts about circulating antibodies. Thus far, most of protective levels of circulating antibodies are not known when known. For example, tetanus and diphtheria, these are highly variable. Next slide. Certainly, circulating antibodies decline a few months after vaccination, but booster doses are not given for most vaccines, except for toxin mediated diseases. Protection against the disease is not necessarily through maintaining high level of circulating antibodies. Much like five nightly. Next slide. Instead of protection by most vaccines. Is through rapid deployment of immune system by activation of immune memory, by the invading pathogens, accept toxin mediated diseases where protective levels are required to be maintained, which is done through periodic boosters every 10 years. The reason is that that isn’t the fear.

Speaker1: [04:04:59] Toxins are highly potent doses of these toxic, that lethal but not enough to activate memory for these toxins, bind immediately to nerve cells and not are not available to immune cells. Next slide. Other justifications for the booster had been incidents of COVID 19 infections in vaccinated individuals. However, there is no baseline data for protection against infections for most vaccines because unfortunately, clinical trials were not designed to evaluate protection against infection. However, vaccines continue to be highly effective against severe disease, and that’s why additional need there is a risk of original antigenic sin phenomena. After a booster dose, when antibodies to immunodominant epitopes are made which get boosted after booster doses with immune memory vaccination with the new strain or infection with the new strain hijack the immune system towards the immune response to same epitopes for which antibodies were originally made, leading to no protection against the new strain after disease or vaccination. Next slide. Finally, booster doses leading to high levels of circulating antibodies make the great escape mutants of SARS CoV two virus. So to finally conclude, based on experience with the protection by existing vaccines who see those is not justified by journal use at this time, it may be justified for immunocompromised or elderly who did not get adequate immune response after initial vaccination. Thank you.

Speaker2: [04:06:30] Thank you, Dr. Gupta. The next speaker is Mr Benjamin Newton.

Speaker1: [04:06:39] Thank you. My name is Ben Newton. The question that we must ask every day is how we can save the most lives. The answer is to approve boosters and file the American Academy of Pediatrics recommendation to approve pediatric vaccines in August before school started. Slide to the FDA. Guidelines for vaccine approval stated that vaccines required to have 50 percent efficacy against symptomatic disease, whether they require the use of the totality of the scientific evidence such that if we only use randomized control trial data, we violate the FDA guidelines. Slide three We saw in April that vaccine efficacy is predicted by neutralizing titers. We have always known this would be the case, but now we had a correlative protection slide for also in April. On the left hand side, we saw that both variants in time would reduce vaccine efficacy. Boosters would be required. On the right side, we saw the 90 day Half-Life of antibodies. It was clear that we would need boosting in the fall of twenty twenty one at the latest. Slide five In June, we saw that the Delta variant and Angola strains had immune escape. The question now became Do we have days or weeks to start boosting Slide six? In July, we had our answer. We had waited too long to start boosting. Israel published data showing vaccine efficacy had dropped below 50 percent, the FDA minimum standard for people vaccinated five months prior. Israel started boosting days later. We should have to find seven. Does the FDA have an ethical obligation? Option one is that they don’t have an ethical obligation, just an obligation to approve safe and effective medicines. They should approve both boosters and follow the American Academy of Pediatrics recommendation to approve vaccines for children. Option two is that the FDA has an ethical obligation. Then we must approve pediatric vaccines. We can’t randomize pediatric trials 50 50 because that would be unethical.

Speaker2: [04:08:27] But there are 50 million

Speaker1: [04:08:28] American children who are not free to be vaccinated today. We should approve lower doses. I and others have explained to the FDA how to optimize dosing to save lives. If you care to watch a long form explanation, you can check out the YouTube video here. In addition, we should approve boosters. If you don’t approve both boosters and the only people, then only people with good doctors can be boosted. Fight eight, the FDA and FDA had a reputation to protect the FDA, built its reputation by saving lives with thalidomide, with calls that the FDA has squandered its reputation. The FDA lagged other regulators, often by months, in approving vaccines and diagnostic tests. Randomized controlled trials became unethical. The instantly knew or importantly, should have known that vaccines worked. If you fail to look at data, it does not mean the data doesn’t exist. It is important to note that developing a vaccine took two days. We are quickly approaching two years. When will all Americans be free to be vaccinated? Slide nine. This is not the last pandemic or variant. The FDA must determine how to approve vaccines as fast as virus’s spread. Boosting with wild type vaccines increases the chance that vaccine efficacy will drop precipitously. I thank you for your time and service.

Speaker2: [04:09:44] Thank you, Mr. Newton. The next speaker is Dr. Jessica Rose. My name is Dr. Jessica Rose, and I’m a viral immunologist and computational biologist. I’ve taken it upon myself to become a verb analyst

Speaker1: [04:09:58] To organize the data

Speaker2: [04:09:59] Into comprehensive figures to convey information to the public in both published work and video. Medium safety and efficacy are the cornerstones of the development and administration of biologic biological products meant for human use. Risk is a measure of the probability of an adverse events occurring and the severity of the resulting harm to health of individuals in a device population. Safety is a judgment of the acceptability of this risk in a specified situation. Efficacy is the probability of benefit to individuals in a defined population from a medical technology preferred to five one. This is a bar that shows the past 10 years of bears data plotted against the total number of adverse event reports for all vaccines for the years 2011 through 2020 and for COVID associated products only for twenty twenty one so far represents all adverse event reports, and the Red Cross represents all death adverse event reports. There’s an over 1000 percent increase in the total number of adverse events for 2021, and we are not done with 2020 one. This is highly anomalous on both fronts. These increased reporting rates are not due to increased rates and injections and not the simulated reporting. This has been shown using a comparative analysis of influenza data.

Speaker2: [04:11:18] The onus is on the public health officials, the FDA, the CDC and policy makers to answer to these anomalies and acknowledge the clear risk signals emerging from their data and to confront the issue of COVID injectable product use risks that, in my opinion, outweigh any potential benefit associated with these products, especially for children. This is a time series that shows the total cumulative number of cardiovascular, immunological and neurological adverse events for twenty twenty one associated with COVID 19, we would have absolute counts are no normalized for the total number of fully injected individuals in the U.S. we can see that one in 660 individuals are succumbing to and reporting immunological adverse events associated with the Coke products. The underreporting factor is not considered Tier three. This is a phylogenetic tree showing the emergence of the alpha delta variant of COVID 19 of COVID 19 over time. The emergence of both of these variants and their subsequent clustering arose in very close temporal proximity to the rollout of the COVID products in Israel. Israeli data from the Ministry of Health and Our World in data revealed that ninety eight point one coalition

Speaker1: [04:12:33] Punish, punish, punish Hamish ifif Shimoni comments on.

[04:12:46] Oh, my God.

Speaker2: [04:12:48] Sorry about that. Israel is one of the most injected countries, and it appears from this data that this represents a clear failure of these products to provide protective immunity against emergent variants and to prevent transmission, regardless of how many additional shots administered. And this begs the question as to whether these injection rollouts are driving the emergence of the new variants. There’s a clear and present danger of the emergence of variants of concern if we continue with these alleged booster shots. Thank you. Thank you, Dr. Rose. Next, the speaker is Professor Lexus leaving.

Speaker1: [04:13:25] Good afternoon, everybody. Good afternoon, everybody, my name is Steve Levy, I hope you can see my personal title slide labeled the slide A. On the bottom right. I’m on the faculty of the MIT Sloan School of Management. I have no conflict of interest to disclose today in my presentation represents only my individual opinions and does not reflect in any way on the positions of MIT. Next slide be. Since the Pfizer’s request for the approval of the boosters is partially based on the so-called study conducted in Israel, it is important to understand that the booster vaccination campaign in Israel was anything but a carefully designed study in a matter of less than six weeks. Israel moved from its initial intention to vaccinate the over 60 population to vaccinating anyone above the age of 12, and it is now about to mandate booster vaccination for anyone to maintain green passport status. This does not allow any reliable learning, definitely not in such a short amount of time, and please understand that the adverse event surveillance system in Israel is truly dysfunctional, particularly around the booster deployment. I know from personal experience that the Ministry of Health in Israel does not address appropriately major concerning safety signals next to Slide C.. This leaves us with the question What drove this massive booster deployment next to slightly trying to reach vaccine induced herd immunity by reducing transmission rates will be consistent with the stated goal of the agreement that Israel signed with Pfizer. As you can see on Slide D, on the left hand side, the problem is that by now, we already know from mounting evidence that reaching herd immunity based on the current vaccines does not seem like a feasible or realistic goal.

Speaker1: [04:15:14] Not surprisingly, as you can see on the right hand side of Slide, the Israel continues to have among the highest infection rates per capita in the world. Next to Slide E! You all listen to a presentation of the Israeli Ministry of Health that praises the efficacy of the boosters. I would like to caution this premature celebration and remind you that similar statements were made just six months ago around February on the two initial doses not on slide on the right hand side that COVID 19 deaths in Israel, in spite of all of the boosters, are on the rise. Whereas in other countries, including many states in the US, they seem to be on a downward trend at the moment. The data from Israel also highlights that the main risk of serious COVID 19 outcomes is focused to a large extent and among the completely unvaccinated population and almost entirely in the over sixty one on the left hand side of Slide. You can also see data from Table one in a research paper by the Ministry of Health in Israel that suggests that the benefits from the boosters compared to the prior two doses in preventing serious illness might be much more limited than desired. There is much more to say about the problems of the current booster efficacy study next to the slide. But let me conclude by stressing how important it is to transition from emergency strategies to long term ones. Hi-def outlines five important considerations in doing so they are self-explanatory. I hope you will hold off on approving these booster for broad use, at least until such a strategy is developed. Thank you for your attention.

Speaker2: [04:16:56] Thank you, Dr. Libby. The next speaker is Dr. Joseph Raymond.

Speaker1: [04:17:02] Hello. Please, if you can go to my first slide. Hello, my name is Dr. Joseph Freeman. No conflicts to declare I’m an emergency physician educated at Cornell Medical School, my residency with Charity Hospital in New Orleans, and I’ve been working in this region since. Where I work, over sixty five percent of the population are not vaccinated. I’m here today to ask for help for those working the front line to help us reduce vaccine hesitancy. For this, we need larger trials that demonstrate the vaccine reduce hospitalization without finding evidence of serious harm. I know many think the vaccine hesitant are dumb or just misinformed. That’s not at all what I’ve seen. In fact, typically independent of education level, the vaccine hesitant I’ve met in the E.R. are more familiar with vaccine studies and more aware of their own COVID risk than the vaccinated. Next slide, please. For example, many of my nurses have refused the vaccine despite having seen COVID 19 cause more death and devastation than most people have. I ask them, why refuse the vaccine? They tell me while they’ve seen the firsthand dangers of COVID and the elderly, the obese diabetics, they think their risk is low. They’re not wrong. Next slide, please. One nurse showed me this Oxford risk calculator. A 30 year old female has about a one in 7000 chance of catching COVID and being hospitalized over 90 days. She asked me, Can I assure her that the studies found her risk of serious harm from the vaccine is lower than her risk of hospitalization? The truth is, I can’t.

Speaker1: [04:18:37] Our trials weren’t big enough. They weren’t big enough to identify the vaccines cause myocarditis. Yet now we know they do. Next slide, please. A recent observational study suggests the risk of vaccine induced myocarditis in young males is higher than their risk of hospitalization from COVID. Is this true? We don’t know. It’s based on observational data to know it’s not true. We need a large trial that proves the vaccines reduce hospitalization more than they cause myocarditis in this age group. Next slide, please. The former FDA commissioner said the original premise of the vaccine was to reduce death and hospitalizations, and that was the data that came out of the initial clinical trials, except, as you all know, very well. Unfortunately, unfortunately, so did my nurse. The initial clinical trials did not find the reduction in death or hospitalization, likely because they were inadequately powered. Yet the former commissioner is correct that the initial trials should have been powered to find a reduction in hospitalization. Next slide, please. We need your help on the front lines to stop vaccine hesitancy. Demand the booster trials are large enough to find a reduction in hospitalisation without this data. We, the medical establishment, cannot confidently call out anti-Covid vaccine activists who publicly claim the vaccines harm more than they save, especially in the young and healthy. The fact that we do not have the clinical evidence to say these activists are wrong should terrify us all. Thank you. Next slide.

Speaker2: [04:20:10] Thank you, Dr. Friedman. The next speaker is Mr. Steve Cash.

Speaker1: [04:20:16] Hi, I’m Steve Kirsch, I’m executive director of the COVID 19 Early Treatment Fund. I have no conflicts advance to slide number four with the elephant. I’m going to focus my remarks today on the elephant in the room that nobody likes to talk about, but the vaccines kill more people than they save. Today, we focus almost exclusively on COVID death saves and vaccine efficacy because we were led to believe that the vaccines are perfectly safe, but this is simply not true. For example, there are four times as many heart attacks in the treatment group in the Pfizer six month trial report. That wasn’t bad luck. The show, as heart attacks happens seventy one times more often following these vaccines compared to any other vaccine. In all, twenty people died who got the drug. Fourteen died, who got the placebo. Few people noticed that if the net all cause mortality from the vaccines is negative. Vaccines, boosters and mandates are all nonsensical. This is the case today. Death rates let slide number seven advance to the number seven in lower apart. This shows that the all cause death light rate, and in three cases, only the various numbers are statistically significant. But the other numbers are troubling. Even if the vaccines had 100 percent protection, it still means we killed two people to save one life. Four experts did the analyses using completely different non-US data sources, and all of them came up with approximately the same number of excess vaccine related deaths about four hundred and eleven deaths per million doses. That translates into one hundred and fifty thousand people have died. Next slide would be slide number 11, the nursing home. Now, the real numbers confirm that we kill more than we save, and I won’t.

Speaker1: [04:22:04] I would love everyone to look at the Israel Ministry of Health data on the 90 plus year olds where we went to. We went from a ninety four point four percent vaccinated group to eighty two point nine percent vaccinated in the last four months in the most optimistic scenario. It means that 50 percent of the vaccinated people died and zero percent of unvaccinated people died. Unless you can explain that to the American public, you cannot approve the booster’s slide number 16, please myocarditis. The paper just posted yesterday on medRxiv entitled mRNA COVID 19 vaccination and development of TMR confirmed by pericarditis, shows that the myocarditis risk was one in a thousand, and that’s an overall age range from 16 18 to sixty five mean age of thirty three. It is not inconsistent with what the various shows next slide would be. Slide number 18 Gaming of the trial. It’s pretty clear that the Pfizer trial results were gained, it’s statistically impossible for protocol violations to be five times higher in the treatment group. Why hasn’t this been investigated? Slide number 19 Nattie Degré was 12 when she enrolled in the Pfizer Phase three trial for kids. Now she’s paralyzed for life. It wasn’t reported by it in the Pfizer results, I told Janet Woodcock. There was no investigation. Please tell us why this was why this fraud was not investigated. And finally, slide number 20, please. Early treatments are a much better alternative to boosters. The proof is that in Israel, cases are at an all time high in India. Uttar Pradesh is now COVID 19 free. As of today, almost nobody there is vaccinated. Thank you.

Speaker2: [04:24:00] Ok, thank you. The next speaker is Mr David Wiseman.

Speaker1: [04:24:05] Thank you, Dr. Monto. Please see our written comments. Next slide, Be for our disclosures and next slide slide. See with this Lancet paper by FDA vaccine officials. We find ourselves agreeing with them, but for different reasons. We have an unclear need with unclear motivation, significant safety concerns, poor evidence of sustained boost efficacy and wrong priorities. So while FDA and Pfizer can’t agree about waning efficacy, let’s go to next Slide D we saw recently. Cdc is apparently withholding apparent withholding of data from ACIP prior to recommending the Pfizer vaccine and revealing that the primary driver for approving commonality was to overcome hesitancy through regulatory misdirection. We agree with others that this has become politicized. Next Slide E! Pfizer’s booster evidence today is weak. They are small studies in mostly younger subjects. They are short term. There is no randomized control. There are no clinical outcome data, only serology in inadequate safety, given this is a gene therapy product. Where are the data from the 10000 patient study? Next Slide F If FDA cannot assure us of the safety of two doses, how can they assure us of three? We see strong signals for death myocardial infarction and coagulopathy that need transparent investigation. Next Slide G. We find three potential pools of vaccine associated deaths. Note the second pool among vaccinees next slide h daily cases in Israel increase upon booster rollout compared with the same period last year. Please note the correct rollout is July, the first at the one hundred and thirty number the Israel booster presented a day has matching censoring bias seen in related studies none comparable populations, possible clustering bias, inadequate accounting for early vaccine effects and a short follow up in mainly older people.

Speaker1: [04:25:56] Next Slide I Others show unexplained Israeli deaths, not stepping with booster roll up roll out. This looks like the second cool death we said before in vaccine is rejected by a New England Journal of Medicine in February. Next Slide J. Other safety concerns not voiced in the label are revealed in studies funded offline by NIH for menstrual disorders. Next Slide K and offline by CDC in a disturbing revelation of an urgent need to monitor safety and pregnancy. Put this in the label next. Slide L. Long term safety No cancer studies were performed. Mcdonough said its vaccine was a gene therapy product. Why is the FDA not requiring five to 15 year cancer and other studies per their gene therapy guidance? Next Slide M. We propose the term P Kobs to describe the wide spectrum of events being reported. Next Slide N. We are running out of options. Vaccine hesitancy won’t be solved by bullying or coercion. Address safety. Show convincing booster efficacy. Revisit repurposed repurposed drugs. Next slide. Oh, we reverse the findings of flawed landmark studies that have misguided policy. Journals refuse to correct these defects, and Dr. Rubin seat on this committee is a conflict. Next slide p. This is what has to be done. Thank you very much.

