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Evaluation of BNT162b2 Covid-19 Vaccine in Children Younger than 5 Years of Age. BACKGROUND: Safe and effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in young children. METHODS: We conducted a phase 1 dose-finding study and are conducting an ongoing phase 2-3 safety, immunogenicity, and efficacy trial of the BNT162b2 vaccine in healthy children 6 months to 11 years of age. We present results for children 6 months to less than 2 years of age and those 2 to 4 years of age through the data-cutoff dates (April 29, 2022, for safety and immunogenicity and June 17, 2022, for efficacy). In the phase 2-3 trial, participants were randomly assigned (in a 2:1 ratio) to receive two 3-μg doses of BNT162b2 or placebo. On the basis of preliminary immunogenicity results, a third 3-μg dose (≥8 weeks after dose 2) was administered starting in January 2022, which coincided with the emergence of the B.1.1.529 (omicron) variant. Immune responses at 1 month after doses 2 and 3 in children 6 months to less than 2 years of age and those 2 to 4 years of age were immunologically bridged to responses after dose 2 in persons 16 to 25 years of age who received 30 μg of BNT162b2 in the pivotal trial. RESULTS: During the phase 1 dose-finding study, two doses of BNT162b2 were administered 21 days apart to 16 children 6 months to less than 2 years of age (3-μg dose) and 48 children 2 to 4 years of age (3-μg or 10-μg dose). The 3-μg dose level was selected for the phase 2-3 trial; 1178 children 6 months to less than 2 years of age and 1835 children 2 to 4 years of age received BNT162b2, and 598 and 915, respectively, received placebo. Immunobridging success criteria for the geometric mean ratio and seroresponse at 1 month after dose 3 were met in both age groups. BNT162b2 reactogenicity events were mostly mild to moderate, with no grade 4 events. Low, similar incidences of fever were reported after receipt of BNT162b2 (7% among children 6 months to <2 years of age and 5% among those 2 to 4 years of age) and placebo (6 to 7% among children 6 months to <2 years of age and 4 to 5% among those 2 to 4 years of age). The observed overall vaccine efficacy against symptomatic Covid-19 in children 6 months to 4 years of age was 73.2% (95% confidence interval, 43.8 to 87.6) from 7 days after dose 3 (on the basis of 34 cases). CONCLUSIONS: A three-dose primary series of 3-μg BNT162b2 was safe, immunogenic, and efficacious in children 6 months to 4 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.).

The phase 1 dose-finding study and ongoing phase 2–3 safety, immunogenicity, and efficacy trial investigated BNT162b2 in healthy children 6 months to 11 years of age. Safety and immunogenicity results are presented for children 6 months to 4 years of age through the data-cutoff date (April 29, 2022). For the assessment of vaccine efficacy, we used a data-cutoff date of June 17, 2022. Participants in the phase 2–3 trial will be followed for 12 to 18 months after dose 3; follow-up will include monitoring for potential cases of Covid-19 and MIS-C. Details on eligibility criteria and ethical study conduct are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org. The protocol, which contains additional details, is also available at NEJM.org. Pfizer was responsible for the design and conduct of the study; the collection, analysis, and interpretation of the data; and the writing of the manuscript. Pfizer and BioNTech manufactured BNT162b2 and placebo. BioNTech was the regulatory sponsor and contributed to data interpretation and manuscript writing. All data were available to the authors, who vouch for the accuracy and completeness of the data and for the adherence of the trial to the protocol.

of the manuscript. Pfizer and BioNTech manufactured BNT162b2 and placebo. BioNTech was the regulatory sponsor and contributed to data interpretation and manuscript writing. All data were available to the authors, who vouch for the accuracy and completeness of the data and for the adherence of the trial to the protocol. A vaccination regimen involving intramuscular injection (anterior thigh for children 6 months to <2 years of age and deltoid for those 2 to 4 years of age) of two BNT162b2 doses administered 21 days apart was initiated at a 10-μg dose level in children 2 to 4 years of age and subsequently at the 3-μg dose level in children 6 months to less than 2 years of age on the basis of the acceptable safety and immunogenicity of the 30-μg dose level in children 12 to 15 years of age (see the Supplementary Appendix for safety data review and stopping rules).9,11 On the basis of safety data as well as immunogenicity results at 1 week after dose 2, the 3-μg dose level was selected for all children 6 months to 4 years of age in the phase 2–3 trial.

he 30-μg dose level in children 12 to 15 years of age (see the Supplementary Appendix for safety data review and stopping rules).9,11 On the basis of safety data as well as immunogenicity results at 1 week after dose 2, the 3-μg dose level was selected for all children 6 months to 4 years of age in the phase 2–3 trial. Starting on June 21, 2021, participants were randomly assigned through an interactive Web-based system in a 2:1 ratio to receive two doses of 3-μg BNT162b2 or saline placebo 21 days apart. The third dose was administered at least 60 days after dose 2 for children 6 months to 4 years of age in January 2022. Data on children who reached their fifth birthday were unblinded, and these children received the 10-μg dose level for dose 2 or 3 on the basis of the emergency use authorization (these data are not included here). Participants and trial personnel, apart from those preparing or administering injections, were not aware of the trial-group assignments. For all the participants in the phase 1 study and a subgroup of participants in the phase 2–3 trial (see the Supplementary Appendix), blood samples were collected for immunogenicity assessments, which included determination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralization titers, as described previously.12,14,15 Neutralizing titers were measured for ancestral SARS-CoV-2 (USA-WA1/2020) (participants in the phase 1 study and the phase 2–3 trial) and omicron BA.1 variants (participants in the phase 2–3 trial).

