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Clinical Context

COVID-19 is generally mild in children aged < 5 years, but severe disease, hospitalizations, and multisystem inflammatory syndrome in children (MIS-C) can occur. In a previous study by Anderson and colleagues, they investigated the safety and efficacy of a 2-dose series of the Moderna vaccine (mRNA-1273) for children aged 6 months to 5 years and found the series to have an acceptable safety profile and to elicit immune responses consistent with higher doses given to older children, adolescents, and adults. Their results were published in the November 3, 2022 issue of the New England Journal of Medicine.^[1]

BNT162b2 vaccine has US licensure for COVID-19 immunization in persons aged ≥ 12 years and emergency use authorization (EUA) for children aged 5 to 11 years. In children aged 2 to 4 years, a 2-dose primary series failed some criteria for immunobridging success. Emerging evidence suggests that 3 mRNA vaccine doses are needed to enhance immune responses against Omicron. The current study by Muñoz and colleagues therefore investigated a third 3-μg BNT162b2 dose given ≥ 8 weeks after dose 2 in children aged 6 months to 4 years.

Study Synopsis and Perspective

In the current study, the authors show the Pfizer-BioNTech vaccine (BNT162b2) is safe and highly effective against COVID-19 in children as young as 6 months old.

A 3-dose series of the vaccine was 73% effective at preventing symptomatic COVID-19 in children aged 6 months to 4 years old, the researchers found. They also discovered that an examination of reactions and safety results “did not suggest any concerns.”

The study, published in The New England Journal of Medicine, included 1776 children aged 6 months to 2 years and 2750 children aged 2 to 4 years. Researchers randomly assigned children to receive either the 3-shot series of the BNT162b2 vaccine or placebo shots. Participants received the first dose of the vaccine by March 31, 2022, and lived in Brazil, Finland, Poland, Spain, or the United States.^[2]

The authors wrote that having safe and effective COVID-19 vaccines for young children is important to protect them from hospitalization or death and because young children play a role in spreading highly transmissible variants of the virus. COVID-19 hospitalizations for children younger than 5 years old peaked at a rate of 14.5 per 100,000 in January 2022, the authors wrote, noting that the Omicron virus variant appeared to affect young children more severely than the previous variant, Delta.

When the researchers evaluated vaccine effectiveness by age group, they found that it prevented symptomatic COVID-19 in 75.8% of children aged 6 months to 2 years and in 71.8% of children aged 2 to 4 years.

Less than 0.5% of participants reported severe reactions to the vaccine. The most common reactions reported were tenderness or pain. Reactions typically appeared within the first couple days after vaccine administration and resolved within 2 days. Participants reported zero cases of inflammation of the heart muscle or its lining.

Uptake of COVID-19 vaccines for young children has been lower than other age groups in the United States. The Centers for Disease Control and Prevention (CDC) said 10% of children younger than 5 years have received at least 1 dose of a COVID-19 vaccine, and 5% have completed a primary vaccine series.^[3]

Please see Study Highlights below for a synopsis of recent studies published on the safety and efficacy of the 2 mRNA COVID-19 vaccines that have received EUA from the FDA for children to aged older than 6 months.

Study Highlights: Pfizer-BioNTech COVID-19 Vaccine (BNT162b2)