Speaker2: [04:27:16] Thank you, the next speaker is Mr Kermit Cubits.

Speaker1: [04:27:21] Hello, my name is Kermit Cubits. I have reviewed this presentation with other friends from Caltech. I have previously commented to the ACP in December in support of EUA for the Pfizer vaccine. At that time, I said my only conflicts were elderly relatives who needed the vaccine yesterday. Since then, two of those three relatives have received the vaccine. One with rheumatoid arthritis has received a booster with no adverse effects. Next slide. The table of booster pros and cons reasons against boosters are lack of need in view of current efficacy risks. Confidence and global vaccine equity However, I believe there are substantial reasons for boosters, including normal vaccination. Protocol involves a delay of month boosters may limit infectious cases in large gatherings, and global vaccine supply will be from a more conventional vaccines not requiring an uninterrupted cold chain. Next slide balancing booster Pros and cons. Breakthrough infections, although milder, are occurring. Vaccine hesitancy is generally not rationally based. A phased booster approach would allow greater global vaccine availability, and the United States could boost international vaccine supply by funding new lower cost vaccines such as Biological E. Next Slide. Country approaches to boost their vaccination support boosters Canada, Italy, Greece, Britain, China and France. Next slide conclusions. As my friend Chuck Wolf has commented, it’s important to plan for boosters now, even if not everyone will receive a booster. There are three priorities one the unvaccinated two children six to 11 and three boosters for other people. There are outbreaks in schools that have nearly shut down schools in Raleigh, North Carolina. Booster vaccination should be offered beginning with age priorities either 65 and older or 50 and older. Booster vaccination may offset quote social hesitancy of those who fear social interactions with anyone else and are thus isolated. But we should plan for boosters, and the commission should promptly approve booster vaccination while dealing with the other priorities the unvaccinated and school children. Thank you very much for your time.

Speaker2: [04:30:22] Thank you, Mr. Cubits. The next speaker is Dr. Peter Doshi.

Speaker1: [04:30:27] Hi, I’m Peter Doshi, and thanks for the opportunity to speak. Hopefully, you can see my title slide with my financial disclosures for identification purposes. I’m on the faculty of the University of Maryland and an editor at The BMJ. I have no relevant conflicts of interest. Next slide, please, which is labeled Slide A. I want to start off by asking the question Just what problem is this third dose aiming to solve if we have a pandemic of the unvaccinated as a public, health officials have repeatedly stated. Why would a fully vaccinated person need a third dose? Next slide, please. The briefing document suggests the rationale for boosters is waning immunity. But the lowest vaccine efficacy figure mentioned is eighty seven eighty three point seven percent, and last month FDA approved Pfizer’s vaccine, stating that efficacy against symptomatic COVID is ninety one percent. Sure, a third dose might nudge up efficacy numbers, but so too might a fourth dose and the fifth dose. The thing is the two dose regimen. Efficacy numbers are already way higher than the 50 percent bar that FDA set in June last year for an approvable vaccine before contemplating the licensure of those three didn’t. Fda first require evidence that the two dose regimen no longer meets the efficacy bar. The agency just weeks ago said it met its vaccine. Efficacy is now below 50 percent. Let’s see the data. Next slide, please. Let’s discuss safety when discussions about a third dose began in July.

Speaker1: [04:32:00] Cdc Deputy Director Dr. Jay Butler said it was vital to find out if the third dose increased adverse reactions, particularly severe ones. Unfortunately, we’re still in the dark. Pfizer’s booster application reports on just three hundred and twenty nine people with no control data. Now there is a Pfizer ongoing, placebo controlled randomized trial of boosters and ten thousand people not discussed in the briefing document, but this trial is unlikely to satisfactorily characterize booster safety first. The trial is too small and the enrollment limited to healthy participants. Second, we really need to know how safe boosters are in people who already had bad reactions to dose one or two. But such people are obviously less likely to volunteer to participate in this trial, so we won’t have the data to answer the question. Yet if the booster is approved, such people will surely be mandated to receive a third dose. Final slide, please. I’ll end with a question. Last week, three medical licensing boards said that they could revoke doctors medical licenses for providing COVID vaccine misinformation. I’m worried about the chilling effect here. There are clearly many remaining unknowns, and science is all about probing unknowns. But in the present supercharged climate, and I’ll point out that multiple members of this committee are certified by these boards. I want to ask FDA, what is FDA doing to ensure that those advising it are able to speak freely without fear of reprisal? Thank you for your attention.

Speaker2: [04:33:36] Thank you, Dr. Bucci. The next speaker is Dr. Michael Carome.

Speaker1: [04:33:41] Hello. I’m Dr. Michael Carome, director of Public Citizen’s Health Research Group. I have no financial conflicts of interest. Public Citizen supported the Emergency Use Authorization and subsequent approval of the Pfizer-BioNTech COVID 19 vaccine because clinical trial data demonstrated the vaccine was highly effective and generally safe. However, Pfizer and BioNTech have failed to provide sufficient evidence to assess the risk benefit profile of a booster or third dose of their COVID 19 vaccine in individuals age 16 or older in the general population. In particular, there is a lack of data on the effectiveness and its duration of booster vaccination in preventing important COVID 19 related outcomes that is, serious illness resulting in hospitalization or death in individuals age 16 and older in the general population, and safety data for booster vaccination is very limited. Importantly, observational studies indicate that the primary series of the Pfizer BioNTech vaccine deal affords robust protection against severe COVID 19 disease and death in the US. We agree with the following assessment and conclusions offered by Drs. Gruber and Krauss and other experts in their Viewpoint article published in The Lancet this week. Quote Current evidence does not appear to show a need for boosting in the general population in which efficacy against severe disease remains high. The limited supply of COVID 19 vaccines will save the most lives if made available to people who are at appreciable risk of serious disease and have not yet received any vaccine.

Speaker1: [04:35:17] Even if some gain can ultimately be obtained from boosting, it will not outweigh the benefits of providing initial protection to the unvaccinated. If vaccines are deployed where they would do the most good, they would have the they would hasten the end of the pandemic by inhibiting further evolution of variants. End quote. Finally, any move to widespread distribution of COVID 19 vaccine boosters in the US would make it even more ethically imperative that the US government move to ramp up global vaccine manufacturing so that everyone on the planet can be vaccinated. The world currently is suffering an artificial scarcity of high quality COVID 19 vaccines because governments are permitting drug corporations to maintain monopolies, while the U.S. has been planning its booster vaccination campaign. The vast majority of people in low and middle income countries have no access to any COVID 19 vaccine, let alone the highly effective mRNA vaccines. If the U.S. is to proceed with COVID 19 vaccine boosters, we take on a special greater obligation to do everything in our power to get as many vaccine doses as possible as quickly as possible to people in low and middle income countries, and especially to invest immediately in expanded and expanded manufacturing to create an adequate supply to vaccinate the entire world. Thank you for your attention.

Speaker2: [04:36:45] Thank you, Dr. Karim, the next speaker is Kim with. I can with pride. My name is Kim Whittock with Woody Matters, a drug safety organization, started after the death of my husband. I’m also on the board of directors of USA Patient Network and have no conflicts of interest. It seems we are here today to discuss Pfizer’s application to redefine the meaning of fully vaccinated from two to three doses from the beginning of the pandemic. The goalposts keep changing. It makes you wonder if the current vaccination strategy is working when looking at the submitted data is just over three hundred people, with only 12 of them over age sixty five, the highest risk group sufficient enough to warrant approval for boosters. If the FDA approves us, we will take what we’ve learned on just three hundred people and then give it no more like mandate it to hundreds of millions of people. This is beyond preposterous. Well, I’m no vaccinologist. It would seem logical that dose three would have an increase in immune response over two four doses, over three, five, over four and so on. At what point will enough be enough? At the end of the day, can we really vaccinate our way out? While boosters may be good for business, let’s be real. These facts in the MMRDA vaccines were never designed to stop transmission or eradicate the virus. These vaccines are not the same as those being used to eradicate polio or smallpox.

Speaker2: [04:38:11] I have to wonder why we chose to go down the vaccine path first versus focusing on treating those with a COVID diagnosis before it was too late or ended up in the hospital, or worse yet, dead. And also, we haven’t heard any discussion from our national leadership on the role of national or natural immunity plays. Instead, NIH, CDC, FDA and the White House have told Americans that vaccines are superior to our innate immune system and beat out any natural acquired immunity. Let’s take a step back and look at the bigger picture. First, our government incentivized more like bribe the public to get these checks. Then we were told about the possible need for boosters while shaming and blaming the unvaccinated. Now the government is forcing them with vaccine mandates. Is there a reason we want everyone to be vaccinated? Is it so adverse events can’t be distinguished between vaccine and the virus? Or is it to help masquerade the waning effectiveness of vaccines and blame the new variants when it may just be the mutating virus? Escaping leaky vaccines, politics and fear seem to be in the driver’s seat. Facts around data and science can no longer be questioned or openly debated without being discredited or labeled as misinformation. Just look at the what the professional medical societies are collectively doing, threatening doctors with losing their medical license if they deviate from the official protocol or narrative established by CDC and public officials like Dr.

Speaker2: [04:39:38] Fauci. People are not able to talk about their negative experiences without being dismissed, harassed or being called an anti-vaxxer. Just look at what happened to rapper Nicki Minaj this week. People came out and attacked her for telling her family story and voicing an opinion. We are walking a slippery slope when regular people, celebrities, doctors and scientists are silenced or worse yet, censored. Finally, I would be remiss if I failed to mention the hundreds of thousands of people who paid the high price by doing the right thing for the greater good. Their lives have been forever changed. I don’t have enough time to begin to touch on the currently reported safety issues impacting tens of thousands, including children and young adults, and all the future safety issues not yet realized. Ladies and gentlemen, we are part of the largest pharmaceutical experiment ever conducted on humankind. Thank you so much, and I appreciate your deliberation. Thank you, Mr. Tuck. The next speaker, Paul Alexander, we could not connect him, so we’ll try it later. So we’ll move on to the next speaker. Linda. Hi, yes, my name is Linda D. I have no conflicts. I have been a community rep for many. Cedar Antiviral Advisory Committee hearings emphasis on the unvaccinated and international vaccine donations from the U.S. issues are misplaced. Fda does not have the power to increase international vaccine donations or create policies to promote increased vaccinations at home or abroad.

Speaker1: [04:41:19] We are here because there are differing

Speaker2: [04:41:21] Opinions on whether there is sufficient data

Speaker1: [04:41:24] To support licensure of a third

Speaker2: [04:41:26] Dose of B.A., one six to be two for people 16 and older. The sponsor is relying on data from a

Speaker1: [04:41:32] Number of sources that show

Speaker2: [04:41:33] Activity wings between six and eight months after the second dose. Data also suggests that

Speaker1: [04:41:39] Breakthrough cases were caused by waning effectiveness, not the Delta variant. Sponsors also conducted a

Speaker2: [04:41:46] Substudy within their registration study that eventually established safety in 306 participants 18 to fifty five. I think the Israeli safety data was helpful, even if it was in mostly older people. The third, 16 to be two dose, was found

Speaker1: [04:42:02] To be as well-tolerated as

Speaker2: [04:42:04] The second dose and elicited responses to wild type virus not inferior to the

Speaker1: [04:42:09] Second dose response.

Speaker2: [04:42:11] The sponsor believes the FDA development guidance permits these data to be extrapolated to include individuals 16 and 17, as

Speaker1: [04:42:19] Well as people over 55. As the sponsor provided

Speaker2: [04:42:23] Sufficient data from

Speaker1: [04:42:24] Adequate clinical trials to justify their request for licensure, reasonable people strongly disagree, as is evidenced by

Speaker2: [04:42:31] The different positions taken in recent New York, New York, New England journal and Lancet articles. I’ve been an

Speaker1: [04:42:39] Aids activist for some thirty

Speaker2: [04:42:40] Five years. I understand only too well the need for

Speaker1: [04:42:44] Access, but I

Speaker2: [04:42:45] Have learned the importance

Speaker1: [04:42:47] Of evidence based medicine the hard way we all rely on the FDA to ensure that interventions are safe and effective. If you do not believe that data are sufficient to justify full approval, please consider the innovative practical solution of accelerated accelerated approval, which we’ve used in the HIV arena for many years, which also permits and is also permitted in some circumstances for vaccines. According to the General Principles for the Development of Vaccines to protect against global infectious diseases guidance, even though this guidance addresses international issues, accelerated approval will permit access and requires the sponsor to conduct or complete at least one adequate well-controlled conformational trial before full approval is granted. This option should be considered as it provides the best solution for both the access

Speaker2: [04:43:40] And additional data

Speaker1: [04:43:41] Dilemma questions presented

Speaker2: [04:43:43] Here. Thank you. Thank you, must be the next speaker is Dr Meg Seymour. Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Meg Seymour, a senior fellow at the center. We analyze scientific data to provide objective health information to patients, health professionals and policymakers. We do not accept funding from drug or medical device companies, so I have no conflicts of interest that you’re asked to discuss whether the data presented support the safety and effectiveness of a booster dose of the COVID 19 vaccine and, if so, for whom. I will focus on the safety simple Typekit simple data discussed in the FDA briefing document. The total safety sample is very small only three hundred and twenty nine patients. Even more important, the sample is not representative of the people who will watch the booster. There are safety data on only 12 patients aged 65 and over, even though people over sixty five are considered a priority group for a booster due to weaker immunity. 12 people over sixty five is much too small to draw conclusions about safety and is obviously not large enough to have any confidence in the claim that adverse events from booster doses are less common in those 65 and over. In addition, there are zero patients ages 16 and 17, and safety for this population is being extrapolated based on safety for those 18 and over. Data should be collected for any population that the boosters would be approved for, rather than extrapolating pediatric safety from adult safety data. Unfortunately, the size of the sample is not the only problem with the safety data.

Speaker2: [04:45:22] A median of two point six months is not enough time for assessing the safety of the booster. In addition, we agree with the FDA that is unknown whether there will be an increased risk of myocarditis, pericarditis or other adverse reactions after a booster dose. We all know that COVID can be deadly, but the efficacy of a booster compared to no booster is not well established since the placebo control group is missing. In addition to uncontrolled variables that could influence the diagnosis of COVID. For those with boosters and those vaccinated without boosters, assurance that the benefits outweigh the risk should be gathered before approving booster vaccines. Otherwise, the potential risks may become obvious only after large numbers of the general population have received boosters and the benefits of boosters may be much less than expected. Fda decisions should be based on proof of the safety and effectiveness of a medical product before the product is widely distributed. To approve a booster without adequate safety or efficacy data undermines the integrity of the FDA. It is unfortunate that the White House announced the need for an availability of boosters prior to FDA’s assessment of the data. We know numerous people who have already received booster doses by merely asking their doctors or local pharmacies for a third dose. We all want to get the COVID 19 pandemic under control and protect as many people as possible, which is exactly why it is so important to carefully and scientifically assess the safety and effectiveness of COVID 19 booster vaccines. The data provided for this meeting do not allow us to draw confident conclusions, and a premature decision will make it impossible to do the research necessary to draw scientific conclusions.

Speaker2: [04:46:59] Thank you. Thank you, Dr. Seymour. The next speaker is this Chaplain Cameron. Good afternoon, my name is Kathleen Cameron, and I’m a pharmacist, public health care professional and senior director of the Center for Healthy Aging at the National Council on Aging, or N.C.A.A. I have no conflicts to declare. I appreciate the opportunity to provide comments today on behalf of NCAA older adults, their family members and caregivers and organizations that serve them. And COA is a respected national leader and trusted partner to help people age 60 plus live with health and financial security. We believe every person deserves to age well. Vaccines are a vital part of aging well, and NCAA is committed to ensuring older adults have accurate and timely information about them to avoid confusion when making decisions. We also advocate for access to approve vaccines using public benefits for which older adults are entitled. Older adults have been disproportionately impacted by the coronavirus pandemic. Those 65 and over represent 13 percent of COVID 19 cases, yet account for nearly 80 percent of the deaths. Covid 19 also is having a disproportionate impact on communities of color who have always had to face health disparities, such as higher rates of chronic conditions, income inequality and inadequate access to quality health care. The older adults in these communities have historically fared even worse. Further, we now know that older vaccinated people are most vulnerable to illness and hospitalization after a breakthrough infection. As the CDC recently reported, this may be due in part to waning immunity at its most significant and people age 65 and who are at greatest risk for hospitalization and death from COVID 19.

Speaker2: [04:48:49] And VOA commends super-PACs diligent and rigorous work as our country continues to face the evolving COVID 19 pandemic. Every day brings new knowledge about the virus, the effectiveness of COVID 19 vaccines and the potential need for vaccine boosters, as discussed during this meeting today. The impact of COVID 19 pandemic on older adults has been tremendous, and we want to do all we can to protect older adults, as well as health care and long term care workers as we continue to learn more about the long term effectiveness of COVID 19 vaccines. We are counting on the FDA to conduct gold standard reviews and to develop appropriate recommendations if as you have done so well for many years. We ask that you carefully examine all available data on safety and effectiveness of COVID 19 vaccines over time among various population groups, especially older adults who are most vulnerable and make your decision about booster shots as expeditiously as possible. Thank you again for the opportunity to provide comments, and we welcome further discussion and involvement as decisions are being made. Thank you. Thank you so much. The next speaker is Miss Beth Battaglio. Hi, thank you for allowing me time today to present on behalf of helping women. I’m Beth Battelino, president and CEO of Helping Women. We were founded in Nineteen Eighty Eight and Healthy Women is the leading nonprofit women’s health information source with the mission of educating women ages thirty five to sixty four years of age to make informed choices. Throughout the years, we have

Speaker1: [04:50:30] Informed consumers

Speaker2: [04:50:31] And health care providers about the advances in women’s health, from the latest information on diseases and conditions to various milestones pertaining to access to care. We ensure that women have accurate, balanced, evidence based information so that they can make informed decisions in partnerships with their health care providers. We also educate our audience regarding innovations in research and science, as well as changes in policy that affects women’s access to treatment and care so that women are prepared to self advocate for better health outcomes. We know the importance of the process and as we continue to educate our audience that the COVID 19 vaccine, like other drugs, are only approved following an established gold standard review process. Covid 19 vaccine development solves the FDA review process that includes research, multi-stage clinical trials, robust regulatory review and approvals, and ongoing safety monitoring. We also know that data on booster shots for all three vaccines continues to be studied, and we anticipate more information from the FDA and the CDC very soon. And healthy women will be ready to share out medically vetted, science based research information on the booster shot with our audience of over one point five million women. Thank you. Thank you, Mr Battellino. The next speaker is Brian Cultic. Sorry, if I didn’t say your name, right?

