The Food and Drug Administration (FDA) and the Center for Biologics Evaluation (CEBR) Vaccines and Related Biological Products Advisory Committee met on June 14th and 15th, 2022 to review the Emergency Use Authorization amendment requests for the Pfizer-BioNTech COVID-19 Vaccine formulated for use in children 6 months to age 5 AND Moderna COVID-19 Vaccine formulated for use in children 6 months to 6 years.
The 174th Meeting of the Vaccines and Related Biological Products Committee meeting on June 15th (open session of over 7 hours long) is available at this link.
While I encourage everyone to review all of the presentations and data, I know that it took me 3 days to find the time to do it. Below are a few highlights and I have added approximate time points so one can speed ahead to parts that they are most interested in learning about. For example the Open Public Hearing with comments from 19 individuals from the American public begins at 4 hours and 39 minutes. Even a member of Congress weighs in.
I look at getting our son vaccinated as similar to the process to prepare our son for school. The decision is a personal one, but the data is compelling. Just as children take time to learn the knowledge and memory needed for writing and recognizing their name, the adaptive immune system needs training for each new pathogen. Over time, recognizing letters and words (foreign RNA and novel spike protein sequences) in new patterns become easier. That said, Omicron is an especially tough lesson for children with no prior SARS-CoV-2 exposure or passive (maternal) immunity. Parents routinely vaccinate their children against influenza, varicella (chicken-pox), rubella, hepatitis A, and rotavirus. Imagine a disease where the deaths per year are higher than each of these combined in their respective pre-vaccine era. That is Omicron and the many Omicron subvariants.
The 3 dose Pfizer and 2 dose Moderna pediatric formulations require TIME to build an ample antibody and immune compartment. These studies were conducted during the Omicron period where a peak of 1. 4 million cases per day were reported in the US. Of the 45,000 children under 5 that have been hospitalized due to COVID-19 since the beginning of the pandemic, half of these were during the Omicron surge of winter 2022. 24% of hospitalizations required ICU-level care. 63% of children under 5 hospitalized due to SARS-CoV-2 had NO underlying conditions. With an Omicron-specific vaccine on the way (Moderna’s 1273.214 in trials now and bivalent vaccines will be discussed by this committee in 2 weeks) getting the first doses underway this summer will begin the immune system training against this quickly evolving coronavirus. Just as adults have had to be boosted when new strains come along, I expect additional doses to be added to these pediatric formulations.
I anticipate when vaccinations roll out there to be reports of febrile seizures after vaccination due to the common reaction of fever post vaccine doses reported in both trials. Febrile seizures happen in about 3% of children in this age population at baseline. There was one case of a 17 month old female that had a seizure and rash within days of her first injection of Moderna. Another viral infection was not ruled out. The care team advised and her parents permitted her to stay in the study and she had no additional neurological sequelae. There were no new safety signals seen in the youngest age group of patients enrolled in either study that were not seen in the adolescent or adult trials.
It is important to caution that these are relatively small studies (5000 to 6000 enrolled for each company) with a short follow-up time. New safety signals that are more rare may come up. More studies are needed and are ongoing. Co-administration with other pediatric vaccines has not been tested.
While not every family will make the choice to vaccinate, it is a great step forward to allow parents and caregivers the option to vaccinate in the hopes to prevent severe illness, Long Covid, hospitalizations, and even deaths due to COVID-19.
Meeting notes:
The committee comprised of the following VRBPAC members: Dr. Arnoldo Monto (Chair), Dr. Prabhakara Atreya, Dr. Adam Berger, Dr. Hayley Gans, Dr. Henry (Hank) Bernstein, Dr. Archana Chatterjee, Dr. Amanda Cohn, Dr. David Kim, Dr. Paul Offit, Dr. Steven (Steve) A. Pergam, Dr. Jay Portnoy, and Dr. Eric Rubin. Temporary voting members include Dr. Oveta Fuller, Dr. James Hildreth, Dr. Jeannette Lee, Dr. Ofer Levy, Dr. Wayne Marasco, Dr. Pamela McInnes, Dr. Cody Meissner, Dr. Michael (Mike) Nelson, Dr. Art Reingold, Dr. Mark Sawyer, and Dr. Melinda Wharton. Dr. Paula Annuziato is the non-voting industry representative. All members were found to be in compliance with Federal conflict of interest laws included in 18 U.S.C. § 208. Dr. James Hildreth has a conflict and was granted a waiver that is available here on the FDA website. (He is the President of the Meharry Medical college that will be involved in upcoming vaccine trials. Dr. Hildreth will not receive any remuneration from those upcoming trials.)