n of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralization titers, as described previously.12,14,15 Neutralizing titers were measured for ancestral SARS-CoV-2 (USA-WA1/2020) (participants in the phase 1 study and the phase 2–3 trial) and omicron BA.1 variants (participants in the phase 2–3 trial). Immunogenicity was analyzed in participants who were without serologic or virologic evidence of previous SARS-CoV-2 infection. In phase 1, SARS-CoV-2 neutralizing geometric mean titers (GMTs) were measured in serum samples that were obtained 7 days after dose 2. In phase 2–3, GMTs were measured before doses 1 and 3 and 1 month after doses 2 and 3. We calculated ratios of GMTs (i.e., geometric mean ratios) 1 month after doses 2 and 3 among children 6 months to less than 2 years of age and children 2 to 4 years of age in phase 2–3 as compared with GMTs 1 month after dose 2 among persons 16 to 25 years of age from the pivotal trial.10 Serum samples for each comparison were assayed in parallel to ensure comparability of titers. We also calculated differences in seroresponse (defined in the Supplementary Appendix) among children 6 months to less than 2 years of age and children 2 to 4 years of age 1 month after doses 2 and 3 as compared with seroresponse among persons 16 to 25 years of age 1 month after dose 2, as well as geometric mean fold rises from baseline to each subsequent time point after doses 2 and 3. Post hoc immunogenicity analyses included an assessment of SARS-CoV-2 neutralizing titers 1 month after dose 2 in a subgroup of children 2 to 4 years of age as compared with titers among persons 65 years of age or older from the pivotal trial.

fold rises from baseline to each subsequent time point after doses 2 and 3. Post hoc immunogenicity analyses included an assessment of SARS-CoV-2 neutralizing titers 1 month after dose 2 in a subgroup of children 2 to 4 years of age as compared with titers among persons 65 years of age or older from the pivotal trial. Information on age-specific reactogenicity events was recorded by parents or guardians in an e-diary for 7 days after each dose. Data on adverse events were collected through 1 month after dose 2 for phase 1 and through 1 month after dose 3 for phase 2–3. Data on serious adverse events are being collected through 6 months after dose 3. Details about monitoring of potential cases of myocarditis or pericarditis are provided in the Supplementary Appendix. Vaccine efficacy against the first occurrence of Covid-19 from at least 7 days after dose 3 to the data-cutoff date (June 17, 2022) was calculated. The methods that were used to identify SARS-CoV-2 infections, Covid-19, and MIS-C are outlined in the Supplementary Appendix.

Information on age-specific reactogenicity events was recorded by parents or guardians in an e-diary for 7 days after each dose. Data on adverse events were collected through 1 month after dose 2 for phase 1 and through 1 month after dose 3 for phase 2–3. Data on serious adverse events are being collected through 6 months after dose 3. Details about monitoring of potential cases of myocarditis or pericarditis are provided in the Supplementary Appendix. Vaccine efficacy against the first occurrence of Covid-19 from at least 7 days after dose 3 to the data-cutoff date (June 17, 2022) was calculated. The methods that were used to identify SARS-CoV-2 infections, Covid-19, and MIS-C are outlined in the Supplementary Appendix. Study populations are defined in Table S1 in the Supplementary Appendix. In the phase 2–3 trial, effectiveness was inferred by an “immunobridging” approach, in which neutralizing titers elicited by 3 μg of BNT162b2 against the ancestral SARS-CoV-2 strain in a subgroup of children 6 months to less than 2 years of age and children 2 to 4 years of age were compared with titers elicited by 30 μg of BNT162b2 in a random sample of persons 16 to 25 years of age from the pivotal trial (see the Supplementary Appendix). Immunobridging success based on the geometric mean ratio of neutralizing titers of serum samples drawn 1 month after doses 2 and 3 was declared if the lower boundary of the 95% confidence interval for the geometric mean ratio (children 6 months to <2 years of age or children 2 to 4 years of age after dose 2 or after dose 3 as compared with persons 16 to 25 years of age after dose 2) was more than 0.67 and if the point estimate for the geometric mean ratio was at least 0.8 (specified in the protocol) or at least 1.0 (requested by the Food and Drug Administration [FDA]). Immunobridging success also required a lower boundary of the 95% confidence interval for the difference in the percentage of participants with seroresponse (children 6 months to <2 years of age or those 2 to 4 years of age as compared with persons 16 to 25 years of age) of greater than –10 percentage points. Immunobridging criteria were based on regulatory authority guidance, as previously reported for children 5 to 11 years of age.11 Calculations of sample size are provided in the Supplementary Appendix.

age or those 2 to 4 years of age as compared with persons 16 to 25 years of age) of greater than –10 percentage points. Immunobridging criteria were based on regulatory authority guidance, as previously reported for children 5 to 11 years of age.11 Calculations of sample size are provided in the Supplementary Appendix. Safety end points are presented descriptively as counts and percentages with two-sided 95% Clopper–Pearson confidence intervals. Adverse events and serious adverse events are presented according to the terms in the Medical Dictionary for Regulatory Activities, version 25.0.