Speaker1: [04:52:14] Thank you for the opportunity for health advocates to provide direct feedback. I have no financial conflicts to disclose. I’m Brian Hokage, executive director of Health HIV, a national nonprofit organization based in Washington, D.C.. We advocate for communities impacted and affected by HIV. Today, I’m speaking to you as a health services advocate in an effort to get us all one step ahead of breakthrough infections among fully vaccinated people. While data clearly show that COVID 19 vaccines are highly effective against current strains. Preliminary data also indicate that protection against infection overall appears to be waning, and that concerns us because it puts the populations we serve at even further risk for infection. Based on the point in time immunity of the general population. Covid 19 is a serious and potentially fatal and life threatening virus, not just for those most at risk like the immunocompromised and immunosuppressed, but for everyday Americans, especially front facing service sector, minority communities and marginalized populations and geographies with the highest viral load concentration. Often a result of vaccine hesitancy or opposition. Not surprisingly, breakthrough infections appear to be more common among those with weakened immune systems. And according to data presented at a CDC Advisory Committee on Immunization Practices, immunocompromised patients represent 44 percent of hospitalized COVID 19 breakthrough cases, even though they only make up about two point seven percent of the total population as part of this data lookback.

Speaker1: [04:53:51] The FDA evaluated the science on the use of a third dose of the Pfizer or Moderna vaccines in people with compromised immune systems, and they rightly determined that a third vaccine dose may protect them and others around them. In fact, they interpreted the findings to state that targeted policies like the booster shot being proposed today need to evolve as both science and risk evolve. It confirms that people with underlying conditions like advanced HIV cancer, organ transplant hemodialysis and those on immunosuppressive therapies are seen as a significant risk for poor outcomes from COVID 19. In that sense, it highlights the need for our populations to stay as healthy as possible, but it also depends on the health of those around us. Fortunately, the vast majority of breakthrough infections are typically mild, but we are discussing the rationale for a booster shot in efforts to prevent the clock from winding backwards. We encourage the advisory committee to recommend booster shots for people aged 16 and above, just as it did to protect people living with HIV. Thank you.

Speaker2: [04:55:02] We thank you so much. The next speaker is Dr. Paul Alexander.

Speaker1: [04:55:08] All right, thank you very much. I got cut off earlier, but thanks for putting me back on that good work by you guys. Look, I wanted to get into this by saying my background is in evidence based medicine clinical epidemiologist, and I’m very interested in the safety and efficacy of the vaccine. I’m following some very good presentations so far. Look, we want these vaccines to work as Americans and as global population. So I think the message has to be we not come into the FDA, we’re not coming at the CDC trying to raise issues and just. Can you hear me? Yes, we can hear you. Yes. It’s not that we want to raise issues and concerns, but here’s the issue we want it to work. But when we look at your surveillance, when we look at the surveillance coming out of the bears right now, CDC, it captures one percent of one to 10 percent by our study of the published literature of the adverse events. And that is very suboptimal because it doesn’t give a proper capture of the burden. So we really do not know what the adverse events and the deaths are. So we want proper safety monitoring boards. We want proper ethics committees following up on these vaccines. We are calling for critical event committees that we do not seem to know whether they exist. So we want the FDA to get on top of this vaccine developers and the CDC and put this in place for the safety of Americans.

Speaker1: [04:56:38] And it’s a simple issue. You are giving us vaccines and this is what we have been clamoring for. If you have an investigation of a vaccine with 1000 samples, you put five hundred in each arm and you follow that for one year versus you have another study of 100000 people. And you follow that for two months and see if the events that we are looking for to see if these signals happens at about five to six months, how could that larger sample detect them? And that’s the issue. We are calling for longer term studies, larger sample size. But longer term, we need the medium and long term studies to best assess the safety and efficacy, particularly safety, particularly when you’re talking about putting these vaccines in our children’s arms. We currently do not have the safety data. We absolutely do not. And for anyone at the CDC, anyone at the NIH and anyone at the FDA to claim so, that is being disingenuous to the public. Now I wanted to end by saying this. When we look, I looked at a study this morning by chance on testicular infection, poursuivi SARS-CoV-2 virus. That means that there is an issue and we are extrapolating, we extrapolating based on the Japanese data that looked at the lipid nanoparticles in the marinade that were accumulating in the tissue in the rat model. Yes, it’s a rat model, but we have to extrapolate to humans that showed that the lipid nanoparticle, the constituency of the vaccine is accumulating in the ovaries, in the testes, in the spleen, in the adrenals, etc.

Speaker1: [04:58:19] So when somebody like Nicki Minaj, I have to invoke, this makes that statement. That’s not a joke. People want to make this a joke and parody it, etc. But this is a very, very serious consideration because we even have animal data that shows us that there’s a drop in fertility in the animal model. So we need this properly investigated. The public needs this answer properly. And I want to end by saying this under no condition, none zero based. Any evidence they must children be indicated for these vaccines? There is no risk to children, nor statistically zero in terms of spreading. And in terms of getting serious illness or dying from this. Dr. Marty Makary at Johns Hopkins. They looked at all of data. Hello. Yes. We’re out of time, sir. Okay, thank you. You can wrap it up. Yes. We looked at the we looked at the children in America that have died and we found that save one. Most of these children had at least one severe illness. So the reality is COVID is not a life ending, life threatening situation for children right now. The CDC and the NIH have not prosecuted the case as to why these children should be vaccinated, period. I say, do not do this and I beg your consideration. Thank you.

Speaker2: [04:59:41] Thank you. This time we will conclude the open public hearing, and then I will hand over the meeting to Dr. Monto, the chase Typekit the man to take it away. I think we are getting to a break now. Would you announce the return timepiece?

Speaker1: [05:00:08] I think we now have a ten minute break, so we’re our busy workers who’ve been. Handling the open public hearing, you have a little break for themselves, and we will reconvene in 10 minutes, 10 minutes from now. I. Somebody else stay muted, please make sure you’re muted. All right, welcome back to our 67th meeting of the Vaccines or related Biological Products Advisory Committee meeting. Dr. Monto, let’s take it away for our afternoon portion. Thank you very much, Mike. This is going to be an open Q&A session involving all the speakers we had present already. When you raise your hand and ask a question, please specify who you would like to ask the question of. But we don’t have a total free for all. Dr. Gruber has indicated that she does have a question she wants to raise, so I’ll start with her.

Speaker2: [05:11:00] Yeah. Hi, this is Molly, and I turn it over

Speaker1: [05:11:02] To Dr. Phil Krauss for the question. Um, yes, hi, this is actually a question for Pfizer, and of course, one of the issues in this is that much of the data that’s been presented is being discussed today is not peer reviewed and has not been reviewed by FDA. And this includes the study of from Kaiser that was presented by Dr. Bill Gruber. And so what I’m hoping is to ask the question about that study so that we can better understand some of the conclusions that come from it. And so what I’ve done here is I’ve taken this slide, which is being presented Appendix five or Appendix Table five. And this this is the appendix from that study from the pre-print of that study, which shows the main data in the study. And what you can see here is in five a to the left, you have unvaccinated people into the right, you have fully vaccinated people. And just to make this easy, I’m focusing on people greater than or equal to 65 years of age. And you can see, you know, among the unvaccinated, there were seventeen thousand two hundred and seventy eight cases in one hundred and sixty eight thousand one hundred and forty three person years, which then if you do the math, you can see down here to about one tenth of a case per person zero point one hundred three cases per person year.

Speaker1: [05:12:32] If you look to the right here, the far right, if you look at the fully vaccinated people, you have five hundred and ninety four cases among eighty six thousand eight hundred and six person years. And here that’s a rate of zero point zero zero six eight cases per person year. If you take these numbers and put them together, you get an efficacy of ninety three point three percent in this study overall in people who are greater or equal to sixty five years of age. But of course, what these studies are done, they involve fairly complicated models. In this case, it’s a Cox model which incorporates a lot of inputs. And one of the questions always, as explained by Dr. Stern, is that you have to make sure that the model is actually giving you the correct results because these models are complex. My question for Dr. Gruber and Pfizer is, is that in a situation where the total cases tell us that the vaccine had ninety three point three percent efficacy, according to the data in this table. Why is it this model is telling us that the efficacy is either fifty eight percent or sixty one percent? Oh. Ok. Dr. Bill Gruber, we’ve got to Gruber’s there. And here. Make sure you make sure you are muted, sir. Onuachu. Here we go. There you go.

Speaker4: [05:14:07] There we go. I actually joined by Donna Boyce in the same room because we had a technical issue here. I think this question to be better. Louise Gallagher and his associates, and they’ve been in close communication with Kaiser.

Speaker1: [05:14:25] So let’s hold on a second. Dr. Gruber. Dr. Gruber. Hold on one second. I see you have you have multiple feeds going on over there. So I want to make sure we have clear audio for you. So let’s just clean up your audio, please.

Speaker3: [05:14:40] She did not,

Speaker1: [05:14:45] And I don’t think it’s Dr. Bill Gruber who’s going to answer right now.

Speaker4: [05:14:50] Right, right, that’s correct. I was just saying, Can you hear me now? I told her to tell me that I should speak.

Speaker1: [05:15:01] We can hear you, but it’s a lot of background noise, but go ahead.

Speaker4: [05:15:07] And so I was going to say, I think there’s a question for. And his associates as they’ve been closely in communication with Kaiser and say about their data. So Dr. Deodhar.

Speaker3: [05:15:32] So for the question and the detailed analysis of the supplementary supplemental paper, as was pointed out in Dr. Stern’s presentation for the critical analysis, is take into account the time and included in the cost models. So this was something that you have to adjust for calendar time, the Cox models. You get a different result than you would if you didn’t adjust for that. But it’s critical to include that because clearly there’s a there’s a relationship between these traits as time progresses in the pandemic and vaccine uptake. So those results that you’re looking at, they’re based on crude data don’t account for underlying calendar time, which is a critical element to include in the analysis and was included in the results that you saw in the paper.

Speaker1: [05:16:30] A total of. But but of course, if you have this huge difference in the raw numbers in this accounting for calendar time, how can you be sure that you counted properly for calendar time? But let’s look here, for instance, under the second dose, partially vaccinated less than seven days after the second dose. Also in people over 65 years of age where you are reporting, according to the model, sixty four percent efficacy. And this is before the second dose really could have had any effect. But then after the second dose, you’re reporting fifty eight to sixty one percent efficacy. So according to your model, it looks like people actually got worse after the second dose or that the second dose really didn’t do anything. Is that really what what, what you’re what you’re saying? So part of this, of course, is is the difficulty of looking at this kind of data without having the chance for FDA to review it or allowing for pure this kind of data to go through the peer review process. And what you heard, of course, is how much. And Dr. Gruber’s presentation, Dr. Bill Gruber’s presentation, how much Pfizer is actually relying on the data from the study, which, as I understand it, they also co-sponsored in reaching some of the conclusions in their study. And so I guess maybe there are some answers to these questions, but I still do not understand how it’s possible that you can have a study in which the total efficacy is ninety three point three percent and somehow that’s accounting for time and coming up with an efficacy of between fifty eight and sixty one percent. Because there’s nothing about this that says we’re accounting for time. This is just the total efficacy over this period of time from December 14th to August eight. So again, this just points up the complexity of these models and the importance of these data being carefully reviewed and I will stop there. Ok.

Speaker3: [05:18:32] Dr. MacLachlan, could you respond to that? Yeah. Absolutely. I think it’s critical to include calendar time models, and this is very standard way to go, just so that we appreciate the complexity of these models. The thing that’s important to note is that

Speaker1: [05:18:49] These hold on a second, hold on a second. Ok, so here’s what you have to do. So first off, and I want to make sure everybody can hear this and because we have using studios and stuff like that. So number one, I need to make sure if you’re not speaking, you need to be muted and to make sure if you are, if you are listening in, do not have any audio through your own personal computers, it is all through your phone. So that’s number one. Also at the studio over at Pfizer, please make sure all other mikes

Speaker2: [05:19:16] Are

Speaker1: [05:19:16] Muted when you have another mic open. That’ll help out a lot. All right. Take it away, Pfizer. Let’s hope that fixes that.

Speaker3: [05:19:26] Ok. Just just a quick response. This is a very standard way of doing Cox models, doing this model where you’re evaluating the vaccine rollout, so it’s a very

Speaker1: [05:19:40] Complex thing either. I apologize. Pfizer, you have again, you have multiple you’re in our room multiple times, but you have three mikes that are picking up audio at the same time. So we’re seeing it on our end. So I just want to make sure people can hear you. So let’s just take a quick second here. We’re going to take a quick, unexpected break. Go ahead and kill our feed for a moment. All right, thank you for that unexpected, quick little technical. We just want to make sure everybody could hear. And and as well as our members and voting members as well. So, Dr. Monto, are you there? I am here. All right, I’m going to hand it back to you. Ok, I think we can summarize that there were differences in the models. And we’ll let the statisticians work this out. There are often these kinds of issues when you’re working with complex models. I apologize to the voting members for cutting into their time with this discussion. Our next call on Dr. Corella. That’s correct. Thank you. Thank you, Arnold. This is a question for the for the Pfizer team. And I think it’s pretty clear that based on the dosing interval between your two, between your two primary doses, that while you get a nice boost in terms of antibody response, you really take a big hit in terms of durability.

Speaker1: [05:22:22] That’s very clear from the available literature on various prime boost strategies that have been done both in animals and in humans. So I think the the waning of immunity should have been anticipated. What I’m concerned with is that while it’s pretty obvious that in the high risk groups for severe COVID tend to be individuals such as the immunocompromised, the elderly, obese diabetics, all of those tend to have diminished or impaired cellular immune responses, which is the exact basis of good cellular immune responses is what gives you the durability. So it’s a little disappointing that there’s been very little reporting of the cellular immune responses in an entire focus on the the the the neutralizing and sera, which clearly for that population at high risk is absolutely essential. But for the broad population in terms of their protection, which seems to be holding up well over time, should be because of adequate cellular immune responses. But we have no indication of that. So it’s unclear that everyone needs to be boosted other than a subset of the population that clearly would be at high risk for serious disease. So I’m curious as to what evidence you have in terms of cellular immune responses and how does that look in terms of durability for the average person who’s been vaccinated?

Speaker3: [05:23:54] Thank you for the question, I will ask Dr. Gruber to comment on this immunity, and then I’ll also ask Dr. Phil Dorman to comment. So first offered to Bill. Yeah, so thanks, Dr. Cuadrilla, for the question. I think we have to sort of deal with two aspects. One is the practical aspect about why we’re here today, and that is, of course, that we’re looking to try to improve on protection that is waning over time. And obviously, the marker that we’ve used to look at that is neutralization response, which has been a good marker, albeit there are other things that accompany that type of immune response that are likely important. And so I think again, our goal here is to prove that the vaccine was safe and effective, which I believe we’ve done, and we’ve obviously met the NONINFERIORITY criteria. And I think there’s every reason to believe, given the protection seen after the first dose with the neutralizing antibody and whatever came along with it, that there should be an expectation after the third dose that we continue to augment those responses. Or at least there are no worse than they were after the the second dose. And you’re beginning to see, of course, evidence of that from the Israeli study. So I agree that it’s important to understand cell mediated immune response. But I think the key message is we know protection wanes. We know a vaccine dose seems to be based on the Israeli experience seemed to restore that protection. We know from our own data that we’re getting three fold higher GMT is that likely are associated with good protection. But let me turn this to Phil just to comment on the nature of CMI. Sure, we have data, so after the initial doses.

Speaker3: [05:25:42] Will we see strong with C-4 positive and create positive responses that are as high or even higher in some cases that are seen after natural infection? And there may be a slide that demonstrate that we have samples for later typhoid. We’re not yet have those data reinforce what Dr. Gruber said that ultimately, regardless of the quality of protection that antibodies are granted, it is the protection that matters. So ultimately, the questions of mechanism are interesting. But it is, of course, the actual efficacy or effectiveness that we observe. That is the key outcome. Thank you. You keep it. Yeah. I think Dr. Jansen may have wanted to add a comment, I don’t know, Dr. Jansen, if you’re connected, but please, can you hear me? Yes, I can. Thank you. Yeah, thanks. I’d like to make two comments. Number one, to answer the question a little bit more directly. That was just us. We have also very good evidence of memory B and T cell responses, which one would assume that if one gives a booster will again not be diminished. But if anything sustained or go up, that’s number one. And secondly, I think T-cell responses are really not important when we look at infection. It is clear that neutralizing antibodies are responsible to prevent the infection. And what we have seen repeatedly that we see an increase in infection over time. We also see an increase in disease over time. Infection usually is a an earlier indicator before we actually see the disease. What’s important to prevent disease is both, I would think, the neutralizing antibodies as well as T cells. But as I mentioned earlier, we have very, very strong as published B in T-cell with memory responses after immunization with BNT162b2. Thank you.

