Evaluation of mRNA-1273 Vaccine in Children 6 Months to 5 Years of Age

Abstract

Background: The safety, reactogenicity, immunogenicity, and efficacy of the mRNA-1273 coronavirus disease 2019 (Covid-19) vaccine in young children 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 evaluation of the selected dose. In part 2, we randomly assigned young children (6 months to 5 years of age) in a 3:1 ratio to receive two 25-μg injections of mRNA-1273 or placebo, administered 28 days apart. The primary objectives were to evaluate the safety and reactogenicity of the vaccine and to determine whether the immune response in these children was noninferior to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives were to determine the incidences of Covid-19 and severe acute respiratory syndrome coronavirus 2 infection after administration of mRNA-1273 or placebo.

Results: On the basis of safety and immunogenicity results in part 1 of the trial, the 25-μg dose was evaluated in part 2. In part 2, 3040 children 2 to 5 years of age and 1762 children 6 to 23 months of age were randomly assigned to receive two 25-μg injections of mRNA-1273; 1008 children 2 to 5 years of age and 593 children 6 to 23 months of age were randomly assigned to receive placebo. The median duration of follow-up after the second injection was 71 days in the 2-to-5-year-old cohort and 68 days in the 6-to-23-month-old cohort. Adverse events were mainly low-grade and transient, and no new safety concerns were identified. At day 57, neutralizing antibody geometric mean concentrations were 1410 (95% confidence interval [CI], 1272 to 1563) among 2-to-5-year-olds and 1781 (95% CI, 1616 to 1962) among 6-to-23-month-olds, as compared with 1391 (95% CI, 1263 to 1531) among young adults, who had received 100-μg injections of mRNA-1273, findings that met the noninferiority criteria for immune responses for both age cohorts. The estimated vaccine efficacy against Covid-19 was 36.8% (95% CI, 12.5 to 54.0) among 2-to-5-year-olds and 50.6% (95% CI, 21.4 to 68.6) among 6-to-23-month-olds, at a time when B.1.1.529 (omicron) was the predominant circulating variant.

Conclusions: Two 25-μg doses of the mRNA-1273 vaccine were found to be safe in children 6 months to 5 years of age and elicited immune responses that were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).

Figure 1. Randomization of Participants 2 to 5 Years of Age and Participants 6 to 23 Months of Age in Part 2 of the Trial.

Discontinuation of the trial regimen indicates that a participant who received the first injection did not receive the second injection. In the cohort of 2-to-5-year-olds (Panel A), 51 participants in the mRNA-1273 group and 16 in the placebo group had planned to receive the second injection, but the injection was delayed because of adverse events, illness, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (the majority of these participants had coronavirus disease 2019 [Covid-19] or SARS-CoV-2 infection); these participants continued in the ongoing trial, and their data remained blinded. Among the participants who discontinued the trial, 15 in the mRNA-1273 group and 6 in the placebo group received one injection, and 34 and 24 participants, respectively, received the second injection. Among the 2982 participants who continued in the ongoing trial, 2897 had data that remained blinded, and 85 had data that were unblinded (5 received the second injection after unblinding, 79 received a second injection before unblinding, and 1 had not yet received the planned second injection) and were entered in the open-label trial. In the cohort of 6-to-23-month-olds (Panel B), among the participants who discontinued the trial, 3 in the mRNA-1273 group and 5 in the placebo group received the first injection, and 14 and 7 participants, respectively, received the second injection. A total of 156 participants in the mRNA-1273 group and 56 in the placebo group had planned to receive the second injection, and their data remained blinded; most of these participants had not reached day 29 after the first injection by the data-cutoff date (February 21, 2022). EUA denotes emergency use authorization.

Figure 2. Solicited Local and Systemic Adverse Reactions in the Cohorts of Children 2 to 5 Years and 6 to 23 Months of Age in Part 2 of the Trial.

Shown are the percentages of participants in the two age cohorts (2-to-5-year-olds [Panel A] and 6-to-23-month-olds [Panel B]) in the part 2 solicited safety population (all participants who received at least one injection and had any data collected on solicited adverse reactions) who had a solicited local or systemic adverse reaction within 7 days after the first or second injection. Local adverse reactions of injection-site pain, erythema, swelling (hardness), and axillary or groin swelling or tenderness were assessed in both age cohorts. Among participants 37 months to 5 years of age, the solicited systemic adverse reactions were fever, headache, fatigue, myalgia, arthralgia, nausea or vomiting, and chills. Among participants 6 to 36 months of age, the solicited systemic adverse reactions were fever, irritability or crying, sleepiness, and loss of appetite. The data-cutoff date was February 21, 2022.

Figure 3. Secondary Efficacy End Points.

Panel A shows the incidences of secondary end points in the cohorts of 2-to-5-year-olds and 6-to-23-month-olds in the per-protocol efficacy population, which included all participants who received both injections per schedule, had no virologic or serologic evidence of SARS-CoV-2 infection at baseline, and had no major protocol deviations. A case of Covid-19 was defined by the Centers for Disease Control and Prevention (CDC) as at least one systemic or respiratory symptom and a positive reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was defined in the Coronavirus Efficacy (COVE) trial as at least two systemic symptoms or at least one respiratory symptom and a positive RT-PCR assay. Vaccine efficacy for secondary end points of the incidence of Covid-19 and SARS-CoV-2 infection regardless of symptoms and asymptomatic infection in the per-protocol efficacy population was defined as 1 minus the ratio of incidence rate (mRNA-1273 vs. placebo). 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. Panel B shows the cumulative incidence of Covid-19 (according to the CDC definition) starting from randomization among the children 2 to 5 years of age and those 6 to 23 months of age in the modified intention-to-treat population, which included all randomly assigned participants who did not have serologic or virologic evidence of SARS-CoV-2 infection at baseline and who received at least one injection of the correct dose. The tick marks indicate censored data. The insets show the same data on an enlarged y axis. The data-cutoff date was February 21, 2022.