Participants who stopped the vaccination regimen were allowed to stay in the study. In the Phase 2-3 study, reasons for not receiving the first dose included withdrawal (14 children), no longer meeting eligibility criteria (2 children), and deviation from protocol (1 child). Discontinuations or discontinuations after the first dose were due to a decision by the parent or guardian or by the participant, except one, for which the reason was classified as “other”. In the Phase 2-3 study, one participant randomly assigned to receive placebo was incorrectly administered BNT162b2 for both doses. Therefore, 1518 participants received dose 1 of BNT162b2 and 750 participants received dose 1 placebo.
From March 24 to April 14, 2021, a total of 50 children aged 5 to 11 years were screened for admission at four sites in the US, and 48 received escalating doses of the BNT162b2 vaccine (Figure 1). Half of the children were male, 79% were White, 6% were Black, 10% were Asian, and 8% were Hispanic or Latinx. The mean age was 7.9 years (Table S2).
From June 7 to June 19, 2021, a total of 2,316 children ages 5 to 11 were screened for inclusion and 2,285 underwent randomization at 81 sites in the United States, Spain, Finland, and Poland; 2268 participants received injections, 1517 were randomly assigned to BNT162b2, and 751 received placebo (Figure 1). One participant randomly assigned to receive placebo was incorrectly administered BNT162b2 for both doses; therefore 1518 participants received dose 1 of BNT162b2 and 750 participants received dose 1 placebo. More than 99% of the participants received a second dose. At the data cut-off date, the median follow-up time was 2.3 months (range 0 to 2.5); 95% of participants had available safety data for at least 2 months of follow-up after the second dose. Overall, 52% were male, 79% were White, 6% were Black, 6% were Asian, and 21% were Hispanic or Latinx (table 1). The mean age was 8.2 years; 20% of the children had co-existing conditions (including 12% with obesity and approximately 8% with asthma), and 9% were SARS-CoV-2 positive at baseline. Aside from younger age and a lower percentage of Black and Hispanic or Latinx 5 to 11 year olds (6% and 18%, respectively) than 16 to 25 year olds (12% and 36%), respectively), demographics were similar between the 5-to-11-year-old and 16-to-25-year-old BNT162b2 recipients included in the immunobridging subset (Table S3).
Phase 1 Safety and Immunogenicity
Most local reactions were mild to moderate and all were transient (Fig. S1A and Table S4). Fever was more common in the 30 g dose level group than in the 10 g and 20 g dose level groups after the first and second dose (Fig. S1B). All four sentinel participants in the 30 g dose level group who received the second 30 g dose had mild to moderate fever within 7 days; the remaining 12 participants in the 30 g dose level group received a second 10 g dose approximately 1 month after the first dose, as recommended by the internal review committee after selecting the phase 2-3 dose. Adverse reactions from the first dose through 1 month after the second dose were reported by 43.8% of participants who received two 10 µg doses of BNT162b2, 31.3% of those who received two 20 µg doses, and 50.0% of those who received two 10 g doses. Doses of 30 g (Table S6). One serious adverse reaction (grade 3 pyrexia) in a 10-year-old participant started on the day of the second 20 µg dose of BNT162b2, with temperature reaching 39.7°C the day after vaccination and disappearing the following day. . Antipyretic drugs were used and the researcher believed the event was related to receiving the BNT162b2 vaccine.
Serum neutralizing GMTs 7 days after the second dose were 4163 with the 10-μg dose of BNT162b2 and 4583 with the 20-μg dose (Fig. S2). Based on these safety and immunogenicity findings, the dose level of 10 g was selected for further assessment in 5 to 11 year olds in stage 2-3.
Phase 2-3 Safety
Panel A shows local reactions and Panel B shows systemic events after the first and second dose in recipients of the BNT162b2 vaccine (dose 1, 1511 children; dose 2, 1501 children) and placebo (dose 1, 748 or 749 children; dose 2 , 740 or 741 children). The numbers refer to the number of children who gave at least one “yes” or “no” answer to the specified event after each dose; responses may not have been reported for every type of event. Severity scales are summarized in Table S5; Fever categories are indicated in the key. The numbers above the bars are the percentage of participants in each group with the specified local response or systemic event. 𝙸 bars represent 95% confidence intervals. One participant in the BNT162b2 group had a fever of 40.0°C after the second dose.
BNT162b2 recipients reported more local reactions and systemic events than placebo recipients (Figure 2). The reported reactions and events were generally mild to moderate and lasted 1 to 2 days (Table S4). Injection site pain was the most common local reaction and occurred in 71 to 74% of BNT162b2 recipients. Severe injection site pain after the first or second dose was reported in 0.6% of BNT162b2 recipients and no placebo recipient. Fatigue and headache were the most commonly reported systemic events. Severe fatigue (0.9%), headache (0.3%), chills (0.1%) and myalgia (0.1%) were also reported after the first or second dose of BNT162b2. The frequencies of fatigue, headache and chills were similar among BNT162b2 and placebo recipients after the first dose and were more common among BNT162b2 recipients than among placebo recipients after the second dose. In general, systemic events were reported more frequently after the second dose of BNT162b2 than after the first dose. Fever occurred in 8.3% of BNT162b2 recipients after the first or second dose. Antipyretic use among recipients of BNT162b2 was more common after the second dose than after the first dose. One recipient of BNT162b2 had a temperature of 40.0°C (104°F) 2 days after the second dose; antipyretics were used and the fever resolved the next day.
