Incidence, determinants and serological correlates of reactive symptoms following SARS-CoV-2 vaccination: a population-based longitudinal study (COVIDENCE UK)

Abstract Prospective population-based studies investigating associations between reactive symptoms following SARS-CoV-2 vaccination and serologic responses to vaccination are lacking. We therefore conducted such a study in 9003 adults from the United Kingdom (UK) general population receiving SARS-COV-2 vaccines as part of the national vaccination programme. Data relating to incidence and type of reactive symptoms after vaccination were captured using online questionnaires, along with information on 56 potential determinants of symptom risk. Titres of combined IgG/IgA/IgM responses to SARS-CoV-2 spike (S) glycoprotein were determined in eluates of dried blood spots collected from all participants before and after vaccination. 4262 (47.3%) participants experienced systemic reactive symptoms after a first vaccine dose. Factors associating with lower risk of such symptoms included older age (aOR per additional 10 years of age 0.85, 95% CI 0.81–0.90), male vs. female sex (aOR 0.59, 95% CI 0.53–0.65) and receipt of an mRNA vaccine vs. ChAdOx1 nCoV-19 (0.29, 0.26–0.32 for BNT162b2; 0.06, 0.01–0.26 for mRNA-1273). Higher risk of such symptoms was associated with a history of symptomatic SARS-CoV-2 infection prior to vaccination (2.23, 1.78–2.81) and presence vs. absence of self-rated anxiety or depression at cohort enrolment (1.24, 1.12–1.39). Post-vaccination anti-S titres were higher among participants who experienced reactive symptoms after vaccination vs. those who did not (P < 0.001). We conclude that factors influencing risk of systemic symptoms after SARS-CoV-2 vaccination include demographic characteristics, pre-vaccination SARS-CoV-2 serostatus and vaccine type. Participants experiencing reactive symptoms following SARS-CoV-2 vaccination had higher post-vaccination titres of IgG/A/M anti-S antibodies. Improved public understanding of the frequency of reactogenic symptoms and their positive association with vaccine immunogenicity could potentially increase vaccine uptake.