Speaker1: [05:27:53] Ok, let’s move on, please. Dr. Meissner. You’re muted. Still muted. By now, Cody. Dr. Meissner. Dr. Miser, you have your own personal phone muted. Go ahead and look at your personal phone. Hello. There you go. Yep. Yes, we can. Ok. My apologies. And thank you, Dr. Monto, and thanks, Mike, for helping me out here. I would like to echo the comments that Dr. Monto gave this morning, acknowledging Dr. Miriam Gruber’s remarkable leadership and contributions to Sieber, and that also applies to Dr. Phil Krauss. The question that I have is what we’ve learned from influenza, where this variation in the neuraminidase and hemagglutinin antigens on an annual basis, we change the vaccine. And so for a for a booster strain. Shouldn’t we try and match the circulating variant as much as we can? That is right now predominantly the the Delta strain. So why did you decide? Why didn’t Pfizer decide to select BMT one six to be two? And this is a question for Dr. Bill Gruber and. Because a new variant, when and if it emerges, will almost certainly be a progeny of the Delta variant. And don’t we want to match the new strains that are most likely to circulate as closely as possible? Thank you.

Speaker3: [05:30:11] Yeah, so thanks, Dr. Meissner, for your question. I think as you realize within the blue field, blue is very different, right? We actually have major antigenic changes, which we can show immunologically escape response. If someone can bring up the slide that I showed during the presentation that shows the immune responses across the various variants, we see something very different here, both in terms of the immune response as well as what we have experienced in terms of protection against hearing. And there we go. If we can bring up slide one, please on the screen. So again, remember that.

Speaker1: [05:31:04] Yeah, but yeah, so this is going to. But sorry, go ahead.

Speaker3: [05:31:10] So I’m going to say that the variants that have been added and we also, you know, the only state that is looking promising for you as well. We’ve not seen a variant that escapes under the. And particular circumstances, the Beetham. I speak very you at least have quite a bit of a neutralizing titer one nine also. Most of the group had a zero non-white in South Africa. In terms of protection against that, so that means perhaps sometime in future. There may be a that states right now there is not one. The obviously. She has a very expensive time, the effort seems to be a potential for a seat. Then I. Very interesting pivot directly to bring that bearing on board, but it’s. That is singing this and encouraging of what we’ve seen. Injury in the city of Delta, which implies aren’t. Do you worry about that? After you’ve restored when you received a booster on 95 percent, you know, we have looked as I mentioned in the study at Beta as as a surrogate so that we would be able to pivot potentially. In the future without having to do additional clinical trial, so we could rapidly react, but for now, there’s no evidence of escape for the variants we’ve looked at. The efficacy data from South Africa suggests even when it’s a little bit lower, we’re protective and the information from Israel shows ninety five percent restoration of protection after a booster. So I think the flu story is different.

Speaker1: [05:32:58] Yes, but. There, I think there are certain similarities, Bill, in the sense, in your trial, I know that six patients subjects of the three hundred and twelve received a prototype beta vaccine. And but my point still arises the new variants that are. Are very likely to emerge will most likely come from the Delta strain, and they will have either increased capacity for transmission and hopefully not increased capacity for disease, but it’s hard to predict at this stage. And don’t you want to introduce a new vaccine that’s going to be most similar to the ones that? That are likely to emerge in the future. Cody, I’m going to park the answer to that question. We all know what the what the what the answer would we would like to see, but we’ve got a question in front of us right now. So please, let’s move on. I just want to remind the committee that the people and our colleagues in Israel are staying up late to answer our questions. And if there are questions for them, I would like to give that priority. So I can’t see because there’s a share of my screen in front of the. Ok, now I can see Dr Hildreth. Do you think? Did. Part. Ok, we’re here. Thank you, Dr. Monto, can you hear me now? Yes. Ok. My question is from a team from Pfizer or from Israel, for that matter. It was not unexpected that the antibody levels would wane after the vaccinations. But has anyone attempted to correlate a certain titer with protection because if we knew the minimum titer needed for protection? That would be a great way for us to monitor whether or not we really needed booster shots. So that’s something someone in the team can speak to. Please. Anybody from Israel want to talk about the data from from Sheba Medical Center. I can’t hear Dr. Monto. I can’t, either.

Speaker2: [05:35:51] Yeah. I have to unmute first. So, yes, we are. We’re doing a research with Sheba Medical Center that involves families of confirmed cases, so we have taken confirmed cases and registered their family members who were vaccinated into this research that follows them for 10 days and then try to establish whether they were confirmed on the first PCR being enrolled into the study. And then on day 10 and at the same time upon enrollment, we’re taking antibodies, neutralizing antibodies and cell mediated immunity levels to

Speaker1: [05:36:32] Try to find out the correlation of protection.

Speaker2: [05:36:35] Hopefully, we’ll have that results in a month.

Speaker1: [05:36:39] Ok, well, that would be very. The bottom line is we we do not have a car look right now, which is part of the issue. Ok, thank you, doctor.

Speaker3: [05:36:50] Dr. Monto. I’m sorry to interrupt. What is it permitted for Dr. Janssen? She’d like to just comment on that last point. Ok.

Speaker1: [05:37:00] Ok, quick, quickly, please. And without a and I hope we can hear her. It’s a chronic problem, isn’t it?

Speaker3: [05:37:07] Yeah, she’s in Berlin and seems to have a better connection all the way from there than we do. So hopefully. No, go ahead. I’m kidding. I just wanted to say that we actually looked in our breakthrough cases in our placebo controlled phase three study and have compared the antibody titers where we had the opportunity in individuals that got disease versus the ones that did. And we were also unable to really come up with a with a antibody threshold. So I think there’s probably a much more complex story and not easily just addressed with neutralizing antibodies. Thank you. Thank you.

Speaker1: [05:37:45] That sounds reasonable. Dr Chatterjee.

Speaker2: [05:37:58] Yes. Thank you, Dr. Monto. My question actually is for Dr Oliver, if she’s still here or anyone on the on the epidemiology side. So it appears that what’s happening with regard to breakthrough infections among the vaccinated is different in the U.S. compared to what’s happening in Israel. The Delta variant has been, I think, prominent during the same period of time in both countries. And yet the outcomes seem to be quite different. So could you shed some light on that, Dr. Oliver? Yes, I think so, I don’t know that I will have kind of the definitive answer, I can give a couple of thoughts. First of all, I would note that the definition of severe disease that Israel has used is quite different than what we’ve used in the U.S. So they have said that an elevated respiratory rate or an oxygen level less than ninety four percent just severe disease, whereas CDC and the studies have primarily been know, clinical hospitalization, ICU or death. So that is that is one aspect when we try to compare point estimates. I think another thing that is likely relative or importance is just the size of the country and the heterogeneity of the pandemic across the U.S. when we look and combine data across 50 states, these broad platforms that it’s likely just very heterogeneous compared to to a smaller country, as well as the way the vaccine has rolled out, that they achieved high vaccine coverage very quickly.

Speaker2: [05:39:51] Whereas, you know, in the U.S., we’ve had a little bit more of a rolling kind of gradual uptick. So, you know, I think there’s a variety of factors that could play into it, but those are the first three that come to mind. And we I will also say they kind of exclusively have used Pfizer. We have a variety. We’ve used Pfizer, Moderna and JNJ. And so it could be that the heterogeneity of vaccines used as well could could be a somewhat of a role in what the U.S. is seeing. Thank you. I think it’s important to note that the difference is quite striking because as from CDC data that we’re all looking at, it appears that only two percent of the hospitalizations, if you’re just looking at hospitalization data are among vaccinated individuals in the U.S. has been true for many weeks now, whereas that is not true. According to the data that was shared with us from Israel, which seemed to be only 40 percent of their hospitalizations were among

Speaker1: [05:40:56] Those who are unvaccinated.

Speaker2: [05:40:57] So I just like to point that out to the committee. Thank you.

Speaker1: [05:41:02] So I think there’s a difference in the percent in the country that are vaccinated, which is. Which may may be a factor there. Uh-huh. Dr. Pearlman. You know, we know good. Yes, my doctor. Yeah, if I may just if I may just add one sentence. I think the proportion in Israel, as Sharon presented most of the elderly population in Israel, has been vaccinated very early. Almost all of it around the month of January and February. And I think that is also a difference that most of the population now are about six or seven months post the vaccinations. Thank you, Dr. Pearlman. Yes. So I wanted to ask a question, is the continuation actually of these questions? So in Israel, there’s both the question of the high vaccination rate that was just pointed out and also the fact that in the months and the last one or two months, there’s been huge gatherings within Israel, whether over the High Holidays or other venues. And when you do your analyses and try to compare the effects of vaccination on boosting, certainly the data show the boosting is very effective. But when you put these other factors in, how strong are the data if you subtract these other issues, how strong are the data supporting really a booster immunization? Ok, so maybe I’ll begin and maybe Dr. Price would continue, so the analysis that we did was either in the month of July or in the month of August. Those gatherings you referred to in the High Holy Days, we really are in that season now during September. So all of those all of those studies that I’ve shown you are actually still in the month prior to the gatherings and the High Holidays.

Speaker3: [05:43:18] Dr. Monto, this is Bill Gruber again. Could I ask your indulgence to have Louis Giridhar

Speaker1: [05:43:25] Comment on this, obviously,

Speaker3: [05:43:26] In part because we didn’t get a chance to my running over time to speak to our interpretation, so Dr. Joe. So.

Speaker1: [05:43:34] Thank you very. We didn’t have to hear you twice, but we have feedback again. Really?

Speaker3: [05:43:42] So you kind of hear me, do you hear me with an echo,

Speaker1: [05:43:46] With an Echo?

Speaker3: [05:43:51] We apologize for the technical.

Speaker1: [05:43:53] We don’t have any microphones. Technically, we don’t have any. Why don’t we move on and then when we get a chance, we’ll go back to you because it’s a real it’s a real problem. Amanda Cohen Dr. Cohen.

Speaker2: [05:44:22] Thank you. Can you hear me? Yes, perfectly. Brit, I have a question specifically for our colleagues in Israel and its two part one is whether or not in the breakthrough cases that you have seen in particular in young adults, if you’ve seen reports of myocarditis, long COVID or MIS-C in those young adults who had two doses but had breakthrough disease, or were most of those cases asymptomatic or mildly symptomatic with no long term sequelae? And then second, can you explain? I think we’ve got to part of this answer in the last question, but why is it that if you are not below one in recent weeks, you’ve started to actually you’re at your highest rates right now and your test positivity rate is increasing, at least from the data that you have online from the last couple of weeks. I’ll start with with the second question. And that goes to the High Holidays and this very weird period. And in addition, the first of

Speaker1: [05:45:40] September when we opened schools despite of the increase of the fourth

Speaker2: [05:45:45] Wave. So I think the combination of these things in September are making our numbers a bit funny and not really reliable. But we do know and we

Speaker1: [05:45:57] Are aware of the fact that we’re in the fourth

Speaker2: [05:45:59] Wave. We are not at all at the end of it. We are still with high numbers, with six to seven percent positivity in test results. And I think once the holidays settle down, we’ll see the true effect of where we are. But until the high holidays we saw as Ron showed a continuous drop in the reproductive number and and stabilization in the active, severe and critically ill patients. So we definitely feel

Speaker1: [05:46:30] The booster effect, but we’re

Speaker2: [05:46:32] Not over the fourth wave yet. And you need to remind me the first question, sorry. So I think it was just really the two in in young adults who had two doses, have you had any? Reports of breakthrough cases of myocarditis or long COVID or miss. That we had cases of myocarditis among young adults, as I’ve shown you before, it was mainly with males. And that was the signal.

Speaker1: [05:47:09] The very clear signal was after the

Speaker2: [05:47:12] Four in the four fifth day after the second dose.

Speaker1: [05:47:15] So there was

Speaker2: [05:47:16] Like an epidemic curve after this second can. Ninety five percent of them were not severe water discharge after a

Speaker1: [05:47:23] Few days in the hospital.

Speaker2: [05:47:25] And we have seen in this fourth

Speaker1: [05:47:28] Wave

Speaker2: [05:47:30] Hospitalizations of people who are younger than 60 years old, some of them with mortality who were doubly vaccinated and did not receive yet the third dose. So among the mortality, one of the speakers in the public hearing actually refer to us having a high rate of mortality in Israel, about 1000 people dying in this fourth wave. And that is true, but 40 percent of them are unvaccinated and 54 percent of them received two doses and did not have the chance to receive the third dose yet. And the minority are those who were in between vaccinations or in the process of being vaccinated, and a really minority received the third dose and died from corona. So it is clear that in our fourth wave, the vaccinated, doubly vaccinated individuals play a major role not just in confirmed cases, but also in hospitalized in severely ill and critically ill and in death.

Speaker1: [05:48:35] I hope that answered the question. Thank you. Thank you, Dr. Gantz.

Speaker2: [05:48:52] I thank you so much. I did have a follow up to our Israeli colleagues because I had brought up the idea of secondary cases. Nice, but the real part of that question that I thought was of us today is and maybe you can’t say this because September has been blood. An odd behavioral month. I’m wondering if actually the third dose has brought the secondary cases down in people who are immunized. A lot of spread again, I would saying to younger individuals that would be a real reason.

[05:49:35] Stop the spread. During a few.

Speaker2: [05:49:39] That dynamic. Secondary. But we are experiencing here in this country. Do I have to say? As for the first time, I was able to unmute my phone and. Then truck, all the previous times, I stopped first and then unmuted. So, yes, we have we have seen a decrease in the number of people who are getting infected from people who are now with a boost. For those it’s not, it’s we haven’t done yet the full analysis of that, we’re in the midst of that, but I think that the fact that the reproductive number is coming down, this is what it means. Every one

Speaker1: [05:50:30] Person who is now confirmed

Speaker2: [05:50:32] Actually infect less people so that that is clearly part of the of the equation now. The people who are thirdly vaccinated.

Speaker1: [05:50:43] Vaccinated with a booster.

Speaker2: [05:50:45] Are are getting less infected and are less infected, others

Speaker1: [05:50:50] Weren’t there once they’re confirmed, but this is really preliminary vote.

Speaker2: [05:50:55] You know, and the only safety question I had that probably. Are U.S. data? And hopefully, those who are ongoing studying this B and the other safety nets that continue, there’s already been about one million third doses. Cases that have happened in the U.S., and I’m wondering if somebody from this. Talk about the safe. I guess I would say stay tuned. I think there’s an upcoming analysis on this that could come out within the next week or so. So I don’t have the data right in front of me, but I know that that is actively being investigated and will be reported very soon.

Speaker1: [05:51:47] Thank you, Dr. Sawyer. Much my question is for Dr. Lee or colleagues at FDA, and it sort of extends Dr. Gans line of thinking just now, and it’s about the safety profile, as I understand the clearly the mRNA vaccines are among the most reactogenicity of any vaccine we’ve given in recent years. As I understand, the question posed for the committee today, we are not to consider the data from Israel. We’re supposed to look at the sponsors data from their clinical trial, and I came into today thinking that was a very small safety database of three hundred people. So I’m interested in comparisons to other vaccines. That we have decided to give a booster dose for in recent years, like meningococcal conjugate vaccine. And B vaccine Tdap. What is the size of the database in those studies? I took from Dr. Lee’s presentation that FDA is comfortable with this sample size of three hundred, but it strikes me as a little bit small. Hi, this is Dawn. Can you hear me? Yes. Okay, thanks. So the size of the safety database that FDA has relied upon to support licensure of booster doses for preventive vaccines has varied somewhat and depends in large part on the understanding of the safety profile from the primary series, both in terms of clinical trial data from pre licensure studies as well as potential licensure safety experience.

Speaker1: [05:53:42] So, for example, in the case of Japanese encephalitis vaccine zero, we had a booster dose clinical trial safety database of about 300 adults, mainly younger adults, but also some post making sure safety experience, although not huge in the case of several meningococcal conjugate vaccines, the pre licensure safety database for booster doses has been somewhat larger than that nearing 1000 and with perhaps more post marketing post licensure safety experience there as well. And then with tetanus, diphtheria and acellular pertussis vaccines that have been approved for a a second dose in adults. Again, we have a clinical trial safety database preceding licensure of the booster dose of about a thousand or so and extensive experience with that vaccine being used off label as a booster dose. In the case of these COVID vaccines, yes, the pre licensure clinical trial database is around three hundred, which is on the lower end of the range that I just mentioned. But we also have a very extensive post authorization safety database for the primary series that we can consider as well.

Speaker1: [05:55:20] Does that answer your question? Yes, thank you very much. Thank you, Dr. Portnoy. And one more question after that before we move on. All right, thank you. So I guess my question is for the Israeli group, because our job is really to determine the risk versus the benefit of the COVID vaccine, a third dose versus just going with two doses. The emphasis in Israel was on reducing the rate of infection using the third dose because infection rates were starting to go up. We know that people who get the COVID infection also have these side effects to get myocarditis. They have adverse events and so on. And we’re trying to compare the rate of those with the rate of getting the same adverse events from the vaccine. I was just wondering in the Israeli experience when the number of people who had the two vaccines, but not one did they need if they saw a decrease in the. Frequency of getting the vaccine or getting the infection after the third dose. This was the decrease enough to also reduce the rate of getting these adverse events from the actual infection as opposed to getting the same. Impacts from the vaccine. Did you compare the two?

