Effect of a Third COVID-19 Vaccine Dose on the Incidence of Long COVID Among Adults Who Completed a Primary Vaccine Series: a Target Trial Emulation in a Community-Based Cohort

Background: Evidence on whether a third COVID-19 vaccine dose lowers long COVID risk is mixed. We estimated the effect of receiving >=1 third dose versus completing only a primary series on 6 and 12 month long COVID incidence using a target trial emulation in a U.S. community cohort. Methods: We analyzed the CHASING COVID Cohort, a prospective, community based study of U.S. adults. Eligible participants were >=18 years, had completed a two dose primary series, had no prior long COVID, and had no SARS-CoV-2 infection in the 3 months before time zero. Strategies compared were: receive a third dose at time zero vs. not receive a third dose during follow up. Long COVID was defined as >=1 new symptom at or beyond 3 months post infection with concurrent activity limitation, both absent in the prior year. Follow up was 6 and 12 months. We used a per protocol analog: participants were artificially censored upon deviating from their assigned strategy or lost to follow up, with inverse probability weights to address selection due to censoring and time varying confounding. We fit weighted pooled logistic models to estimate weighted incidence, differences, and ratios at each horizon. Results: Across 16 sequential trials (18,930 person trials; 4,044 unique individuals), 3,321 person trials received a third dose at time zero and 15,609 did not. At 6 months, weighted long COVID incidence was 0.9% (95% CI, 0.5%, 1.3%) with a third dose vs. 1.0% (0.8%, 1.1%) without (risk difference (RD), -0.1%; 95% CI, -0.5%, 0.4%; risk ratio (RR), 0.93; 95% CI, 0.54, 1.44). At 12 months, incidence was 4.9% (4.1%, 5.9%) with a third dose vs. 4.5% (4.1%, 4.8%) without (RD, 0.4%; 95% CI, -0.5%, 1.4%; RR, 1.09; 95% CI, 0.90, 1.33). Conclusion: In this community based target trial emulation, receiving a third COVID-19 vaccine dose did not meaningfully reduce 6 or 12 month long COVID incidence compared with completing only a primary series.