age or those 2 to 4 years of age as compared with persons 16 to 25 years of age) of greater than –10 percentage points. Immunobridging criteria were based on regulatory authority guidance, as previously reported for children 5 to 11 years of age.11 Calculations of sample size are provided in the Supplementary Appendix. Safety end points are presented descriptively as counts and percentages with two-sided 95% Clopper–Pearson confidence intervals. Adverse events and serious adverse events are presented according to the terms in the Medical Dictionary for Regulatory Activities, version 25.0. Vaccine efficacy, defined as 100×(1–illness rate ratio), was assessed for age groups in which immunobridging was successful after at least 21 cases of Covid-19 had accrued from at least 7 days after dose 3. The vaccine was considered to be effective if the lower boundary of the 95% confidence interval for vaccine efficacy was more than 30%. Efficacy evaluations for children 6 months to less than 2 years of age and those 2 to 4 years of age included both age groups for hypothesis testing and were performed separately in the two age groups for descriptive summaries because the same dose level was selected for both groups and both age groups met the criteria for immunobridging success. The illness rate ratio was the ratio of the rate of first cases of confirmed Covid-19 in the BNT162b2 group to the corresponding rate in the placebo group. Two-sided 95% confidence intervals for vaccine efficacy were derived with the use of the Clopper–Pearson method, with adjustment for surveillance time (total time in 1000 person-years for the given end point across all participants within each group at risk for the end point). The 95% confidence intervals were not adjusted for multiplicity. The hypotheses for immunobridging and vaccine efficacy were evaluated sequentially to control the type I error rate. Immunobridging based on geometric mean ratio and difference in seroresponse was assessed sequentially in the order specified for each age group. Immunobridging for the two age groups was assessed separately and not adjusted for multiplicity. The hypothesis for vaccine efficacy was tested if immunobridging criteria for the geometric mean ratio and seroresponse were met for both age groups.

A vaccination regimen involving intramuscular injection (anterior thigh for children 6 months to <2 years of age and deltoid for those 2 to 4 years of age) of two BNT162b2 doses administered 21 days apart was initiated at a 10-μg dose level in children 2 to 4 years of age and subsequently at the 3-μg dose level in children 6 months to less than 2 years of age on the basis of the acceptable safety and immunogenicity of the 30-μg dose level in children 12 to 15 years of age (see the Supplementary Appendix for safety data review and stopping rules).9,11 On the basis of safety data as well as immunogenicity results at 1 week after dose 2, the 3-μg dose level was selected for all children 6 months to 4 years of age in the phase 2–3 trial. Starting on June 21, 2021, participants were randomly assigned through an interactive Web-based system in a 2:1 ratio to receive two doses of 3-μg BNT162b2 or saline placebo 21 days apart. The third dose was administered at least 60 days after dose 2 for children 6 months to 4 years of age in January 2022. Data on children who reached their fifth birthday were unblinded, and these children received the 10-μg dose level for dose 2 or 3 on the basis of the emergency use authorization (these data are not included here). Participants and trial personnel, apart from those preparing or administering injections, were not aware of the trial-group assignments.

A vaccination regimen involving intramuscular injection (anterior thigh for children 6 months to <2 years of age and deltoid for those 2 to 4 years of age) of two BNT162b2 doses administered 21 days apart was initiated at a 10-μg dose level in children 2 to 4 years of age and subsequently at the 3-μg dose level in children 6 months to less than 2 years of age on the basis of the acceptable safety and immunogenicity of the 30-μg dose level in children 12 to 15 years of age (see the Supplementary Appendix for safety data review and stopping rules).9,11 On the basis of safety data as well as immunogenicity results at 1 week after dose 2, the 3-μg dose level was selected for all children 6 months to 4 years of age in the phase 2–3 trial.

Starting on June 21, 2021, participants were randomly assigned through an interactive Web-based system in a 2:1 ratio to receive two doses of 3-μg BNT162b2 or saline placebo 21 days apart. The third dose was administered at least 60 days after dose 2 for children 6 months to 4 years of age in January 2022. Data on children who reached their fifth birthday were unblinded, and these children received the 10-μg dose level for dose 2 or 3 on the basis of the emergency use authorization (these data are not included here). Participants and trial personnel, apart from those preparing or administering injections, were not aware of the trial-group assignments.

For all the participants in the phase 1 study and a subgroup of participants in the phase 2–3 trial (see the Supplementary Appendix), blood samples were collected for immunogenicity assessments, which included determination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralization titers, as described previously.12,14,15 Neutralizing titers were measured for ancestral SARS-CoV-2 (USA-WA1/2020) (participants in the phase 1 study and the phase 2–3 trial) and omicron BA.1 variants (participants in the phase 2–3 trial).

Information on age-specific reactogenicity events was recorded by parents or guardians in an e-diary for 7 days after each dose. Data on adverse events were collected through 1 month after dose 2 for phase 1 and through 1 month after dose 3 for phase 2–3. Data on serious adverse events are being collected through 6 months after dose 3. Details about monitoring of potential cases of myocarditis or pericarditis are provided in the Supplementary Appendix.

Vaccine efficacy against the first occurrence of Covid-19 from at least 7 days after dose 3 to the data-cutoff date (June 17, 2022) was calculated. The methods that were used to identify SARS-CoV-2 infections, Covid-19, and MIS-C are outlined in the Supplementary Appendix.

