Trial Population
Between March and August 2021, a total of 751 participants who were 6 to 11 years of age were enrolled in part 1 of the trial and 4016 participants were enrolled in part 2. In part 1, all 380 participants who were enrolled in the 50-μg dose-level mRNA-1273 group and 371 participants who were enrolled in the 100-μg dose-level mRNA-1273 group received one injection, and 379 participants who were enrolled in the 50-μg dose-level group and 371 participants who were enrolled in the 100-μg dose-level group received two injections (Fig. S2).
Randomization and Analysis Populations in Part 2 of the Trial.
The populations of trial participants (6 to 11 years of age) who received the mRNA-1273 vaccine at a dose level of 50 μg or placebo are shown. The reasons for not receiving a first injection included withdrawal of consent (in 8 participants), screening failure because of error in randomization (in 5), and physician decision owing to a medication change 1 month before consent (in 1). Two participants who were randomly assigned to receive placebo received the mRNA-1273 vaccine. In the placebo group, the two adverse events were related to coronavirus disease 2019 (Covid-19). In the mRNA-1273 vaccine group, of the 36 participants who discontinued the trial, 9 had received a first injection and 27 had received a second injection. In the placebo group, of the 133 participants who discontinued the trial, 10 had received a first injection and 123 had received a second injection. The number of trial discontinuations includes 9 participants in the vaccine group and 67 participants in the placebo group who had data that were unblinded and discontinued the trial. After October 29, 2021, the date of emergency use authorization (EUA) of the BNT162b2 vaccine for children 5 to 11 years of age, participants became eligible to have their data unblinded. The cutoff date for blinded data was November 10, 2021.
In part 2 of the trial, 4016 participants were randomly assigned to receive two 50-μg injections of the mRNA-1273 vaccine or two injections of placebo; 3005 participants in the vaccine group and 997 participants in the placebo group received the first injection, and 2988 participants (99.2%) in the vaccine group and 973 participants (96.9%) in the placebo group received both injections (Figure 1). A total of 13 participants (0.4%) in the vaccine group and 14 participants (1.4%) in the placebo group did not receive the second injection, most commonly because of withdrawal of consent in both groups; 2 participants (0.2%) in the placebo group received a vaccine that was available under an EUA, outside the protocol. In the vaccine group, 36 participants (1.2% of those who received the first injection) discontinued the trial, and these discontinuations were attributed mainly to withdrawal of consent. In the placebo group, 133 participants (13.3% of those who received the first injection) discontinued the trial; these discontinuations were attributed mainly to receipt of an EUA vaccine outside the protocol.
Demographic and Clinical Characteristics in the Safety Population at Baseline (Part 2 of the Trial).
The demographic characteristics of the participants at baseline were generally balanced between the trial groups, similar in parts 1 and 2 of the trial, and representative of a diverse population (Table 1 and Tables S3 and S4). In part 2, the mean age of the participants in the safety population was 8.5 years (approximately 50% of the participants were 6 to 8 years of age), 49.2% were female, 51.9% were White non-Hispanic, and 47.9% were from communities of color. The distribution of race groups included 65.6% White, 10.0% Black, 9.9% Asian, and 10.6% multiracial participants, and 18.5% of the participants were Hispanic or Latinx. Characteristics of the per-protocol immunogenicity subgroup in part 2 of the trial, including representativeness of communities of color, were generally similar to those in the safety population in part 2 and those in the per-protocol immunogenicity subgroup in the COVE trial involving young adults (18 to 25 years of age).
Safety
On the basis of the combined safety, reactogenicity, and immunogenicity results in part 1 of the trial, the 50-μg dose level was selected for evaluation in the 6-to-11-year-old age group in part 2 (Part 1 Results section in the Supplementary Appendix). Data on safety are provided in Tables S5 through S10, and data on immunogenicity are provided in Figures S3 and S4 and Tables S11 through S14.
Solicited Local and Systemic Adverse Reactions in Part 2 of the Trial.
Shown is the percentage of participants in the solicited safety population who had a solicited local or systemic adverse reaction within 7 days after the first or second 50-μg injection of the mRNA-1273 vaccine or placebo. The numbers above the bars are the percentage of participants in each group with the specified reaction. Lymphadenopathy was defined as axillary or groin swelling or tenderness. The data-cutoff date was November 10, 2021.
In part 2 of the trial, the median duration of follow-up was 82 days (interquartile range, 14 to 94) after the first injection and 51 days (interquartile range, 45 to 57) after the second injection. Solicited local adverse events were more common in the mRNA-1273 vaccine group than in the placebo group after the first injection (94% vs. 48%) and after the second injection (95% vs. 51%); the most common adverse event was injection-site pain (Figure 2A and Table S15). Most solicited local adverse events after any injection were grades 1 or 2. In the mRNA-1273 group, the incidence of local grade 3 adverse events was higher after the second injection (4%) than after the first injection (2%).
The incidence of solicited systemic adverse events after the first injection was similar in the mRNA-1273 vaccine group (58%) and the placebo group (52%) and higher after the second injection in the mRNA-1273 vaccine group than in the placebo group (in 78% vs. 50%) (Figure 2B). In both groups, the most common solicited systemic adverse events were headache and fatigue. In the mRNA-1273 vaccine group, the incidences of chills and fever were higher after the second injection than after the first injection; these increases in incidence were greater than the increases observed with other adverse events. Most systemic adverse events were grade 1 or 2. After the second injection, the incidence of systemic grade 3 adverse events — most commonly fatigue, headache, and fever — was higher in the mRNA-1273 group (12%) than in the placebo group (1%).