These physicians and scientists representing academic and non-profit research groups, industry, and hospitals were asked after hearing the data to answer two YES or NO questions:
“Based on the totality of scientific evidence available, do the benefits of the Moderna COVID-19 Vaccine when administered as a 2-dose series (25 mcg each dose) outweigh its risks for use in children 6 months through 5 years of age?”
“Based on the totality of scientific evidence available, do the benefits of the PfizerBioNTech COVID-19 Vaccine when administered as a 3-dose series (3 µg each dose) outweigh its risks for use in children 6 months to 4 years of age?”
The votes were
Moderna: 21 YES, with 0 NO votes, and no abstentions.
PfizerBioNTech: 21 YES, with 0 NO votes, and no abstentions.
Here are a few highlights and I have added approximate time points so one can speed ahead to parts that they are most interested in learning about.
26 minutes: Dr. Peter Marks highlighted the data from the MMWR March 18, 2022 report (Vol. 71. No. 11) remarking that the omicron wave brought significant pediatric hospitalizations in the youngest children.
42 minutes: Dr. Carla Vinals of Moderna reported that in terms of safety, immunogenicity, and efficacy results that no NEW safety concerns were identified and real-world efficacy was shown during the omicron period a few months ago.
46 minutes: Dr. Evan Anderson described the unmet medical need for this vaccine and debunked misperceptions about the burden of COVID-19 in children 0 to 4.
63% of children 0-4 that are hospitalized with COVID-19 have NO underlying medical conditions.
There have been 147 deaths due to COVID19 in the 0 to 4 year old population in the first 5 months of 2022 and educational pre-school and childcare settings have been extremely disrupted in this population due to the high burden of disease.
The take-home for me from his remarks are the number of deaths per year due to COVID-19 are higher than the pre-vaccination levels of death per year for influenza, varicella, rubella, hepatitis A, and rotavirus (ALMOST combined each year)!
53 minutes: Dr. Ritaparna (Rita) Das discussed Study 204, and the dose responses of 25 ug, or 50ug versus the saline placebo. This study period had a peak of 1.4 million cases per day in the United States, where the majority of patients were enrolled. Only one severe adverse event (SAE) was determined to be vaccine-related. A 17 month old female had a febrile seizure and had a rash shortly after vaccination. Upon follow-up it was determined that it was safe for the patient to remain in the study and she received a second dose with no adverse events after the second dose.
For local reactions, pain was the most common and was characterized as low grade (1 or 2 severity) but it was similar to placebo groups that received saline injections, especially in the 6 to 23 month age group. Systemic reactions were fatigue and fevers, but most less than 39 degrees C. Fever was also common in the placebo group as this study group was conducted during a peak viral illnesses in the winter months of 2022.
There were 4 infections over 40 degrees C or 104 degrees F. One fever and resulting febrile seizure was considered study-related and an SAE as I shared before. Two of the high fevers were attributed to viral illness and one fever was attributed to the patient’s history of an underlying fever-related syndrome. One child had uticaria (hives) after Dose 1 and was discontinued in the study as this is considered an Adverse Event and the child is not likely a good candidate for this vaccine.
The immunogenicity data compared Study 204 to Study 301, or the 18-25 year old age group receiving two 100 ug doses, 1 month apart. The 6 to 23 month group had a GMT of 1.28 and the 2-5 year old group had a GMT of 1.01 showing non-inferiority.
Vaccine efficacy (VE) had both a CDC definition and a 301 case definition.
CDC VE 2-5 year olds: 36.8%
Study 301 VE in 2-5 year olds: 46.4%
CDC VE 6 to 23 month olds: 50.6%
Study 301 VE in 6 to 23 month olds: 31.5%
Compared to real-world data generated through Kaiser Permanente, vaccination was 84.5% effective against HOSPITALIZATION in this population.
