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BACKGROUND: Rotavirus vaccine protects against severe rotavirus-related gastroenteritis. Its effectiveness is substantially lower in low- and middle-income countries (LMICs) compared to high-income settings, partly due to interference from maternally derived rotavirus-specific immunoglobulin G (IgG) resulting from high rotavirus burden. These antibodies wane over time, reducing their capacity to inhibit vaccine-induced immune responses, including immunoglobulin A (IgA). We aimed to estimate the optimal window for administering an additional rotavirus vaccine dose, beyond the routine doses given at 6 and 10 weeks of age, to maximise immunogenicity in an LMIC, high-disease-burdened setting.METHODS AND FINDINGS: We collected longitudinal serum samples from 84 infants at five time points between January 2021 and October 2023, and cross-sectional serum samples from 798 healthy individuals aged 0-86 years between December 2022 and June 2024. For participants under 18 years of age, a written consent was obtained from parents or guardians, with assent from the child where appropriate, individuals aged 18 years and above provided written informed consent directly. Rotavirus-specific IgG and IgA concentrations were measured using a gold standard enzyme-linked immunosorbent assay (ELISA). Rotavirus gastroenteritis case data were extracted from ongoing surveillance during the same period. All participants were recruited from the Southern Region of Malawi, a rotavirus high-burden setting. We applied linear mixed-effects and generalised linear models with natural splines to assess age-dependent trends in antibody levels. Prior to scheduled Rotarix rotavirus vaccine dose 1, the median maternally derived rotavirus-specific IgG levels were significantly lower in infants who were seropositive following vaccination compared with those who remained seronegative (5,745.0 IU/ml versus 9,689.8 IU/ml; Wilcoxon-test, p = 0.015). Infants with the lowest maternal IgG levels were over five times more likely to seroconvert (odds ratio [OR] = 5.8, 95% confidence interval (CI): 1.6-24.2; Chi-square test, p = 0.012). An exponential decay model estimated that the median IgG concentration in non-seroconverters crossed the seroconversion-probability threshold at 6.2 months. Population-level analyses revealed IgG concentrations reached their nadir at 8.4 months, coinciding with a peak in severe rotavirus gastroenteritis cases at 9 months. Serum IgA levels peaked at 9 months and were associated with a decline in disease incidence between 9 and 17 months. Key limitations include the small number of non-seroconverting infants (n = 27) who were unexposed during follow-up and the observational study design. These factors may influence interpretation, but the findings nonetheless provide important insights into rotavirus antibody dynamics.CONCLUSIONS: These findings suggest that administering a booster dose between 6 and 8 months of age, when maternal antibody titer is low and severe rotavirus gastroenteritis risk is high, may enhance the immunogenicity and effectiveness of the rotavirus vaccine in LMICs.