To estimate the relative effectiveness of vaccination (0, 1, 2, ≥3 doses) and prior infection, in combination, on risk of SARS-CoV-2 infection/reinfection.

Prospective cohort study.

We recruited participants for the Aegis Study from nine clinics across five US states. Participants must have been 18 years or older, had a history of a positive PCR for SARS-CoV-2, SARS-CoV-2 antigen or antibody test for SARS-CoV-2 with documentation or had no suspected or documented prior SARS-CoV-2 infection, intended to remain in study area for the next 12 months, and had elevated risk of future SARS-CoV-2 exposure. Exclusion criteria included acute illness, contraindication to phlebotomy, use of immunosuppressants or receipt of systemic immunoglobulins.

We used extended Cox regression with robust standard errors to estimate the association between time-varying number of vaccine doses and baseline prior infection on risk of infection/reinfection among a prospective cohort of US adults between February 2021 and January 2023, accounting for censoring using inverse probability of censoring weights. Additionally, to quantify possible exposure misclassification of prior infection by comparing prior infection operationalised as (1) documented/self-reported prior infection and (2) documented/self-reported prior infection plus nucleocapsid antibody indication of prior infection.

Of n=2178 who completed enrolment, n=1887 adults (63% female; 65% non-Latino White) contributed 366 905 days of observation. Participants contributed an average of 7.2 months of follow-up between February 2021 and January 2023. 28% (n=533) of individuals were infected or reinfected during the study period. Similar relative effectiveness was observed between the two different operationalisations of prior infection. After correction for prior infection status in the nearly 16% of those without study documentation of prior infection who had nucleocapsid antibody levels comparable to documented cases, relative to the unvaccinated with no prior infection, estimated effectiveness generally increased with increasing vaccine doses and prior infection (without prior infection: one (17%, 95% CI –31% to 47%), two (49%, 95% CI 31% to 63%), ≥three (71%, 95% CI 58% to 80%) vaccine doses; with prior infection: none (56%, 95% CI 30% to 72%), one (71%, 95% CI 42% to 86%), two (65%, 95% CI 49% to 76%), ≥three (80%, 95% CI 68% to 88%) vaccine doses). Pairwise comparisons at each vaccine dose (ref: no prior infection) revealed that prior infection provided additional protection, with stronger relationships for no and one dose (none: 56% (95% CI 30% to 72%), one: 66% (95% CI 28% to 84%), two: 31% (95% CI 7% to 49%), ≥three 31% (95% CI 0% to 53%)). There was a marked decrease in the protection offered by vaccination, prior infection, or both in the Omicron period versus pre-Omicron period.

In our real-world observational sample, vaccination (with two and ≥three vaccine doses of any Food and Drug Administration Emergency Use Authorization approved vaccine) and prior infection conferred benefits for protection against infection/reinfection. Re-classification of prior infection status based on antibody levels had little effect on results.