Study populations are defined in Table S1 in the Supplementary Appendix. In the phase 2–3 trial, effectiveness was inferred by an “immunobridging” approach, in which neutralizing titers elicited by 3 μg of BNT162b2 against the ancestral SARS-CoV-2 strain in a subgroup of children 6 months to less than 2 years of age and children 2 to 4 years of age were compared with titers elicited by 30 μg of BNT162b2 in a random sample of persons 16 to 25 years of age from the pivotal trial (see the Supplementary Appendix). Immunobridging success based on the geometric mean ratio of neutralizing titers of serum samples drawn 1 month after doses 2 and 3 was declared if the lower boundary of the 95% confidence interval for the geometric mean ratio (children 6 months to <2 years of age or children 2 to 4 years of age after dose 2 or after dose 3 as compared with persons 16 to 25 years of age after dose 2) was more than 0.67 and if the point estimate for the geometric mean ratio was at least 0.8 (specified in the protocol) or at least 1.0 (requested by the Food and Drug Administration [FDA]). Immunobridging success also required a lower boundary of the 95% confidence interval for the difference in the percentage of participants with seroresponse (children 6 months to <2 years of age or those 2 to 4 years of age as compared with persons 16 to 25 years of age) of greater than –10 percentage points. Immunobridging criteria were based on regulatory authority guidance, as previously reported for children 5 to 11 years of age.11 Calculations of sample size are provided in the Supplementary Appendix.

From April 5, 2021, a total of 16 children 6 months to less than 2 years of age and 48 children 2 to 4 years of age received two BNT162b2 doses (Fig. S1). Overall, 59% were male; 81% were White, and 6% were Hispanic or Latinx. The median age was 15.5 months among children 6 months to less than 2 years of age and 3.0 years among children 2 to 4 years of age (Table S2). From June 21, 2021, a total of 1776 children 6 months to less than 2 years of age and 2750 children 2 to 4 years of age underwent randomization; 1178 and 1835, respectively, received BNT162b2, and 598 and 915, respectively, received placebo (Figure 1). More than 99% of the participants received dose 2. At the data-cutoff date (with recruitment and administration ongoing), some participants had not yet received dose 2, and 32.2% had received dose 3 (see Table 1 for time between dose 2 and dose 3). The median blinded follow-up after dose 3 was 1.3 months (range, 0 to 3.2) among children 6 months to less than 2 years of age and 1.4 months (range, 0 to 3.2) among children 2 to 4 years of age; 31.8% of children 6 months to less than 2 years of age and 35.0% of children 2 to 4 years of age had at least 2 months of follow-up safety data available after dose 3.

as 1.3 months (range, 0 to 3.2) among children 6 months to less than 2 years of age and 1.4 months (range, 0 to 3.2) among children 2 to 4 years of age; 31.8% of children 6 months to less than 2 years of age and 35.0% of children 2 to 4 years of age had at least 2 months of follow-up safety data available after dose 3. Half the participants were male; 79.3% were White, 4.4% Black, and 13.5% Hispanic or Latinx (Table 1). Among children 6 months to less than 2 years of age, the median age was 16.0 months, 4.7% had coexisting conditions, and 7.5% were SARS-CoV-2–positive at baseline. Corresponding values among children 2 to 4 years of age were 3.0 years, 12.8%, and 13.0%. Demographic characteristics were generally representative of the expected participant population (Table S3).

rs of age, the median age was 16.0 months, 4.7% had coexisting conditions, and 7.5% were SARS-CoV-2–positive at baseline. Corresponding values among children 2 to 4 years of age were 3.0 years, 12.8%, and 13.0%. Demographic characteristics were generally representative of the expected participant population (Table S3). For children 2 to 4 years of age, higher frequencies and greater severity of reactogenicity to the BNT162b2 10-μg dose level than to the 3-μg dose level were observed; fever was reported in approximately 19% of the participants who received 10 μg for both doses 1 and 2 (Fig. S2). Because postvaccination immunogenicity after dose 2 for the ancestral strain across dose levels was similar to that in older age groups (Fig. S3), a 3-μg dose level was selected for children 2 to 4 years of age. The reactogenicity profile of the 10-μg dose level in children 2 to 4 years of age resulted in forgoing evaluation of that dose level in children 6 months to less than 2 years of age. In children 6 months to less than 2 years of age, because immune responses at the 3-μg dose level were similar to those observed in children 2 to 4 years of age, and in light of the favorable safety and reactogenicity profile of the 3-μg dose level in this age group (Table S5), the 3-μg dose level was selected for phase 2–3 evaluation. Immunobridging data after dose 2 met success criteria in children 6 months to less than 2 years of age and met success criteria for seroresponse but not for GMT in children 2 to 4 years of age (Table 2). Therefore, we assessed a third primary dose for both age groups.

