Changes in self-reported Long COVID in different variant-dominant phases of the SARS-CoV-2 pandemic: the influence of vaccination on a diverse Israeli cohort study

Purpose of research Long COVID (LC) risk varies across SARS-CoV-2 variants, but causal inference is complicated by rising vaccine coverage coinciding with viral evolution. We examined whether pre-infection vaccination status modifies the association between SARS-CoV-2 variant and LC risk, to disentangle the contributions of viral evolution and vaccine-induced immunity. Principal results In this prospective cohort study of Israeli adults with SARS-CoV-2 infections from July 2021–March 2023, participants completed baseline and follow-up online surveys ≥60 days post-infection. LC was defined as ≥3 symptoms within validated symptom clusters. Infections were assigned to dominant circulating variants (Wild type, Alpha, Delta, Omicron). Pre-infection vaccination was categorized as unvaccinated (0–1 doses), partially vaccinated (2 doses), or fully vaccinated (≥3 doses). Generalized estimating equations estimated multivariable risk ratios, adjusted for age, sex, and follow-up time. Among 1715 participants reporting 2018 infections, LC was reported following 30·4% of infections. In models adjusted for vaccination, LC risk did not differ between Delta and Omicron variants (aRR 1·01, 95% CI 0·80-1·26). Among partially vaccinated individuals, Omicron infections carried lower LC risk than Delta (aRR 0·62, 95% CI 0·40–0·98). LC prevalence did not differ by variant among unvaccinated or fully vaccinated individuals. Major conclusions Variant-specific differences in LC risk may be largely explained by concurrent increases in vaccine coverage rather than intrinsic changes in variant pathogenicity. Full pre-infection vaccination confers consistent protection against LC regardless of variant. ​