BNT162b2 vaccine protection against omicron and effect of previous infection variant and vaccination sequence among children and adolescents in Singapore: a population-based cohort study

BACKGROUND: Information on variant-specific vaccine protection and the effect of previous infection variant is scarce in children. We aimed to ascertain the level of protection conferred by BNT162b2 COVID-19 vaccination against omicron variant infection (BA.4 or BA.5, and XBB) in a previously infected national paediatric cohort. We also explored the association between sequence of previous infection (variant) and vaccination on protection. METHODS: We did a retrospective, population-based cohort study using the national databases of all confirmed SARS-CoV-2 infections, vaccines administered, and demographic records maintained by the Ministry of Health, Singapore. The study cohort consisted of children aged 5–11 years and adolescents aged 12–17 years who had a previous SARS-CoV-2 infection from Jan 1, 2020, to Dec 15, 2022. People who were infected during the pre-delta period or were immunocompromised (received three vaccination doses [children 5–11 years old] and four vaccinations doses [adolescents 12–17 years old]) were excluded. Those who had multiple episodes of infection before the study start date, were not vaccinated before infection but completed three doses, received bivalent mRNA vaccine, or received non-mRNA vaccine doses were also excluded. All SARS-CoV-2 infections confirmed by reverse transcriptase polymerase chain reaction or rapid antigen testing were grouped into delta, BA.1, BA.2, BA.4 or BA.5, or XBB variants using a combination of whole-genome sequencing, S-gene target failure results, and imputation. For BA.4 or BA.5, the study outcome period was June 1–Sept 30, 2022, and for XBB variants the outcome period was Oct 18–Dec 15, 2022. Incidence rate ratios between vaccinated and unvaccinated were derived using adjusted Poisson regressions and vaccine effectiveness was estimated as (1–risk ratio) × 100%. FINDINGS: 135 197 people aged 5–17 years (79 332 children and 55 865 adolescents) were included in the cohort for the vaccine effectiveness analysis against omicron BA.4 or BA.5, and 164 704 people aged 5–17 years (97 235 children and 67 469 adolescents) were included for the analysis against omicron XBB. Approximately 47% of participants were female and 53% were male. Among those previously infected, vaccine effectiveness against BA.4 or BA.5 infection in fully vaccinated children (two doses) was 74·0% (95% CI 67·7–79·1) and in adolescents (three doses) was 85·7% (80·2–89·6). Against XBB, protection conferred with full vaccination was lower at 62·8% (95% CI 42·3–76·0) in children and 47·9% (20·2–66·1) in adolescents. In children, receipt of two-dose vaccination before first SARS-CoV-2 infection provided them with the highest protection against subsequent BA.4 or BA.5 infection at 85·3% (95% CI 80·2–89·1); however, this was not shown to be the case for adolescents. First infection variant had an effect on vaccine effectiveness against omicron BA.4 or BA.5 reinfection in the following descending order: BA.2 conferred the highest protection (92·3% [95% CI 88·9–94·7] in children and 96·4% [93·5–98·0] in adolescents) followed by BA.1 (81·9% [75·9–86·4] in children and 95·0% [91·6–97·0] in adolescents), and delta which conferred the lowest protection (51·9% [5·3–75·6] in children and 77·5% [63·9–86·0] in adolescents). INTERPRETATION: In previously infected children and adolescents, BNT162b2 vaccination provided additional protection against omicron BA.4 or BA.5 and XBB variants compared with those who remained unvaccinated. Hybrid immunity against XBB was lower than against BA.4 or BA.5, especially in adolescents. Early vaccination of previously uninfected children before their first SARS-CoV-2 exposure could potentially strengthen population immunity resilience against future variants. FUNDING: None.