The Food and Drug Administration (FDA) and the Center for Biologics Evaluation (CEBR) Vaccines and Related Biological Products Advisory Committee met on October 26, 2021 to, in part, review the Emergency Use Authorization amendment request for Pfizer-BioNTech COVID-19 Vaccine for use in children 5 through <12 years of age.
The 170th Meeting of the Vaccines and Related Biological Products Committee full meeting (open session of over 8 hours long) is available at this link.
The committee comprised of Dr. Arnoldo Monto, Dr. Amanda Cohn, Dr. Hayley Gans, Dr. Michael Kurilla, Dr. Cody Meissner, Dr. Paul Offit, Dr. Steve A. Pergam, Dr. Oveta Fuller, Dr. James Hildreth, Dr. Jeannette Lee, Dr. Patrick (Pat) Moore, Dr. Michael (Mike) Nelson, Dr. Stanley Perlman, Dr. Jay Portnoy, Dr. Eric Ruben, Dr. Mark Sawyer, Dr. Melinda Wharton and the non-voting industry representative Dr. Paula Annuziato were in compliance with Federal conflict of interest laws included in 18 U.S.C. § 208. These physicians and scientists representing academic and non-profit research groups, industry, and hospitals were asked after hearing the data to answer one question:
“Based on the totality of scientific evidence available, do the benefits of the PfizerBioNTech COVID-19 Vaccine when administered as a 2-dose series (10 µg each dose, 3 weeks apart) outweigh its risks for use in children 5-11 years of age?”
The vote was 17 YES, with 0 NO votes, and 1 abstention.
While I encourage everyone to review all of the presentations and data, here are a few highlights:
Dr. Doran Fink introduced the latest data of the US burden of disease due to COVID-19 including 1.9 million reported cases in children 5 to 11. The most recent data (week ending October 10th) shows that while children age 5 to 11 make up 8.7% of the population, they were accounting for 10.6% of all COVID-19 cases, the highest of any age group.
Dr. Ram Naik describes the change from the PBS buffer in the formulation to a TRIS buffer. This allows for a 10 week storage at 2 to 8 degree C storage versus using -20 to -80 degree storage.
Dr. Fiona Havers describes the epidemiology and risk factors in the pediatric population, noting that COVID-19 is the now the 8th leading cause of death in children. 39% of MIS-C cases have occurred in children 6 to 11 years old as well as the high levels of seroprevalence in their surveillance efforts of 50,000 samples in children every two weeks. Of note, 42% of samples from 5 to 11 year old-children in the May-June 2021 time period were positive for antibodies to the nucleoprotein. Perhaps most disturbing was her data on Post-COVID conditions in children that have a myriad of symptoms weeks and months after the infection. In addition, Dr. Havers described the closures affecting 2074 schools from August 2, 2021 to October 8, 2021 due to large scale outbreaks mostly in Texas, Georgia, and Kentucky. This has affected over 1 million children and their families in a two month period.
Dr. Matthew Oster (begins at 1 hour and 28 minutes) shares the prevalence data of myocarditis in the pre-COVID era, prevalence of myocarditis seen in individuals after SARS-CoV-2 infection, and review of myocarditis cases after COVID-19 vaccination. Dr. Oster is careful to describe how myocarditis differs in “classical” myocarditis, MIS-C myocarditis, post-COVID-19 myocarditis, and post- mRNA vaccine myocarditis in terms of measures of troponin, lymphocytes, C-reactive protein, platelets, and Echocardiogram ejection fraction recovery time. The data presented includes a review of 169,740,953 mRNA vaccine doses in males and 193,215,313 doses in females. Dr. Oster describes the 877 cases that met case definitions that result in an estimated 54 excess cases of myocarditis per one million adults fully vaccinated. Dr. Oster emphasized that children with acute myocarditis do well over time, while adults have more difficulty recovering than children.
The full data for the EUA amendment is available for download here.
