Protection against symptomatic disease with the delta and omicron BA.1/BA.2 variants of SARS-CoV-2 after infection and vaccination in adolescents: national observational test-negative case control study, August 2021 to March 2022, England

BackgroundLittle is known about the protection following prior infection with different SARS-CoV-2 variants, COVID-19 vaccination, and a combination of the two (hybrid immunity) in adolescents. MethodsWe used national SARS-CoV-2 testing and COVID-19 mRNA vaccination data in England to estimate protection following previous infection and vaccination against symptomatic PCR-confirmed delta and omicron BA.1/BA.2 variants in 11-17-year-olds using a test-negative case-control design. FindingsBy 31 March 2022, 63.6% of 16-17-year-olds and 48.2% of 12-15-year-olds had received [≥]1 COVID-19 mRNA vaccine dose.Between 08 August 2021 and 31 March 2022, 1,161,704 SARS-CoV-2 PCR-tests were successfully linked to COVID-19 vaccination status. In unvaccinated adolescents, prior infection with wildtype, alpha or delta provided greater protection against subsequent delta infection than subsequent omicron; prior omicron infection provided had the highest protection against omicron reinfection (59.3%; 95%CI: 46.7-69.0). In infection-naive adolescents, vaccination provided lower protection against symptomatic omicron infection than delta, peaking at 64.5% (95%CI; 63.6-65.4) 2-14 days after dose two and 62.9% (95%CI; 60.5-65.1) 2-14 weeks after dose three, with rapidly waning protection after each dose. Previously infected and vaccinated adolescents had the highest protection, irrespective of primary infecting SARS-CoV-2 strain. The highest protection against omicron was observed in vaccinated adolescents with prior omicron infection, reaching 96.4% (95%CI, 84.4-99.1) at 15-24 weeks post dose two. InterpretationAll variants provide some protection against symptomatic reinfection and vaccination adds to protection. Vaccination provides low-to-moderate protection against symptomatic omicron infection, with waning protection after each dose, while hybrid immunity provides the most robust protection. FundingNone Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe have previously reported COVID-19 vaccine effectiveness in previously uninfected adolescents. There are, however, limited data on the protection offered by natural infection with different SARS-CoV-2 variants, and the added value of vaccination in previously-infected adolescents. Most studies have focused on adults and show significant protection from previous infection against re-infection with pre-omicron variants, but lower protection against omicron variants, with hybrid immunity providing the most robust protection. Added value of this studyUsing national SARS-CoV-2 testing and COVID-19 mRNA vaccination data in England, we were able to estimate protection afforded by previous infection, vaccination, and a combination of the two using a test-negative case-control design against PCR-confirmed symptomatic COVID-19. We found that protection against symptomatic infection with the delta variant was greater than protection against symptomatic omicron infection in those previously infected with wild-type, alpha or delta variants. Similar trends were observed in previously uninfected but vaccinated individuals. Prior omicron infection along with vaccination provided the greatest protection against further omicron variant infections. Implications of all the available evidenceAll variants provide some protection against future SARS-CoV-2 infection, as does COVID-19 mRNA vaccination. Our findings demonstrate, for the first time in adolescents, the additional protection afforded by hybrid immunity. In the context of the UKs recent waves of omicron infections, our findings provide important evidence of only modest short-term protection against mild disease with omicron variants following vaccination. This has important implications for the consideration of future adolescent COVID-19 vaccination and booster programmes.