Post-acute sequelae after SARS-CoV-2 infection by viral variant and vaccination status: a multicenter cross-sectional study

Abstract Background Disentangling the effects of SARS-CoV-2 variants and vaccination on the occurrence of post-acute sequelae of SARS-CoV-2 (PASC) is crucial to estimate and reduce the burden of PASC. Methods We performed a cross-sectional analysis (May/June 2022) within a prospective multicenter healthcare worker (HCW) cohort in North-Eastern Switzerland. HCW were stratified by viral variant and vaccination status at time of their first positive SARS-CoV-2 nasopharyngeal swab. HCW without positive swab and with negative serology served as controls. The sum of eighteen self-reported PASC symptoms was modeled with univariable and multivariable negative-binomial regression to analyse the association of mean symptom number with viral variant and vaccination status. Results Among 2’912 participants (median age 44 years, 81.3% female), PASC symptoms were significantly more frequent after wild-type infection (estimated mean symptom number 1.12, p<0.001; median time since infection 18.3 months), after Alpha/Delta infection (0.67 symptoms, p<0.001; 6.5 months), and after Omicron BA.1 infections (0.52 symptoms, p=0.005; 3.1 months) compared to uninfected controls (0.39 symptoms). After Omicron BA.1 infection, the estimated mean symptom number was 0.36 for unvaccinated individuals, compared to 0.71 with 1-2 vaccinations (p=0.028) and 0.49 with ≥3 prior vaccinations (p=0.30). Adjusting for confounders, only wild-type (adjusted rate ratio [aRR] 2.81, 95% confidence interval [CI] 2.08-3.83) and Alpha/Delta infection (aRR 1.93, 95% CI 1.10-3.46) were significantly associated with the outcome. Conclusions Previous infection with pre-Omicron variants was the strongest risk factor for PASC symptoms among our HCW. Vaccination prior to Omicron BA.1 infection was not associated with a clear protective effect against PASC symptoms in this population.