1 hour 31 minutes: Dr. Robin Wisch described the immunobridging data and efficacy results. 6% of the vaccine-arm and 7% of the children in the placebo group were seropositive for SARS-CoV-2 at baseline in the 6-23 month age group. 9% of the vaccine-arm and 8% of the placebo—arm were seropositive at baseline in the 2 to 5 year olds.
No events met the CDC criteria for probable or confirmed myocarditis or pericarditis through the data cutoff of February 21, 2022 (median 68 days follow-up post Dose 2) in the 6-23 month group or the 2 to 5 year olds.
2 hours 35 minutes: Dr. William (Bill) Gruber discussed the BNT162b2 vaccine data.
7% of study participants were SARS-CoV2 seropositive. There were no severe or Grade 4 reactions including:
NO vaccine-related anaphylaxis
NO myocarditis/pericardidis
NO Bell’s palsy
NO MIS-C
Immunogenicity results: Non-inferior compared to 16-25 year olds receiving 2 doses of 30 ug
GMR of 1.3 for 2-5 year age group and 1.19 for 6-23 month age group
Efficacy: (Taken with a grain of salt due to the large confidence intervals): 80.3% after the third dose
6-23 month age group: 75.5% and 2-5 year age group: 82.3%
3 hours 19 minutes: Dr. Susan Wollersheim, FDA CBER review of Effectiveness and Safety
Dose selection considerations were discussed.
Patients from the US, Finland, Poland, and Spain were enrolled.
6-23 months: n=1776
2-4 years: n=2750
The study was blinded with some cases of unblinding described, i.e. when a child turned 5 before the added Dose 3, a child would be unblinded to allow to leave the study to get vaccinated or not with the approved formulation.
Immunogenicity results: Non-inferior compared to 16-25 year old age group receiving 2 doses of 30 ug
GMR of 1.3 for 2-5 year age group and 1.19 for 6 to 23 month age group
Used: USA WA1/2020 (Reference), B.1.617.2 Delta variant, and B.1.1.529 Omicron variant ratios at 1 month post Dose 3 versus Dose 2:
Efficacy (Taken with a grain of salt due to the large confidence intervals):
Two weeks after Dose 3 (Roughly 4 months after Dose 1):
6 to 23 month age group: 75.6%
2-5 year old age group: 82.4%
LIMITED by small numbers and short follow-up time.
4 hours 39 minutes: Open Public Hearing
Speakers: Jasmine King, Dr. Ashley Serrano, Michael Baker, Fatima Khan, Nicholas Giglia, Lauren Dunnington, Kathlyn Kinesley, Melissa Braveman, Congressman Louie Gohmert, Dr. Harvey Klein, Dr. Kailey Soller, Shae Lynn, Kate Schenk, Tamara Thomson, Sam Dodson, Donna Treubig, Catharine Diehl, Jessica Nehring, Katarina Lindley, and Caroline Bishop.
5 hours 46 minutes: Q&A Moderna Panel
The panel responded to questions about the choice of 25 ug vs. 50 ug. While the response was dose-dependent, the safety advisors recommended the lower dose to balance the safety and still achieve non-inferior immunogenicity.
6 hours 4 minutes: Safety Data
6 hours 11 minutes: Moderna Vote Discussion
7 hours: Q&A Pfizer
7 hours 7 minutes: Pfizer Voting Discussion
Dr. Paul Offit asked about the data following Dose 2 and shared his concerns of low to no visible change in the curves. Namely, his fear is the 3ug may be under dosed and that parents should be aware that life does not go back to normal after Dose 1 or 2, but rather months later after Dose 3.
Others echoed his concerns.
7 hours 19 minutes: Pfizer/BioNTech Vote
7 hours 23 minutes: Vote explanations
Dr. Archana Chatterjee describes the evolution of her confidence in this technology and WHY she was a NO vote in December of 2020 for the 1st mRNA vaccine. She was not alone as 4 voted NO then and wanted more data before providing an EUA.