Speaker2: [05:56:48] Out. Try to answer. So I think the the third dose reduces your risk to get an infection, so it reduces significantly your risk of getting adverse events or reaction or complications from. The disease itself, because you are more protected now and you’re getting back

Speaker1: [05:57:15] Basically to what we saw

Speaker2: [05:57:18] After the second dose. Pre waning effect. I have to say that I was pretty surprised with the fluffy comment that

Speaker1: [05:57:30] Israel doesn’t follow

Speaker2: [05:57:32] Adverse events. It’s our data. I’m in charge of it. So. I know exactly what is being reported to us and I set our reservation, but we actually have two very large studies from our biggest HMO

Speaker1: [05:57:45] That covers seventy five percent

Speaker2: [05:57:47] Of the population and they looked into adverse events. In and Clalit, they looked at adverse events one week following the third dose in those who are 60 plus, and they saw the same thing. We saw that there was the same, there was some local and systemic adverse events, but not to. Risk adverse event. Most people said that they felt like they felt after the second dose, between 80 to 90 percent said they felt like after the second dose, and about 10 percent said they felt worse. There was no adverse event at about one percent went to seek medical

Speaker1: [05:58:27] Help because they didn’t feel well, so it’s really

Speaker2: [05:58:29] Not significantly different than what we saw in the second dose. So. The adverse event

Speaker1: [05:58:36] From the third booster dose based on our three

Speaker2: [05:58:40] Million vaccines, and I have to say again, part of them have. Not we haven’t followed for 30 days

Speaker1: [05:58:48] Because we just rolled for the younger

Speaker2: [05:58:50] Adults recently. But for the older people, we have past 30 days and this is the profile that we seeing pretty safe. And we saw an increase, a dramatic increase in their protection against disease, so

Speaker1: [05:59:08] The risk

Speaker2: [05:59:09] Of them having disease with

Speaker1: [05:59:10] Complication reduces significantly. So the. Mean might have been less than the risk of getting those same events if they were not vaccinated and they just got the disease. So what we saw prior to

Speaker2: [05:59:27] Our booster campaign was that the 60 percent of the

Speaker1: [05:59:31] People in severe and critical conditions were. There were immunized,

Speaker2: [05:59:37] Doubly immunized, fully vaccinated, and as I said, forty five percent of the people who died in this fourth wave were doubly vaccinated.

Speaker1: [05:59:46] So there was a huge. A huge importance

Speaker2: [05:59:53] Of this booster effect, not to just reduce confirmed cases, but actually to save

Speaker1: [05:59:59] Lives for those who

Speaker2: [06:00:00] Are getting the disease and getting into severe and critical condition.

Speaker1: [06:00:06] Thank you. Thank you. We’re moving to Dr. Levy. For me. Yes, we can hear you, Dr. Levy, we can hear you. Right? Well, I wanted to thank Dr. So late, particularly on the Sabbath. Shabbat Shalom. I know in your prior answer, but I specifically wanted to drill down to males where that group appears to suffer the highest risk of vaccine associated myocarditis. And specifically around the booster doses. Do you have data? Do you have numbers to say whether the risk of, I’m particularly thinking, 16, 17, 18 years of age, whether that number is similar to that after the second dose? How does that compare with the third dose specifically in that group? Thank you. And Shabbat Shalom.

Speaker2: [06:00:54] Thank you for the questions, so you could pull up the slide, I think one before the last from my presentation. But basically what we did in the first and second doses. Back then, when we had a signal of myocarditis and we actually heard it from, you know, from people in the hospital that they’re seeing epidemiological analysis of bad by three different groups trying to figure out if this is a true signal. And the article is about to be published on that topic. And we did see a signal after the second dose. As I said, with a rate of about the highest rate was about one to six thousand vaccines among 16 years of up to 10000 in the older

Speaker1: [06:01:40] Group age

Speaker2: [06:01:42] Group between 20 and 29 and over over that when you go up by the age, we have vaccinated more than 6000 people at the age we’re talking about, and we haven’t seen the same, the same adverse event. And I want to emphasize again that for myocarditis, we’re actually doing active surveillance. We’re calling the hospital every week to find out about new cases, regardless of vaccination. They’re supposed

Speaker1: [06:02:11] To report

Speaker2: [06:02:12] To us all cases of myocarditis. And so we’re really on top of the myocarditis issue on.

Speaker1: [06:02:18] The only report that we had so far

Speaker2: [06:02:20] Was of one case 30 years of age that I that I showed. But I want to be very, very clear that we have not followed them yet for 30 days. So we’ll continue, obviously to follow.

Speaker1: [06:02:34] But the the

Speaker2: [06:02:35] Results that we have so far from the actual civilians are reassuring just to say that at least for

Speaker1: [06:02:41] Now, we have a lower rates of myocarditis than we saw in the second dose. Thank you very much. And I think we can excuse our speakers now because we’re in transition to our next session, which will be led off by Dr. Peter Marks.

Speaker2: [06:03:08] All right, um, Dr. Monto, would it be possible to have one more comment from Pfizer? I think we finally have a phone line that works.

Speaker1: [06:03:15] Oh OK, let’s have Pfizer give us sorry, which I cut off. Um, served up Vermont. This is Louise Jr., I’m the chief medical officer for Pfizer. I just wanted to give perhaps a little bit a different interpretation or I do not necessarily think that the epidemiological patterns that you are seeing in Israel are significantly different to what you are seeing in, um, in the United States or elsewhere. I mean, I actually think that Israel saw it first because as Dr. Sharon Alroy-Preis said, there were just three months ahead. And if you look at the epidemiological patterns and I’m not discussing about the Kaiser Permanente, I’m discussing about the CDC and discussing about the Public Health England discussing about Qatar. You’ll see that epidemiological pattern of reduction in in all the other countries starting with infection. And it’s not only infection. I would just say it’s infection and symptomatic. This is going down to 60, 50 percent in all in all these countries. And and again, if you look at the are reported today here in the United States, you start to see even hospitalization going down seventy seven percent.

Speaker2: [06:04:30] So the conclusion

Speaker1: [06:04:31] Is that the epidemiological patterns around the world are remarkably similar to what you’ve seen in Israel so far. It’s just that Israel, as again, has said before they just vaccinated many more people much earlier. So I just want to make that position. Thanks. Thank you. And now to Dr Marks. You’re muted. Right. Our double muted their sorry, my apologies. Thanks very much, Dr. Monto. I want to take this opportunity to again thank the committee members and chair and our invited speakers and the FDA staff from the Office of Vaccines, along with the advisory committee meetings staff who have made this meeting possible. I also want to take this opportunity to deeply thank Drs. Gruber and Krauss for their incredible work over the past decades in the service of public health and particularly during the century’s worst pandemic. As I noted this morning, the decision that FDA needs to make is based on complex data that’s evolving in front of our eyes. There are different views of the data and the discussion of differing opinions is critical to assist us in making our regulatory determination. It’s no secret here that there is still the debate over the need for an additional COVID 19 vaccine at this phase of the pandemic, but the emerging evidence such as that from our Israeli colleagues is very helpful. We also know that a breakthrough infections, including some that are severe, are occurring in the United States, and FDA is tasked with reviewing an application that shows data highlighting the need and potential benefit of a third dose for the prevention of COVID 19 due to SA’s coronavirus two.

Speaker1: [06:06:34] And in this regard, I want to bring two points to the attention of the public and to the committee and if I could have the slide. Ok. Let’s see if we can get the slide that I asked for up. While they’re doing that, I’ll just go ahead. First. Um, the need for an additional vaccine dose at six months, but should not be surprising based on our knowledge of the immune system and our experience with other vaccines. I think this was already referred to by Dr. Koirala, as shown here on the CDC ACIP adult immunization schedule for twenty twenty one. Nearly half of the non influenza non live virus vaccines require a second or third dose, including a dose at six months. And therefore, the need for an additional dose at six months to provide longer term protection should not come as a surprise as it’s likely necessary for the generation of a mature or immune response and acknowledging the continuing generation of evidence that we have for the COVID 19 vaccines. This may end up being the case here as well. Second, the vaccines for other diseases noted here that are given to adults are not. Only indicated for the prevention of severe disease or hospitalization, realizing the benefits of reducing disease occurrence or transmission.

Speaker1: [06:08:05] These. Other vaccines are indicated for various severity of disease prevention and the intended population. Similarly, the question of safety and effectiveness for the third dose of commonality before us today may not just be related to preventing severe disease requiring hospitalization, but also. To preventing cases of COVID 19 that are associated with significant morbidity, including debilitating symptoms such as long COVID. There’s also the issue of preventing the continued spread of COVID 19 to vulnerable populations, particularly children who are of an age where they cannot yet be vaccinated. So to conclude, if you enter your deliberations, I greatly appreciate the work of the committee members helping to sort through the data and make a recommendation, which is a critical step as the agency moves to act on the application and does its best to ensure that the rationale for its decision is clear not only to health care providers, but also to the American public. We look forward to your deliberations and thank you so much all once again for taking the time. Yeah, introduced the voting question and hat and have some clarification about what we are to consider in responding to the vote. I will turn this over to my FDA colleagues who will bring up the the voting question. So that question is here now. Do the safety and effectiveness data from. Go ahead, Marion. Thank you.

Speaker2: [06:09:51] Yeah, I thank you so, and thank you, Mike, for putting up this question, so we have one voting question and that we do the safety and effectiveness data from clinical trials. Three four, five nine one or

Speaker1: [06:10:06] One support the approval of a community booster dose

Speaker2: [06:10:11] Administered at least six months after completion of the primary series for use in individuals 16 years of age

Speaker1: [06:10:18] And older. The point of information I would like to ask is whether we are. Permitted to use any data from outside that extended clinical trial in our consideration in the vote.

Speaker2: [06:10:48] Well, we do make a regulatory decision, of course, based on the safety and effectiveness data that are derived from the clinical trials with that very product. However, as I mentioned in my introductory remarks this morning, we also look at the benefit and risk of this additional booster

Speaker1: [06:11:12] Dose

Speaker2: [06:11:12] When making a decision as to whether this dose is safe and the benefit risk consideration, of course, will look at the benefits. And in this regard, of course, the data and the presentations that you’ve heard today will also be a consideration in making this decision. So in other words, if you do your boat, you know, please look at the data derived from the clinical trials. But if you look at benefit risk, of course, that supportive information will certainly factor in over.

Speaker1: [06:11:49] Yeah, this is I don’t want to just summarize here very, very clearly. You are allowed to look at the totality of the evidence in order to make your recommendations. For us, that is the totality of the evidence before you. Just like we will, we are we are. We are a science based regulatory agency,

Speaker2: [06:12:09] And that means

Speaker1: [06:12:10] The person that ignores data is the one that’s surprised. We’re not going to ignore data just as you don’t have to. You’re not. This is not a legal proceeding. This is a scientific proceeding, so you can take all the data into account. Thank you. Thank you for that clarification. Ok, we have hands being raised now, Dr. Hildreth. Is that a new hand being raised or is that the old old one? Well, since it’s raised, I will take this opportunity, is that all right? That’s fine. I have three considerations that are important to me. One, as I was hoping to hear from either Pfizer or the folks from Israel, that there was a. A neutralizing titer that correlated with protection, because that would allow us to determine whether or not antibody levels had waned enough to make boosters necessary be a very objective way to make that decision. I have a serious concern about myocarditis and in young people, if it’s related to the immune response and the booster shots induce a very strong response, is that going to amplify the risk for myocarditis in those in those individuals? And like Dr. Meissner, I also wonder whether or not boosters would be best if they’d matched the variants that are causing so many challenges now. And the mRNA technology should make that reasonably easy to do. So those are my my three considerations in all of this. Thank you, Dr. Monto. Thank you. Dr. Levy. Dr. Levy, your unmuted and you can turn your camera on. Oh, no, sorry, that was an error. All right. Ok. Dr. Gans. What is your hand raised again?

Speaker2: [06:14:33] Yeah, thank you for this ability to have this conversation. I am struck by. Fda asking us to look at the totality of evidence when there are several key points, I think that we’re lacking right now. One of them is the very strong safety data that we could have actually withheld the third doses that have been given. We are given some thought and. From the the Israeli data, but I think that that’s a really missed opportunity and something that should be considered when the FDA considers these 300 people. Not a large enough study, but we have other data that could be looked at. The other thing, along with Dr. Hildreth, that I think is very important is another missed opportunity that I think the FDA could have asked for is actually looking at those pre third dose, both humoral and T-cell immunity and really trying to parse out what happens in that, plus the fact that we have a lot of breakthrough. We really could have the answers and to be asked that they’re complicated essays or to be told that it’s up and coming is feels that we’re making decisions when they’re data out there that. I think that it’s very important what the Israeli study showed, if it truly does show that secondary infections have been reduced by the ability to. Because I think that is one of the. Essence urged by that. Those are my considerations as. But I just wanted to put that plug in the other piece that I would like to put in a plug for is that Pfizer should be looking at alternative schedules as well. It is true that we sometimes do prime prime boost, but we really haven’t seen other vaccines that use. So there should be some consideration not only to looking at different variants, but looking at different.

Speaker1: [06:16:43] Thank you. Dr. Offit. I’m thank you so. So here’s how I put this together, I think the stated goal of this vaccine by people like Rochelle Walensky and others has been to protect against serious illness and the the data that were presented by Senator Oliver and by Kathleen Dooling previously at the FDA meetings shows that these vaccines do exactly that, and it’s exactly what you’d expect. I mean, these these studies are consistent with the fact that protection against serious illness is mediated by memory B cells, which, as has been shown by researchers like John rary here at Penn as well as at La Jolla or or Long Live, induced by two doses of mRNA containing vaccines and have plenty of time to activate and differentiate to protect against serious illness, which takes a longer period of time. It’s hard for me to understand at some level the Israeli data, which are at variance with these studies, but it’s especially hard for me to buy the fact that because they started, say, doing their immunization schemes three months before us, that that’s why they’re seeing what they’re seeing. Because all the data are the the the the longevity of memory T cells is far longer than that, unless what we’re arguing is that those who are greater than sixty or sixty five have a lower frequency, much lower frequency of memory B and T cells, and therefore are more fragile and more quickly seen as being susceptible to severe disease.

Speaker1: [06:18:17] It’s also clear, however, that the third dose of mRNA vaccines increases the title of virus specific neutralizing antibodies and will likely decrease the incidence of asymptomatic or mildly symptomatic infection, which is associated with contagiousness. So then the question becomes what will be the impact of that on the arc of the pandemic, which may not be all that much? I mean, certainly, we all agree that if we really want to impact this pandemic, we need to vaccinate the unvaccinated. And then my last point then I’ll stop is just the sort of underlying Dr. Hildreth comments that, you know, we’re being asked to approve this as a three dose vaccine for people 16 years of age and older without any clear evidence of the third dose for a younger person when compared to an elderly person is of value. If it’s not a value, then the risks may outweigh the benefits, and we know that the sixteen to twenty nine year old is at higher risk for, you know, for myocarditis. And now we have an even greater booster response in that scene after the second dose. So I guess in summary, I would say that while I would probably support a three dose recommendation for those over 60 or sixty five, I really have trouble supporting this as written for anyone greater than or equal to 16. Thank you. Thank you, Dr. Carola. Thank thank you, Arnold. Yeah, so

Speaker2: [06:19:37] I have a I have I have

Speaker1: [06:19:39] I need some clarification from FDA regarding their question.

Speaker2: [06:19:43] So is is is the question

Speaker1: [06:19:45] Really getting at changing the primary vaccination to a three dose regimen? Or is it just for the third booster this time? Or is it for a booster every six months at this time? Going forward, that’s one. And then so I’d like the FDA to comment on that. I agree with a lot of what Dr. Offit said with the with the caveat that I was a little surprised at the response by the Pfizer team that they find they have very good B and T-cell immunity. And yet they’re saying that they have they don’t see good durability, so they need to have a boost. It’s a little bit conflicting to me in that regard. I can understand where certain populations, as Dr. Offit mentioned, the the elderly, I think also the immunocompromised. There are some very clear populations that have impaired or diminished good cellular responses, and a boost may be very appropriate for them. It’s not clear to me that the data we’re seeing right now is applicable a necessary general population. Dr Marion Gruber, the answer.

Speaker2: [06:20:57] Yeah, I just wanted to clarify for Mike. You know, going back to his initial question, the reason why we posed the question the way we did is because the FISA did ask for an indication for an additional, not an additional dose for a booster dose, a single booster to be administered six months following the primary series. And I know there are different perspectives whether the third dose can be seen as part of the primary series or not. I think the perspectives are different here, but that’s really beside the point right now. What Pfizer has asked is for a single additional dose, which is a booster dose administered six months after the primary series. And that is because that was the request from Pfizer. That’s why we faced the question whether this is the the safety and effectiveness data would support approval about of a booster dose administered the primary series.

Speaker1: [06:22:08] But with the expectation for people who are unvaccinated at this point were a third booster dose to be approved, the expectation is that they would be told the primary vaccination scheme would include three doses. And how does that impact the pediatric indications?

Speaker2: [06:22:27] That that may be the case for the unvaccinated. Of course, there would need to get their primary series and and they but they would not at this point go ahead and say a primary series

Speaker1: [06:22:40] Requires a booster dose. Thank you. Thank you. Thank you all. Dr. Meissner.

[06:22:56] Thank you, Dr. Monto.