For children 2 to 4 years of age, higher frequencies and greater severity of reactogenicity to the BNT162b2 10-μg dose level than to the 3-μg dose level were observed; fever was reported in approximately 19% of the participants who received 10 μg for both doses 1 and 2 (Fig. S2). Because postvaccination immunogenicity after dose 2 for the ancestral strain across dose levels was similar to that in older age groups (Fig. S3), a 3-μg dose level was selected for children 2 to 4 years of age. The reactogenicity profile of the 10-μg dose level in children 2 to 4 years of age resulted in forgoing evaluation of that dose level in children 6 months to less than 2 years of age. In children 6 months to less than 2 years of age, because immune responses at the 3-μg dose level were similar to those observed in children 2 to 4 years of age, and in light of the favorable safety and reactogenicity profile of the 3-μg dose level in this age group (Table S5), the 3-μg dose level was selected for phase 2–3 evaluation. Immunobridging data after dose 2 met success criteria in children 6 months to less than 2 years of age and met success criteria for seroresponse but not for GMT in children 2 to 4 years of age (Table 2). Therefore, we assessed a third primary dose for both age groups. Geometric mean ratios of neutralizing GMTs for 3 μg of BNT162b2 among children 6 months to less than 2 years of age and children 2 to 4 years of age 1 month after dose 3 to GMTs for 30 μg of BNT162b2 among persons 16 to 25 years of age 1 month after dose 2 were 1.19 (95% confidence interval [CI], 1.00 to 1.42) and 1.30 (95% CI, 1.13 to 1.50), respectively (Table 2). These findings met the immunobridging criterion of a lower boundary of the two-sided 95% confidence interval of more than 0.67; they also met the prespecified and FDA-requested point estimates for the geometric mean ratio of at least 0.8 and at least 1.0, respectively. The differences in the percentages of children 6 months to less than 2 years of age and children 2 to 4 years of age who had a seroresponse after dose 3 and the percentage of persons 16 to 25 years of age who had a seroresponse after dose 2 were 1.2 percentage points (95% CI, −3.4 to 4.2) and 1.2 percentage points (95% CI, −1.5 to 4.2), respectively; these findings also met this immunobridging criterion.

children 2 to 4 years of age who had a seroresponse after dose 3 and the percentage of persons 16 to 25 years of age who had a seroresponse after dose 2 were 1.2 percentage points (95% CI, −3.4 to 4.2) and 1.2 percentage points (95% CI, −1.5 to 4.2), respectively; these findings also met this immunobridging criterion. The serum-neutralizing GMTs against ancestral SARS-CoV-2 were 1407 among children 6 months to less than 2 years of age and 1535 among children 2 to 4 years of age 1 month after dose 3, as compared with 1180 among persons 16 to 25 years of age 1 month after dose 2 (Fig. S4). The geometric mean fold rises from before vaccination to 1 month after dose 3 were 68.4 among children 6 months to less than 2 years of age and 73.3 among children 2 to 4 years of age, as compared with a fold rise of 55.3 from before vaccination to 1 month after dose 2 among persons 16 to 25 years of age. In an exploratory analysis, omicron BA.1 SARS-CoV-2 serum-neutralizing GMTs in response to a third 3-μg BNT162b2 dose among 32 children 6 months to less than 2 years of age and 34 children 2 to 4 years of age were 129 and 114, respectively, as compared with 164 among adults 18 to 50 years of age who received a third 30-μg BNT162b2 dose at a similar time interval after dose 2 as the children in this trial — approximately 3 months (Fig. S5).

32 children 6 months to less than 2 years of age and 34 children 2 to 4 years of age were 129 and 114, respectively, as compared with 164 among adults 18 to 50 years of age who received a third 30-μg BNT162b2 dose at a similar time interval after dose 2 as the children in this trial — approximately 3 months (Fig. S5). Ancestral SARS-CoV-2 serum-neutralizing GMTs 1 month after dose 2 in a subgroup of children 2 to 4 years of age and among adults 65 years of age who received two BNT162b2 doses were 830.0 and 431.8, respectively. The geometric mean ratio was 1.92 (two-sided 95% CI, 1.56 to 2.36). Local reactions were reported more frequently after BNT162b2 than after placebo, with most being mild to moderate; severe reactions after any dose were reported infrequently (≤0.3%) (Figure 2). No grade 4 local reactions were reported. Tenderness was the most frequent local reaction among children 6 months to less than 2 years of age, and pain was the most frequent among children 2 to 4 years of age; swelling and redness were less frequent. The median time of onset for all local reactions was 1 or 2 days after receipt of BNT162b2 or placebo; most reactions resolved within 1 to 2 days. The incidences of local reactions after dose 3 were generally similar to or lower than those after dose 1 or after dose 2.

s of age; swelling and redness were less frequent. The median time of onset for all local reactions was 1 or 2 days after receipt of BNT162b2 or placebo; most reactions resolved within 1 to 2 days. The incidences of local reactions after dose 3 were generally similar to or lower than those after dose 1 or after dose 2. Among children 6 months to less than 2 years of age, systemic events other than fever were generally reported more frequently after BNT162b2 than after placebo (Figure 2). Among children 2 to 4 years of age, systemic events were reported at generally similar frequencies after BNT162b2 and after placebo. Most systemic events were mild to moderate, with severe events after any dose reported infrequently (≤1.1%). No grade 4 systemic events were reported. Irritability was the most frequent systemic event among children 6 months to less than 2 years of age; fatigue was the most frequent among children 2 to 4 years of age. In BNT162b2 recipients, the median onset for most events was 2 to 3 days; most resolved within 1 to 2 days.