• During the dose-finding study, 2 doses of BNT162b2 were given 21 days apart to 16 children aged 6 months to < 2 years (3 μg) and 48 children aged 2 to 4 years (3 or 10 μg).
• In the phase 2 to 3 trial, researchers randomly assigned participants 2:1 to receive two 3-μg doses of BNT162b2 (1178 children aged 6 months to < 2 years and 1835 children aged 2 to 4 years) or placebo (598 and 915, respectively).
• From January 2022, when Omicron emerged, a third 3-μg dose (≥ 8 weeks after dose 2) was given, based on preliminary immunogenicity results.
• Immune responses at 1 month after doses 2 and 3 in children aged 6 months to < 2 years and in children aged 2 to 4 years were immunologically bridged to responses after dose 2 in persons aged 16 to 25 years given 30 μg BNT162b2 in the pivotal trial.
• Both age groups met immunobridging success criteria for geometric mean ratio and seroresponse at 1 month after dose 3.
• Local reactions were more frequent within 7 days after BNT162b2 than after placebo; most were mild to moderate; ≤ 0.3% were severe; none were grade 4.
• The most frequent local reaction was tenderness among children aged 6 months to < 2 years and pain among children aged 2 to 4 years; swelling and redness were less frequent.
• Median time of onset for all local reactions was 1 to 2 days after injection; most resolved within 1 to 2 days.
• Incidences of local reactions after dose 3 were generally similar to or lower than those after dose 1 or 2.
• Low, similar incidences of fever were reported after BNT162b2 (7% among children aged 6 months to < 2 years; 5% among children aged 2 to 4 years) and placebo (6%-7% and 4%-5%, respectively).
• Among children aged 6 months to < 2 years, systemic events other than fever were more frequent after BNT162b2 than after placebo; among children aged 2 to 4 years, systemic events occurred at generally similar frequencies in both groups.
• Systemic events were mostly mild to moderate; severe in ≤ 1.1%; none were grade 4.
• The most frequent systemic event was irritability among children aged 6 months to < 2 years and fatigue among children aged 2 to 4 years.
• Median onset for most events after BNT162b2 was 2 to 3 days; most resolved within 1 to 2 days.
• Overall, adverse event (AE) frequencies were similar for BNT162b2 and placebo in both age groups and were higher among the younger group.
• Few participants withdrew for AEs.
• There were no deaths, myocarditis or pericarditis, facial weakness, thromboembolism, thrombocytopenia, MIS-C, Kawasaki disease, acute respiratory distress syndrome, meningitis, myelitis or encephalomyelitis, vaccine-related anaphylaxis, demyelination, peripheral neuropathy, or vasculitis.
• Among children aged 6 months to 4 years, there were 13 COVID-19 cases in the BNT162b2 group and 21 in the placebo group from ≥ 7 days after dose 3 to the data-cutoff date, entirely during the Omicron-dominant phase.
• Vaccine efficacy was 73.2% (95% CI: 43.8%, 87.6%) overall, 75.8% (95% CI: 9.7%, 94.7%) among children aged 6 months to < 2 years and 71.8% (95% CI: 28.6%, 89.4%) among children aged 2 to 4 years.
• Omicron BA.2.12.1 and BA.2 caused most COVID-19 cases from 7 days after dose 3.
• Among children aged 6 months to 4 years, vaccine efficacy was 71.8% (95% CI: 40.5%, 87.1%) against all Omicron variants; 71.1% (95% CI: 9.1%, 91.5%) against BA.2.12.1, 89.2% (95% CI: 45.7%, 98.9%) against BA.2, and 13.3% (95% CI: −5016.9%, 95.5%) against BA.4.
• The investigators concluded that two 3-μg BNT162b2 doses given 21 days apart followed by a third dose ≥ 8 weeks later was safe, immunogenic, and efficacious in children aged 6 months to 4 years from ≥ 7 days after dose 3, during the Omicron-dominant phase.
• Immunogenicity data showed robust vaccine-elicited immune responses, including successful immunobridging to young adults from the original adult efficacy study, according to neutralizing titers against the ancestral SARS-CoV-2 strain.
• Among children aged 2 to 4 years, immunobridging data after dose 2 only partially met success criteria.
• To achieve high effectiveness against symptomatic and severe COVID-19, including from Omicron BA.1 or BA.2, real-world studies in older populations including adolescents also showed the need for additional vaccine doses beyond the initial 2 doses.
• A third dose was therefore authorized for persons aged ≥ 5 years, and a 3-dose primary series was evaluated in children aged < 5 years.
• In an exploratory analysis, three 3-μg BNT162b2 doses induced neutralizing titers against Omicron BA.1, with response patterns generally similar to those in adults aged 18 to 50 years given a third dose (booster) at an interval similar to that used for doses 2 and 3 in young children (~ 3 months).
• Taken together, the evidence supports vaccination of children aged 6 months to 4 years with three 3-μg primary BNT162b2 doses, leading to recent EUA.
• The CDC now recommends BNT162b2 or another COVID-19 messenger RNA (mRNA) vaccine.
• COVID-19 vaccine availability for young children is essential, given their surge in Omicron-related cases and hospitalizations, and the family burden, including childcare–related employment disruption, of COVID-19 in young children.
• Unpredictability of new variants, including Omicron BA.4 and BA.5 sublineages, requires protection against severe COVID-19 among young children.
• As masking and other mitigation measures are lifted, vaccinating young children would expand direct protection and add another layer of community protection against symptomatic, severe COVID-19.
• The observed BNT162b2 safety profile and reactogenicity did not suggest any concerns in young children.
• Study limitations include insufficient power to assess efficacy against severe disease or specific variants or to detect potential rare AEs, predominantly White participants, and lack of assessment of simultaneous administration of BNT162b2 with other vaccines
• Follow-up from this trial (for ≥ 1 year after dose 3) and effectiveness and safety data from real-world use should give further information.
• According to data from older populations, all age groups may need additional doses beyond the primary series to cover waning immunity, with variant-specific formulations to protect against emerging strains.

