Evaluation of the BNT162b2 Covid-19 vaccine in children aged 5 to 11 years

participants

level 1

Screening, randomization and administration of vaccine and placebo among children aged 5 to 11 years in a phase I and phase 2-3 trial study.

Participants who discontinued the vaccination regimen could remain in the study. In phase 2-3 of the 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 of the parent, guardian, or participant, with the exception of one decision for which the reason was categorized as ‘other’. In the phase 2-3 trial, a participant who was randomly assigned to receive placebo was mistakenly given BNT162b2 for both doses. Therefore, 1518 participants received dose 1 of BNT162b2 and 750 participants received dose 1 of placebo.

From March 24 to April 14, 2021, a total of 50 children aged 5 to 11 years were screened for inclusion at four US sites, and received 48 increasing doses of BNT162b2 vaccine (shape 1). Half of the children were male, 79% were white, 6% were black, 10% were Asian, and 8% were Hispanic or Latino. The mean age was 7.9 years (Table S2).

Stage 2 – 3

Demographic and clinical characteristics of children in the experimental phase 2-3.

From June 7 to June 19, 2021, a total of 2,316 children aged 5 to 11 years were screened for inclusion and 2,285 randomized across 81 sites in the United States, Spain, Finland and Poland; 2,268 participants received the injections, with 1517 randomly assigned to receive BNT162b2 and 751 assigned to receive placebo (shape 1). One participant who was randomly assigned to receive placebo was mistakenly given BNT162b2 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 cut-off date, the median follow-up time was 2.3 months (range, 0 to 2.5); 95% of participants had at least 2 months of follow-up safety data available after the second dose. Overall, 52% were male, 79% were white, 6% were black, 6% were Asian, and 21% were Hispanic or Latino (Table 1). The median age was 8.2 years. 20% of the children had coexisting conditions (including 12% who were obese and about 8% had asthma), and 9% were SARS-CoV-2 positive at baseline. Regardless of younger age and a smaller proportion of Blacks, Hispanics, or Hispanics aged 5-11 years (6% and 18%, respectively) of those aged 16-25 (12% and 36%, respectively), Demographic characteristics were similar between BNT162b2 recipients aged 5–11 years and those aged 16–25 who were included in the immunological subgroup (Table S3).

Stage 1 safety and immunity

Most of the local reactions were mild to moderate, and all were transient (Fig. S1A and Table S4). Fever was more common in the 30 μg dose group than in the 10 and 20 μg dose level groups after the first and second doses (Figure S1B). All four sentinel participants in the 30 mcg dose group who received the second 30 mcg dose developed mild to moderate fever within 7 days; The remaining 12 participants in the 30 mcg dose level group received a second 10 mcg dose approximately 1 month after the first dose, as recommended by the internal review committee after phase 2-3 dose selection. Adverse events were reported from the first dose up to 1 month after the second dose by 43.8% of participants who received two 10 mcg doses of BNT162b2, 31.3% of those who received two 20 mcg doses, and 50.0% of those who received two doses. 30 mcg doses (Table S6). A severe adverse event (grade 3 pyrexia) in a 10-year-old participant began on the day of the second 20 mcg dose of BNT162b2, whose temperature reached 39.7 °C (103.5 °F) the day after inoculation and resolved the following day. Antipyretic drugs were used, and the investigator considered the event to be related to receiving the BNT162b2 vaccine.

The neutralizing serum 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 immunological findings, the 10 mcg dose level was selected for further evaluation in children aged 5 to 11 years in stage 2-3.

Stage 2 – 3 Safety

Local reactions and systemic events were reported in phase 2-3 of the trial within 7 days after BNT162b2 or placebo injection.

Panel A shows local reactions and panel B shows systemic events after the first and second doses in BNT162b2 vaccine recipients (dose 1, 1511 children; dose 2, 1501 children) and placebo (dose 1, 748 or 749 children; dose 2, 740 or 741 children). Figures indicate the number of children who reported at least one ‘yes’ or ‘no’ response to the specific event after each dose; Responses may not have been reported for each type of event. The severity measures are summarized in Table S5; Fever categories are specified in the key. The numbers above the bars are the percentage of participants in each group with a specific local reaction or systemic event. 𝙸 Bars represent 95% confidence intervals. One participant in the BNT162b2 group developed 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, and lasted 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 aches (0.1%) have also been reported after the first or second dose of BNT162b2. The frequency of fatigue, headache, and chills were similar between 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. Antipyretic use 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 subsided the next day.