. No grade 4 systemic events were reported. Irritability was the most frequent systemic event among children 6 months to less than 2 years of age; fatigue was the most frequent among children 2 to 4 years of age. In BNT162b2 recipients, the median onset for most events was 2 to 3 days; most resolved within 1 to 2 days. Among BNT162b2 recipients, no more than 2.1% of children 6 months to less than 2 years of age and no more than 1.2% of children 2 to 4 years of age had a fever with a body temperature higher than 38.9°C after any of the three doses. Most fevers resolved within 1 to 1.5 days. Among children 6 months to less than 2 years of age, a fever with a body temperature higher than 40.0°C occurred in three BNT162b2 recipients and one placebo recipient; these fevers resolved in 3 to 5 days. Among children 2 to 4 years of age, a fever with a body temperature higher than 40.0°C occurred in three BNT162b2 recipients; these fevers resolved in 1 to 4 days.

e, a fever with a body temperature higher than 40.0°C occurred in three BNT162b2 recipients and one placebo recipient; these fevers resolved in 3 to 5 days. Among children 2 to 4 years of age, a fever with a body temperature higher than 40.0°C occurred in three BNT162b2 recipients; these fevers resolved in 1 to 4 days. The frequencies of adverse events were similar among BNT162b2 recipients and placebo recipients in both age groups and were higher among children 6 months to less than 2 years of age than among those 2 to 4 years of age (Table S6). Few participants withdrew owing to adverse events, and no deaths occurred. No cases of myocarditis or pericarditis, Bell’s palsy (or facial paralysis or paresis), thromboembolic events, thrombocytopenic events, MIS-C, Kawasaki’s disease, acute respiratory distress syndrome, meningitis, myelitis or encephalomyelitis, or vaccine-related anaphylaxis were reported. No events consistent with demyelination, peripheral neuropathy, or vasculitis were identified.

l paralysis or paresis), thromboembolic events, thrombocytopenic events, MIS-C, Kawasaki’s disease, acute respiratory distress syndrome, meningitis, myelitis or encephalomyelitis, or vaccine-related anaphylaxis were reported. No events consistent with demyelination, peripheral neuropathy, or vasculitis were identified. Among children 6 months to 4 years of age, 34 Covid-19 cases (13 in the BNT162b2 group and 21 in the placebo group) occurred from at least 7 days after dose 3 to the data-cutoff date (i.e., February 7 to June 17, 2022, which was entirely during the omicron-dominant phase), corresponding to an observed vaccine efficacy of 73.2% (95% CI, 43.8 to 87.6) (Figure 3). The efficacy of the vaccine was affirmed because the lower boundary of the 95% confidence interval was greater than 30%. Observed vaccine efficacy was 75.8% (95% CI, 9.7 to 94.7) among children 6 months to less than 2 years of age and 71.8% (95% CI, 28.6 to 89.4) among children 2 to 4 years of age. The majority of Covid-19 cases from 7 days after dose 3 were caused by omicron BA.2.12.1 and BA.2. Among children 6 months to 4 years of age, vaccine efficacy was 71.8% (95% CI, 40.5 to 87.1) against all omicron variants (33 cases). With respect to omicron sublineages, vaccine efficacy was 71.1% (95% CI, 9.1 to 91.5) against BA.2.12.1 (15 cases), 89.2% (95% CI, 45.7 to 98.9) against BA.2 (10 cases), and 13.3% (95% CI, −5016.9 to 95.5) against BA.4 (3 cases) (Table S7). There were 2 or fewer cases for each of the other omicron sublineages.

From April 5, 2021, a total of 16 children 6 months to less than 2 years of age and 48 children 2 to 4 years of age received two BNT162b2 doses (Fig. S1). Overall, 59% were male; 81% were White, and 6% were Hispanic or Latinx. The median age was 15.5 months among children 6 months to less than 2 years of age and 3.0 years among children 2 to 4 years of age (Table S2).

From June 21, 2021, a total of 1776 children 6 months to less than 2 years of age and 2750 children 2 to 4 years of age underwent randomization; 1178 and 1835, respectively, received BNT162b2, and 598 and 915, respectively, received placebo (Figure 1). More than 99% of the participants received dose 2. At the data-cutoff date (with recruitment and administration ongoing), some participants had not yet received dose 2, and 32.2% had received dose 3 (see Table 1 for time between dose 2 and dose 3). The median blinded follow-up after dose 3 was 1.3 months (range, 0 to 3.2) among children 6 months to less than 2 years of age and 1.4 months (range, 0 to 3.2) among children 2 to 4 years of age; 31.8% of children 6 months to less than 2 years of age and 35.0% of children 2 to 4 years of age had at least 2 months of follow-up safety data available after dose 3. Half the participants were male; 79.3% were White, 4.4% Black, and 13.5% Hispanic or Latinx (Table 1). Among children 6 months to less than 2 years of age, the median age was 16.0 months, 4.7% had coexisting conditions, and 7.5% were SARS-CoV-2–positive at baseline. Corresponding values among children 2 to 4 years of age were 3.0 years, 12.8%, and 13.0%. Demographic characteristics were generally representative of the expected participant population (Table S3).