Study Highlights: Moderna COVID-19 Vaccine (mRNA-1273)

• The study was divided into 2 age cohorts: 6 to 23 months and 2 to 5 years. Children were recruited from 79 sites in the United States and 8 in Canada.
• Researchers randomly assigned participants to receive two 25-µg doses of mRNA-1273 or placebo dosed 1 month apart.
• The main study outcomes were the safety and immunogenicity of mRNA-1273 vs placebo. A serologic response to the vaccine was defined by at least a 4-fold increase in neutralizing antibody concentration against SARS-CoV-2. Researchers compared the serologic response of mRNA-1273 in children with that of a previous cohort of young adults aged between 18 and 25 years.
• The secondary study outcome was the incidence of infection with SARS-CoV-2. The diagnosis of COVID-19 required at least one systemic or respiratory symptom along with a positive reverse-transcriptase polymerase chain reaction (RT-PCR) test for SARS-CoV-2.
• Between April 2021 and June 2021, investigators randomly assigned 3040 children between the ages of 2 and 5 years to receive mRNA-1273, along with 1762 children between the ages of 6 and 23 months. 1008 and 593 children in each respective age group received placebo.
• The median age of participants in the 2- to 5 year-old age group was 3 years. 76.5% of participants in this group were White. The median age of participants in the 6- to 23 month-old age group was 16 months, and 78.9% of participants in this group were White. The cohort overall was equally divided among girls and boys.
• Adherence to the study injections exceeded 90%. The median duration of follow-up after the second injection in the 2- to 5-year and 6- to 23-month groups were 71 and 68 days, respectively.
• AEs were more common in the mRNA-1273 groups vs placebo, but most of these events were mild and transient. Among children between the ages of 6 and 23 months, localized reactions occurred in 44% and 54% of participants after the first and second injections of mRNA-1273, respectively. The respective rates of localized reactions in the placebo group were 33% and 30%.
• Among children aged between 6 and 23 months, systemic reactions occurred in 76% and 74% of participants after the first and second injections of mRNA-1273, respectively. The respective rates of systemic reactions in the placebo group were 72% and 67%.
• There was a larger gap in the rate of AEs in comparing placebo and mRNA-1273 among older children, with the second dose particularly associated with a higher rate of local (70% to 75%) and systemic (59% to 68%) reactions.
• 8 serious AEs occurred in the mRNA-1273 group aged 6 to 23 months compared with 0 in the placebo group. There were no serious AEs in the 2- to 5- year-old cohort.
• No cases of death, myocarditis, pericarditis, or MIS-C were recorded.
• At day 57, neutralizing antibody geometric mean concentrations against SARS-CoV-2 were 1410 (95% CI: 1272, 1563) among 2- to 5-year-olds and 1781 (95% CI: 1616, 1962) among 6- to 23-month-olds. These results were similar compared with the immunologic response among young adults and met criteria for noninferiority.
• mRNA-1273 demonstrated robust immunogenicity for ancestral variants of SARS-CoV-2 along with the omicron variant.
• Among 2- to 5-year-old children, the incidence rates of COVID-19 were 4.6% and 7.1% in the mRNA-1273 and placebo groups, respectively. Vaccine efficacy was 36.8% after the second injection.
• Among 6- to 23 month-old children, the incidence rates of COVID-19 were 3.4% and 6.6% in the mRNA-1273 and placebo groups, respectively. Vaccine efficacy was 50.6%.
• mRNA-1273 also demonstrated vaccine efficacy against asymptomatic infection.

Clinical Implications

• Two 3-μg BNT162b2 doses given 21 days apart followed by a third dose ≥ 8 weeks later was safe, immunogenic, and efficacious in children aged 6 months to 4 years.
• New evidence supports vaccination of children aged 6 months to 4 years with three 3-μg primary BNT162b2 doses, leading to recent EUA, or with another COVID-19 mRNA vaccine.
• Implications for the Healthcare Team: Members of the healthcare team should educate patients and caregivers that additional doses beyond the primary series may be needed to cover waning immunity, with variant-specific formulations to protect against emerging strains.

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