Speaker1: [06:22:59] I’d like to just give a couple of thoughts as I listen. First of all, I agree with Dr. Gans that. We still don’t know the proper interval between doses, and I would add to that we we don’t know the proper dose and there is some. Preliminary data regarding another messenger RNA suggesting that a lower dose might be effective and it might be less likely to be associated with complications. And secondly, I think one of the arguments in favor of giving a booster dose is the data on sterilizing immunity that is, if a third dose does in fact reduce the risk of transmission, then that’s a significant observation, but I’m not. Uh-huh. It still sounded as though it’s premature to come to that conclusion. In terms of what Dr. Mark said, I I think it’s very reasonable that for most killed vaccines indeed, we do need to have an interval of time. And a booster dose months after the primary series, but my concern and perhaps the FDA could come in on Israel. We just heard define is experiencing myocarditis in the high risk young male adult male group at about one out of 6000 in the United States. Going by their recent ACIP data describing 50 to 60 cases per million million second doses comes down to about one per twenty thousand. And we really don’t know. What’s going to happen after a third dose, myocarditis may be less common.

Speaker1: [06:25:18] It may have similar rates of occurrence. Or it could be more common. We understand so little about the pathogenesis that it seems to me. We need to know that data before going forward. With the booster dose for the general population and one of the thoughts that. Has come up is why can’t Pfizer check? Protein levels, for example, might there be subclinical myocarditis that occurs after? Third dose, could they look at troponin levels or another parameter before and after administering that third dose to give us some reassurance so that we’re not, we’re not causing a problem? So, Doctor, thank you. You come on, do you have the answer? I don’t know if I have the answer, but I can offer some comments from the FDA perspective. So first of all, in terms of the the risk of myocarditis pericarditis that we’re seeing here in the U.S., yes, the the most recent Bears data are showing reports of myocarditis pericarditis in the range of 60 to 70 cases per million doses in the 16 to 17 year old age group, which is the highest reporting rate among the various age groups examined. And that is numerically lower than the one in six thousand rate that you just heard about from Israel. On the other hand, we do know that Bears is a passive reporting system, and when we query health care claims databases such as Optum, as summarized in our clinical review in summary basis for regulatory action for the original BLA from Pfizer, what we find is actually an estimate with some fairly wide confidence intervals.

Speaker1: [06:27:28] But an estimate of around two hundred cases per million doses can be 16 to 17 year old age, with which, if you do, the math is about one in 5000. So that actually is fairly similar to what the Israelis are finding. Now, as you as you stated, we really don’t have enough data yet to know what the risk of myocarditis and pericarditis would be in any specific age group following a booster dose. It is an important question. It is likely one that can only be answered in the context of post licensure or post authorization use. But also, we agree with you completely that it is important to study whether initially subclinical cases of myocarditis may be occurring and if so, what the outcomes of those cases are. We have discussed the need for such investigations with vaccine manufacturers, and perhaps Pfizer would like to explain what their plan is for investigating that possibility and to continue the discussion. Is it possible to say at what age myocarditis aims to not become a problem? If I to put you on the spot. So if you look at the health care claims data, you see that the there is evidence of some attributable risk at that all age groups, although the older you get the the higher the risk for complications from COVID that then offset the risk of myocarditis.

Speaker1: [06:29:18] So when you when you look at the balances of risks versus benefits, we really start to see a risk of myocarditis being higher in males under the age of 40, and that’s what is written in. Let’s move on, and then we can ask Pfizer for comment later on after the list of those with their hands raised has. I’ve been handled. Dr. Rubin is next. I think thanks, Dr. Monto, I’m I’m going to echo something that everyone most people have said, but I want to just make it slightly different way. We’re gauging risk and benefit here. And so we, we we really have to think about both. We don’t know that much about risks. The truth is very small number of people under 60 who receive the vaccine. But there is a lot of Israeli data that suggests it’s probably OK in people over 60. But we don’t know very little about people under 60 because it’s in such a short time since they started vaccinating. So that’s where the risk calculation stands. There is a big difference between the U.S. and Israel. The use case in Israel is where most people are vaccinated. If it really does limit transmission, then it will be important to take those vaccinated people and further limit transmission in them.

Speaker1: [06:31:09] But remember, in the U.S. is going to continue to be driven by the very large number of unvaccinated people and the marginal benefit of a third dose of vaccine for people who are already vaccinated is likely to be very small for reducing the overall burden. So that really means that the primary benefit is going to be in reducing disease, and that’s largely been defined in various ways of severe disease. And we know that people who benefit from that, there are the people who at heart who are at highest risk of severe disease, which means older people and people with other comorbid conditions. And those are the kinds of people that that the FDA has already approved a third dose for, although so far it’s a relatively contained group. So, so I suspect that many of us are heading toward the suggestion that we can find vaccination at this point to that group, and we’ll add strongly suspect that when we see data that it will prove and is going to be confusing, but it will prove that the that there is a very low risk to the vaccine. But we don’t have that right now, and I don’t think that we’re I’d be comfortable giving it to a 16 year old for all the reasons that everyone has already raised. Dr. Fuller, thank you. Thank.

Speaker2: [06:32:41] Thank you, Dr. Monto. I think what I wanted to say has essentially been addressed by Dr. Rubin in that we don’t have the same data or we have the same context that is in Israel here in the USA. And then I asked myself, what happens if we approve, if we say yes to this, how does it roll out? Will the people who have been vaccinated longest be the first to get the booster? I don’t know who discusses that or who decides that. I’m not comfortable with only 10 12 people as an end for the third booster in the clinical phase three that we’re being asked to evaluate. So I, I I would like us to feel much more comfortable with what we’re looking at from this clinical study in the USA with the differences we have in our population. What happens for people who did not get the Pfizer vaccine but have been vaccinated? There are too many questions for me to feel comfortable saying yes to this when I think with some more detailed study, we can get some more answers. So what’s happening with the clinical trials with

Speaker1: [06:33:55] Others is my question. Thank you, doctor.

Speaker2: [06:34:00] The clinical trial initially in the Pfizer clinical trial.

Speaker1: [06:34:06] Right, Dr. Chatterjee.

Speaker2: [06:34:10] Is there going to be an answer to that? Oh. Which isn’t.

Speaker1: [06:34:17] I think what we are going to do, Dr. Fuller, is to try to move early to a vote. On the question that is in front of us and then see. Where we go from there in terms of the session today. Ok.

Speaker2: [06:34:40] Roger Chatters, yes, thank you, too. I have several thoughts, but I will keep my comments to a couple of things that I don’t think have been quite fleshed out by my colleagues agree with a lot of what’s already been said, it seems to me. I’m taking Dr. Marx’s declaration to take all of the data into consideration that we do really have a very different situation in Israel than what we are facing here in the U.S. at this point in time. The data in Israel, particularly for those who are over 60, appear to me to be quite compelling for a booster dose in that population specifically. But within the context of the U.S., you know, I think that we’re a large country. It’s true, but there are also differences in different parts of the country that we are seeing, and there are parts of the country that are highly vaccinated and they are not seeing breakthrough cases among those people who are highly vaccinated, necessarily in those numbers. So I think that that’s an important point to take into consideration. And then finally, I want to go back to something that Haley started off talking about. Several other people commented on, which is it is true that getting a larger gap between the prime and the boost whenever the boost might be does seem to be beneficial. And that’s true for many vaccines. So would it then be beneficial to put that gap between the first and the second dose, rather than to then give a third dose booster after six months?

Speaker1: [06:36:19] In other words, to summarize. There are a lot of questions to be answered after we take care of the issue in front of us, which is the booster vaccinations and those already vaccinated, correct? Yes, thank you. Ok. Dr. Pergamon. Sacramento. But certainly a lot of comments have been made, I’m I’m happy to hear a lot of similar thoughts by my colleagues. If you want to talk about the issue that that doctor often brought up is the issue of transmission.

Speaker2: [06:37:03] I do think it’s important

Speaker1: [06:37:04] That with a large population in the United

Speaker2: [06:37:07] States vaccinated, that if we can decrease transmission,

Speaker1: [06:37:10] This could have some

Speaker2: [06:37:11] Benefits for the pandemic in general and particularly

Speaker1: [06:37:14] In certain populations. There’s a lot of concern with health care workers of continued breakthrough for folks who are fully vaccinated. That group that’s been vaccinated very early and because of strains on health care systems, this seems like an important issue that could be important. The challenge in front of us is that we’re given this massive group to consider as the booster. And I think in many ways we’d like to be asking if we’d like to be answering a separate question, which is in a specifically high risk groups that we’d like to give the booster to. But that’s not on our on our plate. So I think it is important to consider transmission and how it has, how this could have an effect. I agree that most of the transmission is happening amongst the unvaccinated,

Speaker2: [06:38:01] But I think this can be become more problematic if this trend does continue.

Speaker1: [06:38:05] And I would say in echoing something that Dr. Gan said it felt like there were a number of comments during this

Speaker2: [06:38:12] Discussion where people said there is a paper that is

Speaker1: [06:38:15] Out, we’ll be able to present this data to you soon or it’s coming

Speaker2: [06:38:18] Next week feels like there’s a lot of data that is

Speaker1: [06:38:21] Circulating that could be helpful around this discussion

Speaker2: [06:38:24] That is not available at this moment, which makes it more difficult to make some of these decisions today.

Speaker1: [06:38:31] Thank you, Dr. Wharton.

Speaker2: [06:38:43] Thank you, I I really appreciate the comments from the other committee members and I agree with with a lot of what’s already been said. You know, it’s a frustrating place to be in where we have in the United States. Are more than adequate supplies of vaccine and yet have been unable to achieve the level of coverage that would. Results in much better control of this pandemic than we currently have, so we’re we’re sort of in this position where we’re having to think about about administering third doses of the Pfizer vaccine, which is probably not the action that is going to have the most health impact in the United States. Thinking about everything that’s been presented, it does feel to me like benefits are likely for some part of the population, for people with underlying conditions that immunocompromised people, the the the older population. But I I share the concern that’s already been expressed by others about what we don’t know about myocarditis in younger people. And given that the risk of breakthrough infection in that younger population is is is much lower than it is in other parts of the population, that’s just that recommending a third dose for younger people is just not something I’d be comfortable

Speaker1: [06:40:12] With at this point. Thank you, Dr. Wharton, Dr. Lee. So I would just like to make a little bit a few comments.

Speaker2: [06:40:27] I think we approve the vaccines to begin with. We had a

Speaker1: [06:40:30] Lot of clarity on what we were supposed to be looking at a reduction of symptomatic COVID infection, as well as the incidence of severe infection.

Speaker2: [06:40:39] It’s not clear to me that the that the guidance is as clear cut here. It seems that the

Speaker1: [06:40:45] Sponsor was giving some guidance with respect to the immuno bridging studies

Speaker2: [06:40:50] That they appear to have met. But then there also seems to be a lot of we don’t have a lot of data on the endpoints we had before, as in the symptomatic infection, after the

Speaker1: [06:41:00] Covid, after the booster shot and its improvement or

Speaker2: [06:41:04] Or any on the

Speaker1: [06:41:06] Severe, much more

Speaker2: [06:41:08] Limited. And then a lot of discussion about transmission, which

Speaker1: [06:41:11] I agree is important, but we’re sort of

Speaker2: [06:41:13] Working without data and making those

Speaker1: [06:41:15] Decisions. I’m also a little

Speaker2: [06:41:16] Bit concerned that the study that we’re

Speaker1: [06:41:18] Looking at and with the highest risk group we’ve talked about sixty five and older, as Dr. Fuller point out, only has

Speaker2: [06:41:25] 12 patients.

Speaker1: [06:41:26] I would agree that the Israeli data is really quite compelling that I’m my enthusiasm is somewhat limited by the fact that the follow up period is less than a month, so

Speaker2: [06:41:35] This sustainability is not yet clear.

Speaker1: [06:41:38] Thanks. Thank you, Dr. Lee. Dr Mark Dennis.

Speaker2: [06:41:55] He has signed. Paul, don’t you think it’s plausible that that some people, despite being fully immunized, might not have a robust enough or a more efficient enough immune memory to rapidly mount a response when they see a variant that is like Delta, which has demonstrated not only really high transmissibility but very high viral replication. So I could imagine how if you didn’t have sufficient circulating antibody and an antibody present in the nearest and maybe in the nose of pharynx, you could get overwhelmed with a virus like that. So I get that they could be primed, but maybe you really need in certain people high levels of antibody present because you may not have time to mount that response that you need despite being considered primed.

Speaker1: [06:43:04] Dr. Offit, do you want to reply to that? Going a little out of order. So it’s a good question. So at the heart of that question is what’s the incubation period essentially of serious disease? And so you’re definitely right that if you have high titers of circulating neutralizing antibodies, that’s going to give you your best chance of decreasing the initial viral replication and even mild or moderate infection, usually as a general rule, people believe that it takes a longer time to develop the kind of serious infection that gets you to the hospital. I mean, a couple of weeks, which then means that you are where you have. If you have adequate frequencies of memory B and T cells, the activate the activation of differentiation time for that is usually about three to five days. I mean, that’s why the long incubation period diseases like measles, rubella, you know, you can get essentially sterilizing immunity and you can eliminate those diseases from from your country, as we did actually with those diseases earlier on. So I think I take heart in the fact that the incubation period is fairly long for for serious infections. And therefore, if you have adequate frequencies of memory being T-cells, you’re less likely. Well, I’m sure you’re right that there would be some cases where that incubation period is much shorter. But I think on balance, it’s generally long enough to allow activation, differentiation, memory B cells and T cells to protect. Thanks for the question. Thank you, Dr. Sawyer. Think. But opinion that we need this in our armamentarium, a booster dose now, particularly for the elderly and other high risk conditions, but I share my colleague’s angst about the sparsity of safety data, and I am also anxious about the extrapolations both to older populations and younger populations.

Speaker1: [06:45:02] But we’re not going to get a read on myocarditis until the vaccine booster is used extensively, and we have to rely on the BSD and other systems to capture that signal, and I’m sure they will be looking for it. So I’m hopeful that CDC rolls this out in a gradual fashion, but I think that I would be in favor of approving this because we are going to likely need it for at least some of the population. Dr. Pergamon. Apologies, my hands are still raised, I apologize, but that’s OK. I was wondering, Dr. Portnoy. Great, thank you. You know, it would be great to wait until we have all of the data about safety, but I work at a children’s hospital. My hospital is filling up with kids who have COVID. We didn’t want to rush in to approve the vaccine for them and now look where we are. It’s very frustrating because we’re just inundated with kids who supposedly weren’t going to get COVID. The concern I have the concern that we have that people are going to get myocarditis from COVID vaccine is real person. We really need to be asking, though, is whether it or any other severe adverse reaction from the vaccine is greater than the risk of getting it from breakthrough infection. Myocarditis is generally a short term condition.

Speaker1: [06:46:34] Most people who get it recover from it. I worry more about long term systemic complications of COVID, which are real and can be prevented with the vaccine. Look, antibody titers will help with systemic disease but not infected systemic disease, but not infections that just getting regular infections because that requires mucosal immunity. That’s a different kind of immunity than what we’re getting from a systemic vaccine. We really have two diseases and mucosal disease and a systemic disease. Mucosal is how it spreads. That’s why people who’ve been vaccinated can still get the disease. They get it in their nose. They spread it. They don’t have secretory IGA because it was injected into their muscle. So and that doesn’t induce an IGA response, systemic results in systemic COVID results in hospitalization and long term morbidity. So that’s what I think we should really be concerned with. Immunity clearly seems to decrease over time. We saw that with the data from the United States, also from the Israeli data. Do we want to wait until more previously vaccinated people get sick before we prevent them from getting sick? As one of those people who are at risk, I’ve had two vaccines. I’d rather not get the COVID disease. I’d rather get the third vaccine. My wife already got her third dose. I plan to do the same thing next week. Pharmacies are giving it out off label. I would really love to be able to get it and prescribe it on label rather than have to do it off label because we refuse to recommend approval.

Speaker1: [06:48:01] So I’m strongly in favor of approving this vaccine. Dr. Levy. Hi, Dr. Monto, thank you for all that, and we saw the the question is carefully phrased by FDA to us, and I’m sure the decision will be to have us vote on the question as phrased. My question is given the number of advisory committee members who are expressing similar concerns if the motion doesn’t pass as written, will there be opportunities to propose a modification? Dr. Marks. The answer to that is yes. While you are on good, we where should we be explaining our votes? Did we explain the votes after we have the vote to be of help in future in determining the next question? Yep. Dr. Monto, I think perhaps for efficiency, it may be worthwhile going around the committee to just get a sense of the committee of where people are. And then perhaps we can take a moment and ensure that what we then come back to you with for a vote makes some sense if you’re willing to do so. I’m perfectly willing to do so, so in other words, we don’t have to have a vote on that question. I would say that for right now, maybe we could go through and get a sense of where the committee stands. And rather than going to a vote on that question, if the committee decides that they that they’d like to, we can. We can then see where we stand about putting that, that question forward. Dr. Gruber, Dr. Marion Herbert.

Speaker2: [06:50:02] Yeah. I just wanted to make the point that Pfizer has submitted a supplemental BLA asking to get an additional indication for a booster dose when administered six months after the primary series for individuals 16 years of age and older. And I believe that we do need

Speaker1: [06:50:23] A vote on this question. And I think we can do that efficiently. Which may be quicker as a matter of fact, than going around the table. So what I would propose is that we do have the vote and then we can go around the table and discuss. Where we think a modification would be necessary or or approvable. How about that? Hearing no doctor March. But you actually need a doctor. Yes, thanks, please, please feel free to move ahead to a vote. I think we’ll we’ll go with what Dr. Gruber has suggested. When we can have your explanations and then we can move appropriately thereafter. Thank you. Ok. Ok. Or do anything? Yes.

Speaker2: [06:51:40] Interrupt, is it possible for Pfizer to make any final statements since we kind of had many technical issues and actually weren’t able to address many of the questions,

Speaker1: [06:51:49] We will be briefed. Well, I’ll give Pfizer Pfizer five minutes to make final statements as long as we can hear you. Otherwise, we’ll

Speaker2: [06:51:59] Deal with that. All right. Dr. Gruber, Bill Gruber, please comment. Go ahead, Laurie.