For children 2 to 4 years of age, higher frequencies and greater severity of reactogenicity to the BNT162b2 10-μg dose level than to the 3-μg dose level were observed; fever was reported in approximately 19% of the participants who received 10 μg for both doses 1 and 2 (Fig. S2). Because postvaccination immunogenicity after dose 2 for the ancestral strain across dose levels was similar to that in older age groups (Fig. S3), a 3-μg dose level was selected for children 2 to 4 years of age. The reactogenicity profile of the 10-μg dose level in children 2 to 4 years of age resulted in forgoing evaluation of that dose level in children 6 months to less than 2 years of age. In children 6 months to less than 2 years of age, because immune responses at the 3-μg dose level were similar to those observed in children 2 to 4 years of age, and in light of the favorable safety and reactogenicity profile of the 3-μg dose level in this age group (Table S5), the 3-μg dose level was selected for phase 2–3 evaluation.

Immunobridging data after dose 2 met success criteria in children 6 months to less than 2 years of age and met success criteria for seroresponse but not for GMT in children 2 to 4 years of age (Table 2). Therefore, we assessed a third primary dose for both age groups. Geometric mean ratios of neutralizing GMTs for 3 μg of BNT162b2 among children 6 months to less than 2 years of age and children 2 to 4 years of age 1 month after dose 3 to GMTs for 30 μg of BNT162b2 among persons 16 to 25 years of age 1 month after dose 2 were 1.19 (95% confidence interval [CI], 1.00 to 1.42) and 1.30 (95% CI, 1.13 to 1.50), respectively (Table 2). These findings met the immunobridging criterion of a lower boundary of the two-sided 95% confidence interval of more than 0.67; they also met the prespecified and FDA-requested point estimates for the geometric mean ratio of at least 0.8 and at least 1.0, respectively. The differences in the percentages of children 6 months to less than 2 years of age and children 2 to 4 years of age who had a seroresponse after dose 3 and the percentage of persons 16 to 25 years of age who had a seroresponse after dose 2 were 1.2 percentage points (95% CI, −3.4 to 4.2) and 1.2 percentage points (95% CI, −1.5 to 4.2), respectively; these findings also met this immunobridging criterion.

32 children 6 months to less than 2 years of age and 34 children 2 to 4 years of age were 129 and 114, respectively, as compared with 164 among adults 18 to 50 years of age who received a third 30-μg BNT162b2 dose at a similar time interval after dose 2 as the children in this trial — approximately 3 months (Fig. S5). Ancestral SARS-CoV-2 serum-neutralizing GMTs 1 month after dose 2 in a subgroup of children 2 to 4 years of age and among adults 65 years of age who received two BNT162b2 doses were 830.0 and 431.8, respectively. The geometric mean ratio was 1.92 (two-sided 95% CI, 1.56 to 2.36).

Local reactions were reported more frequently after BNT162b2 than after placebo, with most being mild to moderate; severe reactions after any dose were reported infrequently (≤0.3%) (Figure 2). No grade 4 local reactions were reported. Tenderness was the most frequent local reaction among children 6 months to less than 2 years of age, and pain was the most frequent among children 2 to 4 years of age; swelling and redness were less frequent. The median time of onset for all local reactions was 1 or 2 days after receipt of BNT162b2 or placebo; most reactions resolved within 1 to 2 days. The incidences of local reactions after dose 3 were generally similar to or lower than those after dose 1 or after dose 2. Among children 6 months to less than 2 years of age, systemic events other than fever were generally reported more frequently after BNT162b2 than after placebo (Figure 2). Among children 2 to 4 years of age, systemic events were reported at generally similar frequencies after BNT162b2 and after placebo. Most systemic events were mild to moderate, with severe events after any dose reported infrequently (≤1.1%). No grade 4 systemic events were reported. Irritability was the most frequent systemic event among children 6 months to less than 2 years of age; fatigue was the most frequent among children 2 to 4 years of age. In BNT162b2 recipients, the median onset for most events was 2 to 3 days; most resolved within 1 to 2 days.

Among children 6 months to 4 years of age, 34 Covid-19 cases (13 in the BNT162b2 group and 21 in the placebo group) occurred from at least 7 days after dose 3 to the data-cutoff date (i.e., February 7 to June 17, 2022, which was entirely during the omicron-dominant phase), corresponding to an observed vaccine efficacy of 73.2% (95% CI, 43.8 to 87.6) (Figure 3). The efficacy of the vaccine was affirmed because the lower boundary of the 95% confidence interval was greater than 30%. Observed vaccine efficacy was 75.8% (95% CI, 9.7 to 94.7) among children 6 months to less than 2 years of age and 71.8% (95% CI, 28.6 to 89.4) among children 2 to 4 years of age. The majority of Covid-19 cases from 7 days after dose 3 were caused by omicron BA.2.12.1 and BA.2. Among children 6 months to 4 years of age, vaccine efficacy was 71.8% (95% CI, 40.5 to 87.1) against all omicron variants (33 cases). With respect to omicron sublineages, vaccine efficacy was 71.1% (95% CI, 9.1 to 91.5) against BA.2.12.1 (15 cases), 89.2% (95% CI, 45.7 to 98.9) against BA.2 (10 cases), and 13.3% (95% CI, −5016.9 to 95.5) against BA.4 (3 cases) (Table S7). There were 2 or fewer cases for each of the other omicron sublineages.