The study had 2 cohorts. Cohort 1 was evaluated in terms of safety and immune response (in vitro immune assay responses) had 1,528 BNT162b2 10 µg participants and 757 placebo participants. Safety data included solicited ARs, unsolicited AEs, SAEs and AEs of clinical interest were assessed in a total of 2,268 (1,518 10 µg BNT162b2, 750 placebo) participants 5-11 years of age; 95% of participants in each study group completed at least 2 months of safety follow-up after Dose 2. Comparator group for immunogenicity: The comparator group for immunobridging analyses consisted of 300 evaluable participants 16-25 years of age who received both doses of BNT162b2 30 µg and were randomly selected from study C4591001 Phase 2/3.
In the Phase 2/3 safety expansion, a second cohort of 1,598 participants were randomized to receive BNT162b2 and 796 were randomized to placebo. At the time of the October 8, 2021 cutoff, most participants (98.7%) had received both Dose 1 and Dose 2. Seven participants in the BNT162b2 group did not receive vaccine, for a Safety Population of 1,591. One participant in the BNT162b2 group discontinued from the vaccination period due to AEs of pyrexia and neutropenia that worsened from baseline (see Section 7.6.7, AEs leading to withdrawal). Two participants (0.1%) in the BNT162b2 group withdrew from the study before the 1 month period. Neither withdrawal was due to an AE.
The following AEs were considered Grade 3 in severity: 1 tic, 1 rash (bilateral pleomorphic light eruption on arms). No Grade 4 (life-threatening AEs) were observed in the study. In Cohort 2, lymphadenopathy was reported in 6 (0.4%) vaccine recipients and 3 placebo recipients (0.4%).
Table 6 shows the neutralizing antibody levels comparing 264 samples from vaccinated Age 5-11 to 253 samples of the vaccinated Age 16-25 from study C4591001. The GMT values were an average of 1197.6 and 1146.5, respectively for a ratio of 1.04, showing non-inferiority.
Table 7 shows the same rate of neutralization in those two cohorts. Table 8 shows the difference of the Age 5-11 samples in plaque reduction assays comparing the delta variant strain to the reference strain, recombinant USA_WA1/2020. The GMT for the delta variant was 294, versus 365.3 for the reference strain.
I have included the risk analysis scenarios posed below for the potential of myocarditis/pericarditis post two-doses of 10 micrograms of mRNA vaccine, 3 weeks apart, per 1 million fully-vaccinated 5 to 11 year old children compared to the respective benefit of COVID-19 cases averted taking into account various outbreak scenarios.
For example, using this model in Scenario 2, if children age 5 to 11 become vaccinated and the United States experiences transmission levels like the delta wave we had in late August, at least 54,345 COVID cases in the vaccinated children, and 250 hospitalizations (average of 5 day hospital stay) will be avoided but with the potential of 92 mRNA-vaccine induced myocarditis cases that require a 1 day hospital stay during the same time period.
Myocarditis risks by age and sex.
Scenario 1: COVID-19 incidence as of September 11, 2021, VE 70% vs. COVID-19 cases and 80% vs. COVID-19 hospitalization.
Scenario 2: COVID-19 incidence at peak of U.S. Delta variant surge at end of August 2021, VE 70% vs. COVID-19 cases and 80% vs. COVID-19 hospitalization.
Scenario 3: COVID-19 incidence as of nadir in June 2021, VE 70% vs. COVID-19 cases and 80% vs. COVID-19 hospitalization.
Scenario 4: COVID-19 incidence as of September 11, 2021, VE 90% vs. COVID-19 cases and 100% vs. COVID-19 hospitalization.
Scenario 5: COVID-19 case incidence as of September 11, 2021, VE 70% vs. COVID-19 cases and 80% vs. COVID-19. hospitalization, COVID-19 death rate 300% that of Scenario 1.
Scenario 6: COVID-19 incidence as of September 11, 2021, VE 70% vs. COVID-19 cases and 80% vs. COVID-19 hospitalization, excess myocarditis cases 50% of Scenario 1.