From the first dose until 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 investigators considered to be related to either 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 were reported in two participants by the deadline; All three (post-traumatic abdominal pain, pancreatitis in placebo recipients and arm fracture in BNT162b2 recipients) were considered unrelated to either the vaccine or placebo. No deaths or adverse events leading to withdrawal have been reported.

Lymphadenopathy was reported in 10 BNT162b2 recipients (0.9%) and one placebo recipient (0.1%). Myocarditis, pericarditis, hypersensitivity or anaphylaxis have not been reported in BNT162b2 recipients. Four rashes in BNT162b2 recipients (observed on the arm, trunk, face, or body, with no consistent pattern) were considered to be associated with vaccination; The rashes were mild and self-healing, and their appearance was usually 7 or more days after vaccination. No safety differences were evident when the data were analyzed according to baseline SARS-CoV-2 infection status.

Stage 2-3 Immunity

Serum SARS-CoV-2 neutralization test results 1 month after the second dose of BNT162b2 among participants aged 5 to 11 and 16 to 25 years.

The geometric ratio of GMT neutralization for 10 μg BNT162b2 at age 5 to 11 years to 30 μg BNT162b2 at age 16 to 25 years 1 month after the second dose was 1.04 (95%) confidence interval. [CI]0.93 to 1.18 ( )Table 2), a ratio that meets the immunosuppression criterion for a minimum two-sided 95% confidence interval greater than 0.67, a predetermined point estimate of the geometric mean ratio of 0.8 or more, and the FDA-required point estimation criterion for the geometric mean ratio 1.0 or more. In both age groups, 99.2% of participants achieved a serological response one month after the second dose. The difference between the percentage of children aged 5 to 11 years who achieved a serological response and the percentage of children aged 16 to 25 years was 0.0 percentage points (95% CI, -2.0 to 2.2), which also met the immunogenicity criterion.

The BST serum neutralized 1 month after the second dose of BNT162b2 was 1198 at the age of 5 to 11 years and 1147 at the age of 16 to 25 years (Fig. S3); Corresponding GMT between placebo recipients was 11 and 10. Mean geometric fold rises from baseline to 1 month after the second dose 118.2 in children aged 5-11 years and 111.4 in subjects aged 16-25 years ; The corresponding geometric mean rise between the placebo recipients was 1.1 and 1.0. Of note are the equivalent GMTs reported in Phase 1 from serum samples obtained 7 days after the second dose (while expanding the immune response) and the GMTs in Phase 2-3 from serum samples obtained 1 month after the second dose. .

Stage 2 – 3 activity

Vaccine efficacy in children 5 to 11 years of age.

The graph represents the cumulative incidence rate of the first appearance of Covid-19 after the first dose of the vaccine or placebo. Each icon represents cases of Covid-19 starting from a particular day. The results shown in the graph are all data available for the effectiveness population, and the results shown in the table are those for the efficacy group that can be evaluated (specified in Table S1). Participants with no evidence of previous infection were those with no medical history of Covid-19 and no serological or virological evidence of previous SARS-CoV-2 infection 7 days after the second dose (that is, serum N-antibody was binding negative at the first vaccination visit, SARS-CoV-2 was not detected in nasal swabs by DNA amplification test at vaccination visits, and DNA amplification tests were negative at any unscheduled visit before 7 days after the second dose). The deadline for efficacy evaluation was October 8, 2021. Observation time is the total time in 1000 person-years for the defined endpoint across all participants within each at-risk group for the endpoint. The time period for the accumulation of Covid-19 cases was from 7 days after the second dose to the end of the observation period. The 95% confidence intervals for vaccine efficacy were derived by the Clopper-Pearson method, adjusted for observation 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). Of all participants with evaluable data, 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 have been reported.

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