Protective effect of a second booster dose against long COVID among individuals infected with SARS-CoV-2 in southeastern Brazil

BACKGROUND: Long COVID is a complex condition with diverse symptoms, lacking specific diagnostic or therapeutic tools. Although vaccination reduces the risk of severe COVID-19, its role in preventing long COVID, particularly through booster doses, remains limited. This study assessed the impact of first and second booster doses and identified long COVID risk factors. METHODS: We conducted a multicenter observational study with a cross-sectional analysis of participants previously infected with SARS-CoV-2 during the pre-Omicron and Omicron epidemiological periods. Both periods included mixed populations of healthcare workers (HCWs) and non-HCWs, with HCWs representing 86% of all participants. The study included five medical centers in São Paulo and Rio de Janeiro. Clinical data and long COVID symptoms were collected through a single standardized electronic questionnaire sent to all eligible participants. Predictors of long COVID were evaluated using multivariable logistic regression. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: A total of 2033 participants were included, and 67% (1370) reported long COVID symptoms. Independent risk factors included female sex (OR 2.25, 95% CI 1.81-2.79, p < 0.001), the presence of one, two, or three or more comorbidities (OR 1.74, 95% CI 1.36-2.23, p < 0.001; OR 2.14, 95% CI 1.43-3.20, p < 0.001; and OR 3.10, CI 1.55-6.19, p = 0.001, respectively); the occurrence of one or more reinfections (OR 2.35, 95% CI 1.84-3.01, p < 0.001; and OR 4.22, 95% CI 2.043-7.91, p < 0.001, respectively), and a severe acute illness (OR: 1.91; 95%CI 1.09-3.35; p = 0.02). Vaccination was protective, with the strongest effect observed among those receiving two booster doses (OR: 0.18; 95% CI 0.07-0.46; p < 0.001). In the Omicron period sub-analysis, only the second booster dose was associated with reduced risk compared with a complete primary series (OR 0.50, CI 0.34-0.74, p < 0.001), whereas one booster dose showed no significant effect. CONCLUSION: COVID-19 vaccination, especially two booster doses, reduced long COVID risk. Female sex, comorbidities, reinfections, and severe acute illness were independent risk factors for developing long-lasting symptoms.