The majority of solicited adverse events in the vaccine group occurred within 1 or 2 days after either injection and persisted for medians of 2 or 3 days. The median duration of fever was 1 day (Table S16).
The incidences of local adverse events were similar in children who received the mRNA-1273 vaccine at the 50-μg dose level and in young adults (18 to 25 years of age) who received the mRNA-1273 vaccine at the 100-μg dose level in the COVE trial; the incidences of systemic adverse events were lower among the children than among the young adults. The incidence of grade 3 adverse events was also lower in children than in young adults, with the exception of fever, which occurred more often in children than in young adults after either injection, and in particular, after the second injection (in 4% vs. 1%) (Tables S17 and S18).
In the current trial, the incidence of unsolicited adverse events that occurred up to 28 days after either injection was similar in the mRNA-1273 vaccine group (29.6%) and the placebo group (25.1%) (Tables S19 through S21). The incidence of unsolicited adverse events that were considered by the investigator to be related to the trial vaccine or placebo was higher in the mRNA-1273 group (10.6%) than in the placebo group (5.0%). These events were mostly reactogenicity events; injection-site erythema was the most common. Serious unsolicited adverse events that occurred up to 28 days after any injection were reported for three participants (<0.1%) in the mRNA-1273 group and two participants (0.2%) in the placebo group.
All serious adverse events in the mRNA-1273 vaccine group (appendicitis, cellulitis, and orbital cellulitis) and in the placebo group (affective disorder and Covid-19) were considered by the investigators to be unrelated to the trial vaccine or placebo. The incidence of medically attended adverse events was similar in the mRNA-1273 group (13.4%) and the placebo group (14.2%). No vaccination-related adverse events led to nonreceipt of the second injection, discontinuation from the trial, or both. As of the data-cutoff date, the investigators had not attributed any serious adverse events to the trial vaccine or placebo, and no deaths or cases of anaphylaxis, MIS-C, myocarditis, or pericarditis were reported.
Efficacy
Immunogenicity of the mRNA-1273 Vaccine in Part 2 of the Trial.
At day 57, the geometric mean titer of neutralizing antibodies was 1610 (95% CI, 1457 to 1780) in 320 children who had received the mRNA-1273 vaccine at the 50-μg dose level as compared with 1300 (95% CI, 1171 to 1443) in 295 young adults who had received the mRNA-1273 vaccine at the 100-μg dose level, with a serologic response in at least 99% of the participants in both groups (Table 2 and S22 and Fig. S5). The geometric mean titer ratio of neutralizing antibodies in children as compared with young adults was 1.2 (95% CI, 1.1 to 1.4), and the between-group difference in the serologic response was 0.1 percentage points (95% CI, −1.9 to 2.1), findings that met the noninferiority criterion for the coprimary immunogenicity objective. These findings were further supported by similar results with respect to the distribution of binding antibodies (Tables S23 and S24 and Fig. S6).
Vaccine Efficacy after the First Injection in Part 2 of the Trial.
The cumulative incidence of Covid-19 was based on the Centers for Disease Control and Prevention (CDC) definition (Panel A) and the primary case definition in the COVE trial (Panel B) in the modified-intention-to-treat-1 population, 14 days after the first injection. Covid-19 cases are based on one symptom according to the CDC definition and two symptoms in the primary case definition used in the COVE trial.1 The number of person-years was defined as the total years from the first day of the analysis to the date of the event, to the last date of trial participation, to censoring time, or to the efficacy data-cutoff date, whichever was earliest. Incidence was defined as the number of participants with an event divided by the number of participants at risk, with adjustment for person-years (total time at risk) in each trial group. The 95% confidence interval (CI) was calculated with the use of the exact method (Poisson distribution) with adjustment for person-years. Vaccine efficacy was defined as 1 minus the ratio of the incidence rate (mRNA-1273 vaccine vs. placebo), and the 95% confidence interval of the ratio was calculated with the use of the exact method conditional on the total number of cases, with adjustment for person-years. The data-cutoff date was November 10, 2021. The insets show the same data on an expanded y axis. Tick marks in both panels indicate censored data.
In the mITT1 population, among children who did not have evidence of SARS-CoV-2 infection at baseline, the estimates of vaccine efficacy at least 14 days after the first injection were 88.0% (95% CI, 70.0 to 95.8) according to the CDC definition, with 7 cases (0.3%) in the mRNA-1273 group and 18 cases (2.1%) in the placebo group and 91.8% (95% CI, 74.2 to 98.0) according to the definition used in the phase 3 COVE trial involving adults, with 4 cases (0.1%) in the mRNA-1273 group and 15 cases (1.7%) in the placebo group (Figure 3 and Table S25). The estimated vaccine efficacy against SARS-CoV-2 infection was 74.0% (95% CI. 57.9 to 84.1), regardless of symptoms that occurred at least 14 days after the first injection, with 34 cases (1.3%) in the vaccine group and 40 cases (4.6%) in the placebo group. The estimated vaccine efficacy against asymptomatic SARS-CoV-2 infection was 62.5% (95% CI, 30.9 to 79.4), with 22 cases (2.5%) in the mRNA-1273 group and 27 cases (1.0%) in the placebo group. The analysis of vaccine efficacy at least 14 days after two injections (in the per-protocol population) was limited by the small number of Covid-19 cases and the shortened period of blinded follow-up (Table S26).
In part 1 of the trial, a preliminary analysis showed an increase by a factor of 81.8 (95% CI, 70.4 to 95.0) in the geometric mean titer of neutralizing antibodies (ID50) against the delta variant from baseline to day 57. A total of 99.3% of the children had a serologic response, findings that are similar to those indicated by increased geometric mean titers measured in adults who had received a booster against this variant (Table S27).
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