Pre-infection COVID-19 vaccination and long-COVID mental fatigue severity: Findings from the Johns Hopkins COVID Long Study

Abstract Background: Long-COVID is a post-acute sequela of SARS-CoV-2 infection characterized by persistent, multi-system symptoms. Neurologic symptoms, such as mental fatigue, are often reported. While vaccination prior to infection is known to lessen symptom burden, its impact on mental fatigue remains unclear. Objective: Examine the association between vaccination and long-COVID-associated mental fatigue. Methods: We analyzed data from the Johns Hopkins COVID Long Study, a cohort study of 22,811 participants with and without infection. Among 2,634 participants with complete longitudinal follow-up, we examined the association between pre-infection vaccination and mental fatigue as measured by the Wood Mental Fatigue Inventory (WMFI; range 0-36, with lower scores indicating less fatigue). We considered three groups: long-COVID, recovered, and never infected, with the latter two groups as negative controls. We estimated the score differences between vaccinated and unvaccinated participants using covariate-adjusted quantile regression and mixed-effects linear models. Results: Among participants with long-COVID, receiving a booster dose was associated with lower WMFI scores across the distribution (1.5, 2.6, and 3.8 points lower at the 25th, 50th, and 75th percentiles; p [≤] 0.02) compared to those unvaccinated. Fully vaccinated participants also had lower scores, though these differences were not statistically significant. Findings were consistent in mixed-effect linear models where boosted (4.0 points lower) and fully vaccinated (1.9 points lower) participants with long-COVID had lower WMFI scores (p < 0.05). No associations were observed among recovered or never-infected participants. Conclusion: Pre-infection vaccination was associated with less long-COVID-associated mental fatigue, with the greatest benefit among boosted participants.