Two 3-μg BNT162b2 doses that were administered 21 days apart followed by a third dose given at least 8 weeks later were safe and immunogenic in children 6 months to 4 years of age. Immunogenicity data showed robust vaccine-elicited immune responses to three doses in young children, including successful immunobridging to young adults from the original adult efficacy study on the basis of neutralizing titers against the ancestral SARS-CoV-2 strain.

mmunogenic in children 6 months to 4 years of age. Immunogenicity data showed robust vaccine-elicited immune responses to three doses in young children, including successful immunobridging to young adults from the original adult efficacy study on the basis of neutralizing titers against the ancestral SARS-CoV-2 strain. Among children 2 to 4 years of age, immunobridging data after dose 2 only partially met success criteria. A descriptive analysis showed higher GMTs after dose 2 among children 2 to 4 years of age than among adults 65 years of age or older, for whom efficacy in the pivotal trial conducted before the omicron wave was shown.10 To achieve high effectiveness against symptomatic and severe Covid-19, including that caused by omicron BA.1 or BA.2 subvariants, real-world studies involving older populations, including adolescents, have also consistently shown the need for additional vaccine doses beyond the initial two doses used in these age groups.13,17-20 Given these real-world data in the omicron wave as well as clinical data, a third dose was authorized for persons 5 years of age or older,7,21,22 and a three-dose primary series was evaluated in children younger than 5 years of age. An exploratory analysis suggested that three 3-μg BNT162b2 doses induced neutralizing titers against the omicron BA.1 variant, with response patterns generally similar to those observed in adults 18 to 50 years of age administered a third dose (booster) at an interval similar to that used for doses 2 and 3 in young children (approximately 3 months), findings that further support the need for a three-dose primary series in children younger than 5 years of age.

tterns generally similar to those observed in adults 18 to 50 years of age administered a third dose (booster) at an interval similar to that used for doses 2 and 3 in young children (approximately 3 months), findings that further support the need for a three-dose primary series in children younger than 5 years of age. Our data indicate that vaccinating young children affords efficacy against symptomatic Covid-19. This three-dose primary series was 73.2% effective (95% CI, 43.8 to 87.6) against Covid-19 from at least 7 days after dose 3, a period that was entirely within the omicron-dominant phase. Availability of Covid-19 vaccines for young children is critical, because this population has had a surge in omicron-related cases and hospitalizations, and Covid-19 in this age group places a burden on families, including child care–related employment disruption.1-4,23 Protection against severe Covid-19 among young children is paramount, particularly with the unpredictability of new variants, including omicron BA.4 and BA.5 sublineages. As other mitigation measures are lifted (e.g., masking and restrictions on large gatherings), vaccinating this age group would also expand direct protection and add another layer of community protection against symptomatic and severe Covid-19.

predictability of new variants, including omicron BA.4 and BA.5 sublineages. As other mitigation measures are lifted (e.g., masking and restrictions on large gatherings), vaccinating this age group would also expand direct protection and add another layer of community protection against symptomatic and severe Covid-19. The observed safety profile in this study did not suggest any concerns for BNT162b2 administered as three 3-μg doses in children 6 months to 4 years of age. Reactogenicity to BNT162b2, which included irritability as an adverse reaction in children 6 months to less than 2 years of age, was mostly mild to moderate and short-lived, with most events occurring at frequencies similar to or lower than those after dose 3 as compared with after dose 1 or after dose 2. No deaths were reported, and few adverse events led to withdrawal. No cases of myocarditis or pericarditis, MIS-C, or vaccine-related anaphylaxis were observed in the short term, and surveillance continues. BNT162b2 continues to demonstrate safety and an acceptable reactogenicity profile across age groups.

fter dose 2. No deaths were reported, and few adverse events led to withdrawal. No cases of myocarditis or pericarditis, MIS-C, or vaccine-related anaphylaxis were observed in the short term, and surveillance continues. BNT162b2 continues to demonstrate safety and an acceptable reactogenicity profile across age groups. The trial has some limitations. It was not powered to assess efficacy against severe disease or against specific SARS-CoV-2 variants. We lacked data on omicron BA.4 and BA.5 serum-neutralizing activity and longer-term follow-up to assess immune-response duration as well as safety. In addition, the trial population was predominantly White. Like other phase 2–3 trials, the trial was not powered to detect potential rare side effects. However, follow-up from this trial (which will continue for ≥1 year after dose 3), together with effectiveness and safety data from real-world use (including from older age groups), should provide further information. Simultaneous administration of BNT162b2 with other vaccines that are administered in young children was also not assessed, although coadministration of Covid-19 vaccines with routine childhood immunizations is encouraged by the American Academy of Pediatrics and is endorsed by the Centers for Disease Control and Prevention (CDC).24 Data are available that suggest waning effectiveness of a third BNT162b2 dose in older adolescents and adults within a few months after administration, yet administration of a fourth dose given at least 4 months after dose 3 to older adults increases protection against SARS-CoV-2 infection, symptomatic and severe Covid-19, and Covid-19−associated hospitalizations and deaths.25,26 Therefore, additional doses, including doses beyond the primary series, may be required in all age groups to cover waning immunity, and variant-specific formulations might be needed to protect against emerging strains.

infection, symptomatic and severe Covid-19, and Covid-19−associated hospitalizations and deaths.25,26 Therefore, additional doses, including doses beyond the primary series, may be required in all age groups to cover waning immunity, and variant-specific formulations might be needed to protect against emerging strains. These data support vaccination of children 6 months to 4 years of age with three 3-μg primary BNT162b2 doses. BNT162b2 was recently granted emergency use authorization for this age group27; together with another Covid-19 mRNA vaccine, BNT162b2 is now recommended by the CDC.28