With the surge of new SARS-CoV-2 variants, countries have begun offering COVID-19 vaccine booster doses to high-risk groups and, more recently, to the adult population in general. However, uncertainty remains over how long primary vaccination series remain effective, the ideal timing for booster doses, and the safety of heterologous booster regimens. We aimed to investigate COVID-19 primary vaccine series effectiveness and its waning, and the safety and effectiveness of booster doses, in a UK community setting.

We used SARS-CoV-2 positivity rates in individuals from a longitudinal, prospective, community-based study (ZOE COVID Study), in which data were self-reported through an app, to assess the effectiveness of three COVID-19 vaccines (ChAdOx1 nCov19 [Oxford-AstraZeneca], BNT162b2 [Pfizer-BioNtech], and mRNA1273 [Moderna]) against infection in the 8 months after completion of primary vaccination series. In individuals receiving boosters, we investigated vaccine effectiveness and reactogenicity, by assessing 16 self-reported systemic and localised side-effects. We used multivariate Poisson regression models adjusting for confounders to estimate vaccine effectiveness.

We included 620 793 participants who received two vaccine doses (204 731 [33·0%] received BNT162b2, 405 239 [65·3%] received ChAdOx1 nCoV-19, and 10 823 [1·7%] received mRNA-1273) and subsequently had a SARS-CoV-2 test result between May 23 (chosen to exclude the period of alpha [B.1.1.7] variant dominance) and Nov 23, 2021. 62 172 (10·0%) vaccinated individuals tested positive for SARS-CoV-2 and were compared with 40 345 unvaccinated controls (6726 [16·7%] of whom tested positive). Vaccine effectiveness waned after the second dose: at 5 months, BNT162b2 effectiveness was 82·1% (95% CI 81·3–82·9), ChAdOx1 nCoV-19 effectiveness was 75·7% (74·9–76·4), and mRNA-1273 effectiveness was 84·3% (81·2–86·9). Vaccine effectiveness decreased more among individuals aged 55 years or older and among those with comorbidities. 135 932 individuals aged 55 years or older received a booster (2123 [1·6%] of whom tested positive). Vaccine effectiveness for booster doses in 0–3 months after BNT162b2 primary vaccination was higher than 92·5%, and effectiveness for heterologous boosters after ChAdOx1 nCoV-19 was at least 88·8%. For the booster reactogenicity analysis, in 317 011 participants, the most common systemic symptom was fatigue (in 31 881 [10·1%] participants) and the most common local symptom was tenderness (in 187 767 [59·2%]). Systemic side-effects were more common for heterologous schedules (32 632 [17·9%] of 182 374) than for homologous schedules (17 707 [13·2%] of 134 637; odds ratio 1·5, 95% CI 1·5–1·6, p<0·0001).

After 5 months, vaccine effectiveness remained high among individuals younger than 55 years. Booster doses restore vaccine effectiveness. Adverse reactions after booster doses were similar to those after the second dose. Homologous booster schedules had fewer reported systemic side-effects than heterologous boosters.

Wellcome Trust, ZOE, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, Medical Research Council