Speaker1: [06:52:16] Dr. It was supposed to be speaking here.

Speaker2: [06:52:25] Pfizer, Bill Gruber.

Speaker1: [06:52:27] I bet he’s coming, OK? All right.

Speaker3: [06:52:37] Can you hear me OK? Let me run this door. Yes, we can. Yeah. What?

Speaker2: [06:52:50] He’s here. All right. All right.

Speaker1: [06:52:53] Sorry, I had to run from another room. My apologies for holding up the committee interview. Ok, that’s good. Resolved, at least that problem. So again, I think we’re all centered around the same goal here, and that is to make a safe and effective tool available to map the maximum population that stands to benefit. So we’re obviously eager for the committee to vote on the existing question, and we hope they will keep that in mind. I think there have been a lot of issues that surround the rare risk of myocarditis that is already in the existing label. As you heard from Dr. Sawyer, and I think this

Speaker2: [06:53:29] Is an important piece.

Speaker1: [06:53:31] It’s unlikely that we’d be able to identify myocarditis in clinical trials. We weren’t able to identify that. Obviously, in the circumstances of the original licensure, it was only with the intense pharmacovigilance that occurred after the fact. And I think it’s encouraging to me, and I hope to the committee members that the Israeli data, although it’s not a full month out, it spans the time when myocarditis is most likely to occur based on their own data and based on what’s seen by the CDC. So the expectation, I think, is is that this is going to be a rare event, just as it was after the first two doses and will only be determined by pharmacovigilance. So in thinking about this, and I don’t know whether the CDC members that would want to comment on this, but the published data has made very clear that the risk benefit profile all the way through the age ranges, whether we’re talking about young adolescents 16 to 17 years of age or we’re talking about individuals older, the risk benefit is very clear. In fact, there seem to be more cases of myocarditis in some of those age groups with COVID 19 than there are with the vaccine. And then if you add to that, the hospitalizations, the illnesses, the need to essentially stop the pandemic before we continue to generate variants. So I think the bottom line is the balance of evidence supports a broad recommendation, but we welcome the committee’s voting on the current question, but then certainly not depriving the ACIP or other recommending bodies the opportunity to make a decision about how the vaccine can be best used. The first goal is give the tool to those recommending bodies so they can best apply how the vaccine might be used. Dr. Cohen, would you like to respond on the behalf of the CDC? Sure. We’re going to vote.

Speaker2: [06:55:28] Sure. Thanks. I just want to clarify Pfizer’s comments that the risk benefit analyses that have been done have compared the risk of an adolescent not being vaccinated at all to having two doses. And that risk benefit is in favor of vaccination. But the incremental benefit of a third dose over a second dose has not been presented or completed yet. And so I just don’t want the committee members two to get confused with the incremental benefit of a third dose and the comparative risk of double exposure to both the second and potentially an additional risk with

Speaker1: [06:56:07] That their dose. Thank you. Prabha and Kathleen, are we ready to have a vote?

Speaker2: [06:56:20] Yes, we are.

Speaker1: [06:56:21] We are voting with the proviso that we are going to have further an explanation of vote and further, potentially further voting thereafter. Understood.

Speaker2: [06:56:39] Can you hear me fine? Yes. Ok, great. So. Mike, can you pull up the. We’ve got.

Speaker1: [06:56:52] You’ve got the question, please. Okay, thank

Speaker2: [06:56:55] You. So just for not only our members and temporary voting members, excluding the industry representatives, are going to be voting. Dr. Monto can read the question for the record. And then afterwards, all members and temporary voting members will cast their vote by selecting Yes, No or abstain in the voting pod. You’ll have two minutes to cast your vote once the question is read, and then after all the votes have been placed, we will broadcast the results and read the individual votes aloud, for the record. Please just note that once you cast your vote, you may change your vote within the two minute time frame. However, once the poll has closed, all the votes are considered final unless anyone has any questions. Dr. Monto, if you could, please read the voting question.

Speaker1: [06:57:45] Right, and the voting part is not there yet. But let me read the question first to the safety and effectiveness data from the clinical trial support approval of the community booster dose administered at least six months after completion of the primary series for use in individuals 16 years of age and older.

Speaker2: [06:58:16] Thank you, and Mike, can we pull up the voting pod? Ok, we have the voting pod up. So go ahead and cast your vote at this time, please.

Speaker3: [06:59:12] You and then the work

Speaker2: [06:59:14] To be done. Yes, we’re still getting votes then, so we’ve got about a minute remaining for individuals to cast their votes. Ok, it looks like we’ve received all of the votes. Let me read them aloud for the record, there should be. Eighteen total votes today. Dr. Cohn has a no vote. We have maintained in the past simply. Right. We will figure out where the additional vote came in, so if we can close the poll, I’m going to read the votes aloud. Dr. Cohen voted no. Dr. Portnoy voted yes. Dr. Lee voted no. Um, we did have an accidental vote from a speaker, so that will be disregarded. Dr Chatterjee voted no. Dr. Pearlman voted no. Dr Gans voted no. Dr Meissner voted no. Dr. Levy voted no. Dr Hildreth voted no. Dr Wharton voted no. Dr Fuller voted no. Dr Khairallah voted no. Dr Monto voted no. Dr. MacInnis voted no, Dr. Rubin voted no. Dr. Pergamon voted no. Dr. Sawyer voted yes, Dr. Offit. Voted no. So this vote did not pass since the majority voted no, thank you. Dr. Monto, I will hand it back to you if you wanted to go around the table right now.

Speaker1: [07:01:24] Let’s clear the raised hands and what we will now do is for those who wish to explain their vote and to. Uh, propose something that they might be in favor of, let’s take this up as the next question. So, Dr. Lee, is that your hand?

Speaker2: [07:02:27] You called my name. I did. I wasn’t sure if it was. Your microphone has been turned on. Thank you for allowing us to have this opportunity just to think through what maybe next steps are, and I think, you know, a lot of the concerns were articulated very well previously. I think that a lot of individuals do feel that there is a role for a another dose in populations, and we would like to see that come forward. We would also like to see some of the we don’t need it from the very small data set that was done in this third dose from Pfizer. But we really do need the broader safety data that’s already available to bring this question again further to other populations that would are in question still. So we I think I would support having my third dose available for other high risk groups that weren’t already given a third dose, such as individuals over the age of two, something 50 60. There’s different studies out there and then looking more closely at the safety data for those other individuals, and I would also like to know about

Speaker1: [07:03:47] How difficult I’m going to make it difficult for the speakers and ask them to come up with. And the question they would feel comfortable with. I don’t feel comfortable. Change your mind afterwards, but we need to start somewhere.

Speaker2: [07:04:04] All right. I would love to see something greater than 50. And I would also like to see data on the decrease in ability to spread the virus to those who are not able to get vaccinated.

Speaker1: [07:04:22] Thank you. Dr Chatterjee.

Speaker2: [07:04:29] Yes, thank you, Dr. Monto, I’d echo what what Haley said, but I do want to explain my vote. I have major concerns with regard to the extrapolation of data from much older populations to 16 and 17 year olds. We have no data on the safety in this population at all that have been presented so far and and that concerns me significantly. I also think that the safety database that has been presented is too small in terms of the benefits to clearly an older population. As I mentioned earlier, I think the Israeli data are very compelling for those over 60. I also noted that in most of the presentations, there was a big gap in people who are between 55 and 65. They were missing in the analyses. So I would say I’d like to see more data before I would recommend it for a younger age group, but over 60 is probably OK from my standpoint.

Speaker1: [07:05:30] Thank you. Dr. Carla. I think you are, yeah, agreeing, agreeing with the the the my colleagues, I think the safety safety database is inadequate, particularly in the populations that I really would like to see a boost that might be more much more appropriate. The effectiveness data is pretty much limited to boosting antibody levels and without a very good correlate of protection, we can’t really evaluate how effective that’s going to be. I also agree with the CDC that the incremental benefit to the younger population is really has not been demonstrated at all. And as I questioned the CDC earlier this morning, as the background rate of natural infections continues to increase in the population, the ability to actually discern the vaccine efficacy is going to decline. It’s going to look less effective over time just because of the high rate of prior natural infections that are occurring. So I think this needs to be teased out very carefully. I think we need to target the boosters right now to specifically to the people who are likely to be at high risk. And it’s an older population, it’s immunocompromised. I think if I wanted to include obesity probably be at a BMI of at least over 35 or something, something like that.

Speaker1: [07:07:01] People with diabetes, clearly all of the high risk factors that have been identified for serious COVID disease because I think ultimately that’s what we’re trying to do is to prevent the serious disease. I agree with my colleagues that reducing transmission is a very laudable goal. Ideally, we’d love to have a sterilizing. We’d love to have sterilizing immunity. But I haven’t seen any data to really address that one way or the other. So I don’t know how we would approve boosters on an expectation that transmission would be would be reduced at this point. So I think we need to target where we’re going to do boosters and continue to examine the potential efficacy of boosters in a broader population. Thank you, Dr. Carillo. Dr. Offit. But you know what, if I had to pick an age, by the way, I would pick sixty five. But one thing I would love to have and and I guess I challenge Amanda Cohn and the board with this, I would love to see the CDC provide data to answer the following question Is it possible to get control of this virus, meaning to provide a significant enough level of herd immunity that there is a dramatic decrease in transmission and hospitalization and death with two doses? I mean, so if you look at those countries or regions or states that have very, very high immunization rates in certain regions, do we dramatically reduce the incidence of hospitalization? In other words, because we’re not going to be great at preventing asymptomatic infection, we’re not going to be great at preventing mildly symptomatic infection.

Speaker1: [07:08:36] I really wish we didn’t use the term breakthroughs there, because if that’s true, then pretty much every vaccine that we have has at some level breakthroughs. I mean, the rotavirus vaccine that we worked on was not very good at preventing asymptomatic or mildly symptomatic. It’s very good at preventing moderate to severe disease. And so now residents don’t see rotavirus disease anymore. I’m glad they never called asymptomatic or mildly symptomatic rotavirus infection breakthroughs. So that’s my question to the CDC. Can you get control of this, this this infection with with two doses? What is the evidence factors? If you can’t, then that makes a compelling case for the third dose. But our Dr. Cohen, do you want to answer that question and what do you think the Israeli data with the high vaccination rates there contribute?

Speaker2: [07:09:21] So thanks, Dr. Offit. I am not I don’t have the data or the ability to answer that question completely right now. What I can say is at this moment, it is clear that the unvaccinated are driving transmission in the United States. And when we look at modeling, for example, in in congregate settings, it’s frequently outside community transmission and unvaccinated individuals that contribute to increased cases in the United States at this time, which I will caveat that with. I also think that other interventions, such as social distancing and masking, will have to be part of the solution. It’s I don’t know, vaccination will never, never be perfect, but I do believe that a third dose at some point in time, maybe not right now, maybe for groups of people who were vaccinated early right now will contribute to additional reduced transmission, especially in states and communities that do have high coverage and are still seeing cases. So it does make sense from a from a from the perspective of you need high protection. And given the differences in time in which we’ve vaccinated since last December until people really just getting vaccinated now that people who were vaccinated a long time ago and who may be have lower antibodies now, the boost will presumably prevent some additional transmission. But we really can’t answer that with data right now.

Speaker1: [07:11:02] And what do you think? What do you think the Israeli data and the Provincetown data? Oh, you. Amanda?

Speaker2: [07:11:16] So I think that it’s really data is very compelling, I think that we need a little bit more time we I totally believe that a booster dose will provide protection against disease and potentially even infection in individuals for a period of time. But I think we would prefer to see six weeks out or, you know, these things settle out over a longer period of time to have real evidence that the booster dose is contributing to reduced transmission and their in their overall population.

Speaker1: [07:11:50] One quick follow, if you don’t mind. Yeah, the it’s certainly true that for a vaccine like this is not surprising that neutralizing antibodies will decline over time and so we give a booster dose. It is also therefore very likely that over time, the booster dose and the increase in events will also decline over time. So are we talking about then annual biannual tri annual booster doses? Because I know that we’ve heard two things we’ve heard one booster dosing more frequently into this is a three dose vaccine. And then we’re done. I mean, how do you see it?

Speaker2: [07:12:24] Yeah, I believe Dr. I’m not going to

Speaker1: [07:12:28] Speculate about that. I have my own opinion and probably Amanda has her own opinion. But that’s not the question we’re being asked today. So let’s focus on where we are today, and let’s hear from Dr. Perlman. So I just wanted to make a couple of extra points. So first, I think if when we talk about transmission is many studies that show, in fact, that we really want to deal with transmission, we probably need to do something like deliver vaccine intranasally to actually induce prevent infection at that site. And that’s also a pretty clinical, but that certainly makes sense and it’s said by other speakers. The second thing is that when we talk about age, I also agree that this should be around 60. Others have different ages around there. But the group that I worry about that’s not included in over 60 and doesn’t have co-morbidities or health care workers because the systems are so overstretched now that we can’t even have health care workers get mild infections or be positive because by staying home, that puts even more of a risk on the failure of the whole system. So I don’t know how we put that into our equation, but I think that that’s a group that we have to consider as being possibly a candidate for a third vaccine. Thank you, Dr. Pearlman. That’s very helpful. Dr. Pergram. Dr. Pearlman stole my thunder with that comment, but I think he’s absolutely on target, I’m very concerned about health care systems that are already overstretched and many of which are unable to find additional people to fill in gaps that if we continue to

Speaker2: [07:14:17] Have even mildly symptomatic infections,

Speaker1: [07:14:22] It will actually put many health care systems in trouble. I think health care workers have to be considered as the potential population to be offering their doses because we don’t have a lot

Speaker2: [07:14:34] Of capacity and we can’t be losing

Speaker1: [07:14:35] People in hospitals to illness, which will take them out for a minimum of 10 days. And most of the situations and a large outbreak in a hospital system can be quite problematic. So I think we have to strongly consider to that group and I’d be

Speaker2: [07:14:49] Comfortable with people 60 and

Speaker1: [07:14:50] Older being another additional group that could get boosters beyond

Speaker2: [07:14:55] That. So I actually think the way that the ACIP had laid out how they might approve this

Speaker1: [07:15:00] Looked

Speaker2: [07:15:01] Feasible to me,

Speaker1: [07:15:03] And the groups that were the highest risk were in nursing home residents, people that were 10 to 65 and older and then health care workers who’d be the group that I’d be most comfortable with approving for a booster. Thank you, Dr. Levy. Hi, thank you for that. I agree with some of the other committee members who’ve mentioned that a third dose is likely beneficial. That’s already true for the immunocompromised. It’s likely beneficial, in my opinion, for the elderly and may eventually be indicated for the general population. I just don’t think we’re there yet in terms of the data. As other committee members have pointed out, more needs to be known about the correlates of protection, both antibody and cell mediated immunity. We are in an era of precision vaccinology that’s the basis of our Precision Vaccines program. We need age specific data. The risks for various adverse events vary with age, and therefore the data presented to our committee should mirror that of that age group if we are asked to vote in favor of use in that age group. And we also would like to see some data on impact on transmission. Finally, in terms of a revised question, I would advocate for one that’s phrased for ages 65 and up. That’s an age group where more severe COVID is seen, and that could be one way to to phrase the question, although 60 and up also matches the compelling data from Israel. So those are my opinions. Thank you. Thank you, Dr. Rubin. Well, I’m 63, so I’d like the 60 age instead of the sixty five age, but I and I think just exactly the the reason that Oprah just mentioned that that the safety data we have reflects 60 year olds.

Speaker1: [07:17:15] I think it would be great if we could give a sort of less restrictive language and to the rest of it, though, and offer it to people who are at higher risk of disease. That could be higher risk of developing severe disease because of their risk factors or higher risk because of exposure, such as health care workers. And the reason is we don’t that that’s quite a bit different from saying people should get a third dose because that gets closer to it being written in as a mandate that everyone should get it and we don’t. And I think none of us are ready for that or few of us are ready for that right now. It would be much easier to get practitioners the ability to give doses to people they think really need them based on the data that are out there and are rapidly changing right now. Next week, as people have pointed out, some of these things that are in preprints are actually likely to be out. Thank you, Dr. Rubin, Dr. Monto. Dr. Monto, yes. Dr. Monto, do you mind? We have a lot. We’re getting a lot of questions coming in. So Kathleen, can you please go over the vote total? People are wondering why there was an extra vote, and we want to make sure everybody online also understands why. So Kathleen, are you there?

Speaker2: [07:18:32] Yes, but I’m here. Sure, I can help clarify, we just had one speaker accidentally vote, but the final vote with two yeses and 16 no votes, thank you.

Speaker1: [07:18:52] Thank you. Thank you. Dr. Meissner, who surprisingly is the last one. To have his hand raised and. Would the FDA staff be ready for me to ask what they would propose as the next voting question after we hear from Dr. Meissner? We’ll be. We’ll be ready as soon as Dr. Meisner is done, thank you. All right, thank you. Thank you, Dr. Monitise. Look, you’re up, Cody. We hear we heard you. Is this OK? We’re we hear you. Yeah. Thank you. Ok. I just like to express a few thoughts, first of all. I, as has been stated, I don’t think a booster dose is going to significantly contribute to controlling the pandemic. And I think. It’s very important that the main message that we still transmit. Is that we’ve got to get everybody. Two doses, everyone has to get the primary series, this booster dose is not going to make a big difference. It’s not likely to make a big difference in in the behavior of this of this pandemic. Secondly. Again, I agree with what Dr. Mark said earlier that this is a killed vaccine and our experience with killed vaccines is quite clear that we need to have doses six months or longer apart in order to ensure protective immunity. But one of the questions, I think. It’s going to be very hard to do the trial, but if we could separate the distance, the length of time between the first dose. The second dose, it might not be necessary to give a third dose.

