Participants who discontinued the vaccination regimen could remain in the study. In the phase 2–3 trial, reasons for not receiving the first dose included withdrawal (14 children), no longer meeting eligibility criteria (2 children), and protocol deviation (1 child). Discontinuations or withdrawals 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 trial, one participant who was randomly assigned to receive placebo was administered BNT162b2 in error for both doses. Therefore, 1518 participants received dose 1 of BNT162b2 and 750 participants received dose 1 of placebo.
From March 24 through April 14, 2021, a total of 50 children 5 to 11 years of age were screened for inclusion at four U.S. sites, and 48 received escalating doses of the BNT162b2 vaccine (Figure 1). Half 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 through June 19, 2021, a total of 2316 children 5 to 11 years of age were screened for inclusion and 2285 underwent randomization across 81 sites in the United States, Spain, Finland, and Poland; 2268 participants received injections, with 1517 randomly assigned to receive BNT162b2 and 751 assigned to receive placebo (Figure 1). One participant who was randomly assigned to receive placebo was administered BNT162b2 in error for both doses; therefore, 1518 participants received dose 1 of BNT162b2 and 750 participants received dose 1 of placebo. More than 99% of participants received a second dose. At the data cutoff date, the median follow-up time was 2.3 months (range, 0 to 2.5); 95% of participants had at least 2 months of available follow-up safety data 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 children had coexisting conditions (including 12% with obesity and approximately 8% with asthma), and 9% were SARS-CoV-2–positive at baseline. Apart 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), demographic characteristics were similar among the 5-to-11-year-old and 16-to-25-year-old BNT162b2 recipients who were 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-μg dose-level group than in the 10-μg and 20-μg dose-level groups after the first and second doses (Fig. S1B). All four sentinel participants in the 30-μg dose-level group who received the second 30-μg dose had mild-to-moderate fever within 7 days; the remaining 12 participants in the 30-μg dose-level group received a 10-μg second dose approximately 1 month after the first dose, as recommended by the internal review committee after selection of the phase 2–3 dose. Adverse events 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 30-μg doses (Table S6). One severe adverse event (grade 3 pyrexia) in a 10-year-old participant began the day of the second 20-μg dose of BNT162b2, with temperature reaching 39.7°C (103.5°F) the day after vaccination and resolving the following day. Antipyretic medications were used, and the investigator considered the event to be related to receipt of 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). On the basis of these safety and immunogenicity findings, the 10-μg dose level was selected for further assessment in 5-to-11-year-olds in phase 2–3.
Phase 2–3 Safety
Panel A shows local reactions and Panel B shows systemic events after the first and second doses 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 numbers of children reporting at least one “yes” or “no” response for 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 designated in the key. The numbers above the bars are the percentage of participants in each group with the specified local reaction or systemic event. 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 reactions and events reported were generally mild to moderate, lasting 1 to 2 days (Table S4). Injection-site pain was the most common local reaction, occurring 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 in no placebo recipients. Fatigue and headache were the most frequently reported systemic events. Severe fatigue (0.9%), headache (0.3%), chills (0.1%), and muscle pain (0.1%) were also reported after the first or second dose of BNT162b2. Frequencies of fatigue, headache, and chills were similar among BNT162b2 and placebo recipients after the first dose and were more frequent among BNT162b2 recipients than among placebo recipients after the second dose. In general, systemic events were reported more often 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. Use of an antipyretic among BNT162b2 recipients was more frequent after the second dose than after the first dose. One BNT162b2 recipient 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 events 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 adverse events that were considered by the investigators to be related to the vaccine or placebo. Severe 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 by the cutoff date; all three (postinjury abdominal pain and pancreatitis in a placebo recipient and arm fracture in a BNT162b2 recipient) were considered to be unrelated to the vaccine or placebo. No deaths or adverse events 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 in BNT162b2 recipients was reported. Four rashes in BNT162b2 recipients (observed on the arm, torso, face, or body, with no consistent pattern) were considered to be related to vaccination; the rashes were mild and self-limiting, and onset was typically 7 days or more after vaccination. No safety differences were apparent when the data were analyzed according to baseline SARS-CoV-2 infection status.
Phase 2–3 Immunogenicity
The geometric mean ratio of neutralizing GMTs for 10 μg of BNT162b2 in 5-to-11-year-olds to that for 30 μg of 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 boundary of the two-sided 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 estimate criterion of a geometric mean ratio of 1.0 or greater. In both age groups, 99.2% of participants achieved seroresponse 1 month after the second dose. The difference between the percentage of 5-to-11-year-olds who achieved seroresponse and the percentage in 16-to-25-year-olds was 0.0 percentage points (95% CI, –2.0 to 2.2), which also met an immunobridging criterion.
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. Geometric mean fold rises 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 rises among placebo recipients were 1.1 and 1.0. Of note, the neutralizing GMTs reported in phase 1 are from serum samples obtained 7 days after the second dose (during immune response expansion) and the GMTs in phase 2–3 are from serum samples obtained 1 month after the second dose.
Phase 2–3 Efficacy
The graph represents 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 starting on a given day. Results shown in the graph are all available data for the efficacy population, and results shown in the table are those for the efficacy population that could be evaluated (defined in Table S1). Participants without evidence of previous infection were those who had no medical history of Covid-19 and no serologic or virologic evidence of past SARS-CoV-2 infection before 7 days after the second dose (i.e., N-binding serum antibody was negative at the first vaccination visit, SARS-CoV-2 was not detected in nasal swabs by nucleic acid amplification test at the vaccination visits, and nucleic acid amplification tests were negative at any unscheduled visit before 7 days after the second dose). The cutoff date for the efficacy evaluation was October 8, 2021. Surveillance time is the total time in 1000 person-years for the given end point across all participants within each group at risk for the end point. The time period for Covid-19 case accrual 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 without evidence of previous SARS-CoV-2 infection, there were three cases of Covid-19 (with 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). Among all participants with data that could be evaluated, regardless of evidence of previous 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 were reported.