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Background: Although SARS-CoV-2 vaccination was a critical component to mitigate impact of the pandemic, it also brought specific challenges related to adverse drug reactions (ADRs) when large cohorts of healthcare workers were vaccinated.

Methods and findings: This study reports solicited ADRs and IgG anti-SARS-CoV-2 levels from 3805 healthcare workers in Sweden following primary immunization during 2021. Differences in systemic reactions at a level where study participants needed sick-leave or rescheduling of work shifts differed substantially between vaccine regimens, ranging from 12 % (Comirnaty) to 48 % (heterologous vaccination with Vaxzevria/Spikevax). Multivariable linear regression showed that the anti-S IgG response was dependent on vaccine label and that higher age and increased time from vaccination significantly correlated with lower antibody titers. Multivariable logistic regression models describing the risk for each ADR category in relation to vaccine label, age, sex, anti-S IgG levels post vaccination and time from vaccination showed vaccine label-dependent statistically significant differences in adjusted odds ratios for wide range of ADR categories, as high as OR 10 (95 % CI 7.6-13.5) for fever and chills when comparing Vaxzevria to Comirnaty. Among the mRNA vaccines, use of Spikevax (compared to Comirnaty) correlated with a statistically significant 1.3 to 3.5-fold increase in adjusted ORs for several ADR categories.

Conclusions: Based on a large cohort of health workers, our study confirms that adverse reactions after COVID-19 vaccination can lead to a substantial amount of missed work shifts, potentially causing organizational-level disturbances in staffing. There are significant differences in ADR frequencies related to vaccine type, age and sex, at overall levels not observed for other commonly used vaccines for adults.