Increasing children's global access to COVID-19 vaccines.

Expanding COVID-19 vaccination to children is an issue for parents and decision makers worldwide. Among nine vaccines with WHO Emergency Use Listing (EUL), only two are authorised for children: Pfizer-BioNTech's BNT162b2 and Moderna's mRNA-1273. The WHO EUL is required for vaccines purchased through the COVAX mechanism, but other vaccines without EUL for paediatric use, such as BBIBP-CorV (SinoPharm), CoronaVac (SinoVac), and Covaxin (Bharat Biotech), are used in children with local approvals. Because of lower rates of severe COVID-19 in children than in older adults, and inequities in vaccine supply, the WHO SAGE Roadmap for prioritising the use of COVID-19 vaccines classifies children as a lower priority group. However, a COVID-19 risk in children does exist. Complications in children with COVID-19 have included respiratory failure, neurological involvement, cardiovascular dysfunction, multisystem inflammatory syndrome, and long COVID.4, 5 In the USA alone, as of May 14, 2022, the Centers for Disease Control and Prevention reported 804 deaths involving COVID-19 among children aged 5–18 years. Moreover, COVID-19 in children has disrupted education, sports, and community activities, with commensurate mental health consequences. Importantly, real-world studies have shown the promise of vaccines in averting life-threatening paediatric COVID-19 and multisystem inflammatory syndrome.7, 8, 9

In The Lancet, Grace Li and colleagues present promising findings that help improve our understanding of COVID-19 vaccines for paediatric populations worldwide, paving the way for better access globally to safe and efficacious COVID-19 vaccines. In a phase 1/2 trial, the researchers assessed the tolerability and immunogenicity of AstraZeneca's ChAdOx1 nCoV-19 vaccine (n=211) compared with a control vaccine (n=51) among healthy children aged 6–11 years and adolescents aged 12–17 years from the UK (129 [49%] of 262 participants were girls and 236 [90%] were White). ChAdOx1 nCoV-19 had an acceptable safety and reactogenicity profile and the humoral immune responses were similar to those in adults, in whom protective efficacy has been high against severe COVID-19. The study also evaluated a 28-day interval versus a 112-day interval between dose 1 and 2 in adolescents. As observed in adults, the ChAdOx1 nCoV-19 vaccine elicited higher humoral immune responses after the long interval than the short interval (geometric mean titres 73 371 arbitrary units [AU]/mL [95% CI 58 685–91 733] vs 43 280 AU/mL [95% CI 35 852–52 246]). Importantly, the first dose of ChAdOx1 nCoV-19 generated substantial cellular immune responses.

The study was adequately powered to address vaccine tolerability outcomes. However, the study was not designed to evaluate vaccine efficacy against infection or disease, or to exclude rare safety events detected for other vaccines in post-licensure evaluations such as thrombosis with thrombocytopenia syndrome and myocarditis. Ongoing paediatric trials powered to detect protection against mild disease will probably find lower efficacy against omicron (B.1.1.529) than previous SARS-CoV-2 variants of concern. Vaccines might prevent severe COVID-19 but detecting efficacy against this outcome would require tens of thousands more children than the two largest published paediatric trials. A trial evaluating BNT162b2 in 2268 children aged 5–11 years identified 16 cases of mild COVID-19 in placebo versus three in BNT162b2 recipients (91% efficacy after the second dose [95% CI 68–98]). Another recent trial evaluating mRNA-1273 in 4016 children identified 18 cases of mild COVID-19 in placebo versus seven in mRNA-1273 recipients (88% efficacy after the first dose [95% CI 70–96]). These trials were done before the emergence of omicron and had a short duration in follow-up. Investments in strong post-licensure vaccine effectiveness and safety monitoring systems are needed for ongoing monitoring of vaccine effect and rare adverse events following immunisation.

Because it does not need cold storage and due to the substantially lower cost than other COVID-19 vaccines, use of ChAdOx1 nCoV-19 could overcome logistical and financial barriers that might exist to supply safe and efficacious COVID-19 vaccine to paediatric populations across the globe. However, to achieve adequate global vaccination coverage, the world needs more WHO EUL vaccines for children. ChAdOx1 nCoV-19 has the additional advantage of one dose providing sufficient cellular responses that might provide protection against severe disease. Coupled with the advantage of immunity gains from a prolonged interval between doses, ChAdOx1 nCoV-19 could be administered in countries with supply restrictions to initiate vaccination of the eligible paediatric population while supplies are replenished.

A pressing question also remains of whether current vaccines will protect against emerging SARS-CoV-2 variants. To this end, more consideration should be given to the prevention of severe disease than to blocking infection and the interruption of transmission. Traditionally, for mucosal respiratory viruses vaccine efficacy against infection is imperfect, wanes with time, and declines with virus evolution. However, severe disease after breakthrough infection can be substantially reduced in the context of immunity because of memory B-cell and T-cell responses, which remain conserved across evolving variants. The strong cellular responses observed in the ChAdOx1 nCoV-19 trial offer hope for sustained protection against severe disease from a wide range of variants, as observed from real-world studies of COVID-19 vaccines in adults and children that have focused on critical illness, respiratory failure, and death.8, 14

What further evidence is needed that would encourage regulatory decisions on ChAdOx1 nCoV-19 and candidate vaccines for children, and what should be the number and size of future trials and outcomes? WHO recently provided guidance on immunobridging approaches for COVID-19 vaccine approval, whereby neutralising titres elicited by vaccines under consideration could be compared with titres elicited by a similar vaccine in a previously studied group in whom protection was observed against severe disease from currently circulating variants. This guidance is welcome news for diversifying the portfolio of available, safe, and effective vaccines. The excellent immune responses and tolerability profile of ChAdOx1 nCoV-19 in children bring much needed hope for increasing global access to COVID-19 vaccines for paediatric populations.