Evaluation of mRNA-1273 Covid-19 Vaccine in Children 6 to 11 Years of Age

Abstract

Background: Vaccination of children to prevent coronavirus disease 2019 (Covid-19) is an urgent public health need. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in children 6 to 11 years of age are unknown.

Methods: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled expansion evaluation of the selected dose. In part 2, we randomly assigned children (6 to 11 years of age) in a 3:1 ratio to receive two injections of mRNA-1273 (50 μg each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of the vaccine in children and the noninferiority of the immune response in these children to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives included determination of the incidences of confirmed Covid-19 and severe acute respiratory syndrome coronavirus 2 infection, regardless of symptoms. Interim analysis results are reported.

Results: In part 1 of the trial, 751 children received 50-μg or 100-μg injections of the mRNA-1273 vaccine, and on the basis of safety and immunogenicity results, the 50-μg dose level was selected for part 2. In part 2 of the trial, 4016 children were randomly assigned to receive two injections of mRNA-1273 (50 μg each) or placebo and were followed for a median of 82 days (interquartile range, 14 to 94) after the first injection. This dose level was associated with mainly low-grade, transient adverse events, most commonly injection-site pain, headache, and fatigue. No vaccine-related serious adverse events, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were reported as of the data-cutoff date. One month after the second injection (day 57), the neutralizing antibody titer in children who received mRNA-1273 at a 50-μg level was 1610 (95% confidence interval [CI], 1457 to 1780), as compared with 1300 (95% CI, 1171 to 1443) at the 100-μg level in young adults, with serologic responses in at least 99.0% of the participants in both age groups, findings that met the prespecified noninferiority success criterion. Estimated vaccine efficacy was 88.0% (95% CI, 70.0 to 95.8) against Covid-19 occurring 14 days or more after the first injection, at a time when B.1.617.2 (delta) was the dominant circulating variant.

Conclusions: Two 50-μg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).

Figure 1. 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.

Figure 2. 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.

Figure 3. 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. 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.