From the first dose through 1 month after the second dose, adverse reactions were reported by 10.9% of BNT162b2 recipients and 9.2% of placebo recipients (Table S7). Slightly more BNT162b2 recipients (3.0%) than placebo recipients (2.1%) reported side effects that the researchers said were related to the vaccine or placebo. Serious adverse events were reported in 0.1% of BNT162b2 recipients and 0.1% of placebo recipients. Three serious adverse events in two participants were reported at the cut-off date; all three (post-injury abdominal pain and pancreatitis in a placebo recipient and arm fracture in a BNT162b2 recipient) were considered unrelated to the vaccine or placebo. No deaths or side effects leading to withdrawal were reported.
Lymphadenopathy was reported in 10 BNT162b2 recipients (0.9%) and 1 placebo recipient (0.1%). No myocarditis, pericarditis, hypersensitivity, or anaphylaxis was reported in recipients of BNT162b2. Four rashes in BNT162b2 recipients (seen on the arm, trunk, face, or body, with no consistent pattern) were considered to be related to vaccination; the rash was mild and resolved on its own, and onset was usually 7 days or more after vaccination. No safety differences were apparent when data were analyzed by baseline SARS-CoV-2 infection status.
Stage 2-3 Immunogenicity
The geometric mean ratio of neutralizing GMTs for 10 g BNT162b2 in 5-to-11-year-olds and that for 30 µg BNT162b2 in 16-to-25-year-olds 1 month after the second dose was 1.04 (95% Confidence Interval [CI], 0.93 to 1.18) (table 2), a ratio meeting the immunobridging criterion of a lower bound of the two-tailed 95% confidence interval greater than 0.67, the predefined point estimate of a geometric mean ratio of 0.8 or greater, and the FDA-requested point estimation criterion of a geometric mean ratio of 1.0 or greater. In both age groups, 99.2% of participants achieved a seroresponse 1 month after the second dose. The difference between the percentage of 5-to-11-year-olds achieving seroresponse and the percentage in 16–25-year-olds was 0.0 percentage point (95% CI, –2.0 to 2.2), which also met a criterion for immunobridging.
Serum neutralizing GMTs 1 month after the second dose of BNT162b2 were 1198 in 5-to-11-year-olds and 1147 in 16-to-25-year-olds (Fig. S3); corresponding GMTs among placebo recipients were 11 and 10. The geometric mean increases from baseline to 1 month after the second dose were 118.2 in 5-to-11-year-olds and 111.4 in 16-to-25-year-olds; corresponding geometric mean fold increases among placebo recipients were 1.1 and 1.0. Note that the neutralizing GMTs reported in phase 1 are from serum samples obtained 7 days after the second dose (during the extension of the immune response) and the phase 2-3 GMTs are from serum samples collected 1 month after the second dose have been obtained.
Phase 2-3 Efficacy
The graph shows the cumulative incidence of the first occurrence of Covid-19 after the first dose of vaccine or placebo. Each symbol represents cases of Covid-19 that start on a particular day. The results shown in the graph are all available data for the efficacy population and the results in the table are those for the efficacy population that could be evaluated (defined in Table S1). Participants with no evidence of previous infection were those who had no medical history of Covid-19 and no serological or virological evidence of previous SARS-CoV-2 infection before 7 days after the second dose (i.e., N-binding serum antibody was negative on the first visit, SARS-CoV-2 was not detected in nasal swabs by nucleic acid amplification test at the vaccination visits, and the nucleic acid amplification tests were negative at each unscheduled visit prior to 7 days after the second dose). The cut-off date for the efficacy evaluation was October 8, 2021. Surveillance time is the total time in 1000 person-years for the given endpoint for all participants within each group at risk for the endpoint. The time period for the build-up of Covid-19 cases was from 7 days after the second dose to the end of the surveillance period. The 95% confidence intervals for vaccine efficacy were derived by the Clopper-Pearson method, adjusted for surveillance time.
Among participants with no evidence of prior SARS-CoV-2 infection, there were three cases of Covid-19 (onset 7 days or more after the second dose) among BNT162b2 recipients and 16 among placebo recipients; the observed vaccine efficacy was 90.7% (95% CI, 67.7 to 98.3). Of all participants with data that could be evaluated regardless of evidence of prior SARS-CoV-2 infection, no additional cases were reported; the observed vaccine efficacy was 90.7% (95% CI, 67.4 to 98.3) (figure 3). No cases of severe Covid-19 or MIS-C have been reported.