Speaker1: [07:21:26] I don’t know how we’ll be able to go about addressing that, that that issue, but I think that’s deserves some consideration. And then. Fourthly, and thirdly, in terms of the risks, people who have risk factors such as obesity. That that should have been my thinking is that that should apply to people under 65 years of age. I mean, there are clear risk factor groups who who fall into the risk of hospitalization and more severe disease who are under 60 or 65. And it seems to me we should probably include. Them in consideration of. A booster dose, and I’ll stop at that point, thank you. Thank you, Cody and Dr. Marks. And. I believe we’ve been getting ready a revised voting question, but I can while we’re getting that together for you, I believe hearing what you’ve been saying, what we would probably suggest is something along the lines of based on the totality of scientific evidence available, including the safety and effectiveness data from clinical trials. See five four or five nine one zero zero one. The potential benefits outweigh the potential risks of a Pfizer-BioNTech COVID 19 mRNA vaccine booster dose administered at least six months after completion of the primary series for use in individuals. Sixty five years of age and older and those judged to be at high risk of complications due to occupational exposure or underlying disease. Thank you. Question of problem, Kathleen, do we need that in writing before we vote? And if so, should we take a break?

Speaker2: [07:23:39] Dr. I think we can get the question ready in the voting pod, are we OK to do that or. Dr. Troy, I think you’re muted.

Speaker1: [07:23:53] We take a 10 minute break for. And Dr. Gruber, the Marion Gruber, do you have some comment?

Speaker2: [07:24:01] Yeah, I just wanted to make a suggestion while we actually put the slide together, as suggested by by Dr. Marx. Can we take a short break to to get this right? And also because it is now an area that is on the table, we could also remind the committee briefly, you. Boy, if that’s what people think, we don’t need these discussion questions any longer.

Speaker1: [07:24:30] We’re. Ok, let’s take let’s take a break then for. Is five minutes enough, would you think 10 minutes better and No.

Speaker2: [07:24:46] 10, but not more than 10 minutes?

Speaker1: [07:24:48] Ok, ten minutes, we’ll reconvene at five minutes after 4:00 Eastern. You. Enjoy this for yourself.

Speaker3: [07:31:31] I. And.

Speaker1: [07:41:57] Homestretch. All right, welcome back and thank you for allowing us to do that little break. We are all set. So, Dr. Monto, you want to take it away? Yes, I’d like to call on Dr. Fink from FDA, who is going to tell us about the next steps. Thank you, so following the vote for our first voting question, FDA recognizes that the committee had several concerns. One Concerns related to benefit risk balance in the general population of individuals 16 years of age and older, and a second question related to the data and level of evidence to support the safety and effectiveness of a booster dose. And so in response to these concerns, FDA has formulated a second voting question, and I want to make clear that the second voting question involves emergency use authorization rather than approval or licensure, which was the subject of the first voting question. So I’d like to spend just a few moments reminding the committee of some principles around emergency use authorization. These slides were previously presented in the October 20 20 VRBPAC meeting. So here on this slide are the criteria the statutory criteria for FDA issuance of an emergency use authorization. First, the agent referred to in the Emergency Use Authorization Declaration can cause a serious or life threatening disease or condition. We know this to be true for coronavirus, too. Secondly, the medical product may be effective to prevent, diagnose or treat the serious or life threatening condition caused by the agent. Third, the known and potential benefits of the product outweigh the known and potential risks of the product.

Speaker1: [07:44:10] In these second and third criteria are tied together in an overall benefit risk assessment. And finally, that no adequate, approved and available alternative to the product for diagnosing, preventing or treating the disease or condition. And so in this case, we are talking about the potential for emergency use authorization of a booster dose of the Pfizer BioNTech COVID vaccine that is not currently available. Next slide, please. Because. They have the next slide, please. Thank you. So issuance of an EUA for a COVID 19 vaccine or in this case for a booster dose of a specific COVID 19 vaccine, will specify the conditions for use in which benefit risk has been determined to be favorable based on the review of the totality of available data. And these conditions include the population to be included in the Emergency Use Authorization. The conditions for vaccine distribution and administration. And requirements for safety monitoring and reporting of adverse events for this specific proposed emergency use authorization. We would expect that the conditions for distribution and administration and requirements for safety monitoring and reporting of adverse events would remain the same as in the current emergency use authorization for the vaccine. Secondly, the Emergency Use Authorization will provide information to vaccine recipients and health care providers by way of prescribing information and factsheet to describe the investigational nature of the product, the known and potential benefits and risks and available alternatives, and the option to refuse vaccination. So what we’re talking about here is a revision of the current sheets for vaccination providers and vaccine recipients and their caregivers.

Speaker1: [07:46:12] Next slide, please. I also want to remind the committee that issuance of an EUA for any product, including a COVID 19 vaccine or a booster dose of the specific COVID 19 vaccine, may be revised or revoked if circumstances justifying the emergency use authorization no longer exist. If criteria for issuance are no longer met, either statutory criteria on the first slide or if other circumstances arise that warrant changes necessary to protect public health or safety, such as those based on new information concerning vaccine safety. Vaccine effectiveness, vaccine manufacturing or quality. Or a new information about COVID 19 epidemiology or pathogenesis. Next slide, please. So this is the voting question, number two, that we will ask the committee to consider based on the totality of scientific evidence available, including the safety and effectiveness data from clinical trial, see four or five nine one zero zero one two. The known and potential benefits outweigh the known and potential risks of the Pfizer-BioNTech COVID 19 vaccine booster dose administered at least six months after completion of the primary series for use in individuals 65 years of age and older, and individuals at high risk of severe COVID 19. That is the end of my presentation, thank you. Thank you, Doctor, thank. What I am proposing is that we move directly to this voting question. We’ve already had a lot of discussion and then for anybody who wants to explain their vote, we will go on to explanations of votes before we adjourn. So the voting question, should I be reading it for the record?

Speaker2: [07:48:13] So you think you.

Speaker1: [07:48:15] Based on the totality of scientific evidence available.

Speaker2: [07:48:32] Dr. Monto, I can’t hear you. Did we lose your audio?

Speaker1: [07:48:36] I think we did lose Arnold. I don’t know. Yeah, he dropped us. He hung up accident. Got me noticed it. The Prime. Michael Farr, chat checkboxes disappeared. Just a moment. I don’t know. I don’t know, we’ll just have we saw that. We’ll just let you start again. You just. Yes, go ahead. Yep. Have you got me? Yeah, we do, sir. Go ahead. Ok. We were doing too well in terms of the technology. So do the known and potential risks. I outweigh the known and potential known and potential risks of the Pfizer BioNTech vaccine booster dose administered at least six months after completion of the primary series for use in individuals 65 years of age and older, and individuals of higher at an individual at high risk of severe COVID 19.

Speaker2: [07:50:05] Three zero nine two two seven. Thank you. Hello.

Speaker1: [07:50:12] Yep, we have it. Okay, so again, to all my members, please make sure you control your own muting. Please make sure you are muting yourself. All right.

Speaker2: [07:50:23] Kathleen Hays, take it away. Yeah, thank you, Mike and Dr. Monto. So same process is the first voting question when you see the voting pod come up. Please select Yes, No or abstain and you will have two minutes. And just as a reminder, only voting members and temporary voting members can vote. Thank you. Go ahead. Ok, that was pretty quick. It looks like all of the votes are in. So we can close the poll and we do have a unanimous 18 out of 18 who voted yes for this question. And I will read the books aloud, for the record. Dr. Cohn. Yes, Dr. Portnoy. Yes, Dr. Lee. Yes, Dr. McInnis. Yes. Dr. Pearlman. Yes. Dr. Gans. Yes. Dr. Meissner. Yes. Dr. Chatterjee. Yes. Dr. Hildreth. Yes. Dr. Wharton. Yes. Dr. Fuller. Yes. Dr. Khairallah. Yes. Dr. Levy. Yes. Dr. Opiate. Yes. Dr. Rubin, yes. Dr. Pergram, yes, Dr. Sawyer. Yes. And Dr. Monto, yes. So thank you for your votes, and I will hand it back to Dr. Monto.

Speaker1: [07:51:56] Ok. Explanation of votes for those who have raised their hands, Cody Meissner. Dr. Monto, do you hear me? Yes. Yes. I would just like to ask Dr. Fink one question. So this the second bullet will apply to everyone who is 16 years of age or older that is at high risk. Is that correct? Well. But yeah, it’s the second bullet would apply to individuals for whom the vaccine is authorized, who are at high risk of severe COVID 19. Thank you. Well, maybe you understand, Typekit. Dr. Pergamon. Thanks. Thanks, Dr. Monto. I think the my only I voted yes on this, my only concern was the comment of high risk severe COVID 19

Speaker2: [07:53:20] Because

Speaker1: [07:53:20] I do think this will potentially put health care workers in a different situation. They’re not necessarily at risk for severe COVID, but for developing COVID. So I just want to reiterate that I think that health care workers are a particularly high risk group for acquisition as

Speaker2: [07:53:39] The antibodies wane, and we have not addressed that in this particular statement.

Speaker1: [07:53:47] Thank you, Dr. Pergram, I just want to remind the committee that the ACIP will be meeting to fine tune some of our recommendations. Dr. Sawyer. They. I just wanted to explain both my votes since I voted yes on the first question, one of the distinct minority. Are you hearing me OK? My camera is not working for some reason. Yes, we hear you. Ok. So I voted yes on the first question because I thought it was the quickest, most efficient way and most flexible way for providers to be able to target certain populations. But I’m certainly comfortable with this as long as the ACIP provides enough additional guidance about exactly who we think are most concerning. Dr. Portnoy’s. So you’re inviting the two guest speakers from the previous question to address each other at one right after the other. I’d like to explain it was just chance. Oh OK. Well, both of my answers are kind of like what we just heard. I think that it’s great that this becomes available because this vaccine is something that I believe really has an opportunity to stem the COVID epidemic. Health care workers are at high risk of catching COVID. They’re not at risk of severe COVID, but we’re at risk of spreading it to our patients. So I think it’s really important that we not get infected with.

Speaker1: [07:55:33] The most dangerous thing is that asymptomatic infection, if you get infected with COVID and you don’t know you have it, you’re more likely to spread it. And that’s what the doubly vaccinated people are most at risk of having. So I think it’s really important that we consider that when we decide about approval, but I’m really glad that we authorized this vaccine for a third does and I plan to go out and get my third vaccine this afternoon. Thank you. Thank you, Dr. Carla. Thank you. Thank you, Arnold gets my camera isn’t working again, either. Yeah, just want to do. Just wanted to say that I really appreciate the rewording of the question. I think it more targets what with the available data that we have where where a a booster dose is going to be likely to be most effective. I think it does highlight, though, in a lot of the discussions, we had some of the outstanding questions that still remain and the vaccine manufacturers and the academic community really need to be focused on addressing some of those transmissibility and the relationship between vaccination and the number of doses, I think is a very important question and really understanding the true correlates of protection and how that can inform durability assessments going forward, I think still remain an open question.

Speaker1: [07:57:05] We just can’t simply be in a position where we would just be vaccinating people every time we think there’s a problem. So we really need to get a better handle on understanding exactly how these vaccines are mediating protection and the durability of that protection. Thank you. Thank you, Dr. Pearlman. Yeah, I just wanted to extend the question that Dr. Rice. So at the ACIP meetings, can they consider basically the use of the vaccine in a group that wouldn’t necessarily be under either these two categories? So the with the health care workers not being in either one, the the. I think I believe you said that the ACIP could still include them, but can they include them if it’s not in these categories that the FDA has may approve? Dr. Pearlman, the next one who has raised her hand as Dr. Cohen, who may be Dr. Marks, who would you like to jump in? This is Dr. Mark. I would very much like to jump in here. We are not bound at FDA by your vote, just so you understand that we can tweak this as need be. And I would ask formally, Dr. Monto, without further ado from anyone else from FDA jumping in for you to pull the members as to whether or not health care workers at be included or not in this, or whether there’s any other risk group that they would like to.

Speaker1: [07:58:51] We do not have to take a vote on that question. We will take that back and then we can refine this question as we need to base on the member. So this is not a voting question, but I am requesting that you ask all 18 members to ask and tell them how they might further refine this in any way. We would really appreciate that because that is why we moved to this kind of a pathway because we have more flexibility. Thanks very much. Ok, we need instructions as how to be polled rather than ask. Dr. Monto, and problem that I can put up a what we call a short answer with the question being and clarify will clarify the question how how should we further refine? And then, Dr. Marx, what would you ask? He said of that. Let’s ask the question. Good health care workers be included. In this EU. But that’s fine by me. That’s fine. I’m always against open ended questions. Ok. Before anybody vote, I’m just going to answer.

Speaker2: [08:00:10] This is Amanda, could I suggest even some language like people at high risk for occupational exposure as opposed to even just do that?

Speaker1: [08:00:21] I totally agree. I totally agree with Amanda because I think we’d be leaving a lot of people out if we did. I want to make sure that the committee understands when we’re saying people at high risk for occupational exposure. What we will be taking that to mean at FDA is health care workers, frontline workers such as teachers and potentially essential infrastructure workers as well. Is that is that what we’re taking there? Yes. Yes. Ok, thank you. Ok, so can I just I want to make sure I captured what Dr. Cohen said, you said, should health care workers and somebody else be included in this eoa? What was the other one?

Speaker2: [08:01:08] It’s going to our

Speaker1: [08:01:10] Own Amanda, can you just. I think you had it very nicely formulated if you could just say it slowly so that it can be captured. Thank you.

Speaker2: [08:01:20] I think it’s individuals at high risk for occupational exposure.

Speaker1: [08:01:26] Ok. Should individuals and. High risk for occupational. Exposure. Exposure be included in this, OK? All right. I’m just going to check this real quick. Kathleen, let’s just see. Should health care workers? I got it. I do have one question, though why does it have to be occupational exposure? Can it just be any exposure? Does it have to just be in part of their job? I think that’s a can of worms, frankly. All right, so Dr. Marks and Arnold, Dr. Monto, if you would please check what I put on there. I think that that really makes makes it very difficult to interpret because anybody could be at high risk. If you have a if you have a child who’s in school, you might consider yourself being at high risk. So I would prefer leaving it as occupational exposure. Ok, so right now, this is again, this is not a voting question, this is just a question to the committee. Hold on. I just want to make sure we we just get there’s a. It looks like to me, there’s maybe a parsing error because it should health care workers or others at high risk, right? Because I think that was what was added there. It wasn’t just health care workers, it was other individuals. Is that correct, Dr. Monto? Yes, that is correct. And there’s an arm missing from workers. Thank you. Sorry. Spelling is not my strong suit, but actually that one I thought I caught you. There you go. Yep, got it. There we go. Should health care workers or others at high risk for occupational exposure be included in this eoa? Ok. Again, this is not a voting question. Doctor Dr. Atreyu or. Could you could you

Speaker2: [08:03:44] Excuse spelling on health care, please?

Speaker1: [08:03:47] Hold on. I can’t even read I can’t even see what I’m typing here. Here we go. There you go. People who are doing gardening, right? Yep, there we go. No, no. Here we go. Ok. I think we’re good. Will ACP further define these groups? That’s certainly within their purview that they could do that. Now, this is not a voting question, again, this is just you are polling the committee, am I correct? That’s what they they’re. Kathleen, how would you like to looks like it’s become a voting question? Well, it’s just this is just a poll I just putting an out of voting question, but just a poll just to pull you, ask for it to be a poll perfect. Thank you very much. And I will clarify it, even in the language on top. That we are just pulling. Polling the committee. Ok.

Speaker2: [08:05:12] And Dr. Monto, it looks like everyone was in agreement for this question.

Speaker1: [08:05:18] For all, thank you very much as a whole, I will simply report. For the record, that everybody was in agreement with the poll based on this statement, should health care workers or others at high risk for occupational exposure be included in this EÜ? Ok. Now, a number of people still have their hands raised. Do all of them? Continue to wish to make give explanations of votes. Starting with Dr. Cohen.

Speaker2: [08:06:20] Sure, I think I had my hand raised from previously, but I just want to say that I think this is a really amazing vote for people who are at severe risk for older adults and as well as people who are at risk in health care settings and other high risk settings and service will protect them. And I and I just wanted to remind everyone that if you look at when people got vaccinated and how many months out they are, that these are the groups that got vaccinated last December and January and February. So these are the groups that are really beyond six months out and should be boosted in the present time. I’m hopeful that FDA and or VRBPAC come back when there are more data available to do evaluate use of this vaccine as a booster dose in younger age groups.

Speaker1: [08:07:17] Thank you. And I think that’s the beauty of an EUA. I think based on past experience, it can be changed based on changing data. Dr. Chatterjee.

Speaker2: [08:07:37] I said, come on until. I just wanted to echo what what Amanda said, so I’m not going to do that, but I do want to take one moment to actually recognize our colleagues at the FDA and their willingness to work with us on these questions, on the voting questions. I think this should demonstrate to the public that the members of this committee are independent of the FDA and that in fact we do bring our voices to the table when we are asked to serve on this committee.

Speaker1: [08:08:06] Thank you very much, Dr. Chatterjee. A good note to. Below is the meeting. Let me just thank the committee members, and especially Dr. Marion Gruber, carnival crowds for their long time service. And I’d like to turn the meeting over to Dr. Atreyu to formally close it.

Speaker3: [08:08:40] Thank you all, thank you for the wonderful discussions and

Speaker2: [08:08:43] Productive meeting today, and this meeting is formally in June. And thank you all.

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