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Background: Immune responses to vaccination vary widely between individuals. The aim of this study was to identify health-related variables potentially underlying the antibody responses to SARS-CoV-2 vaccination in older persons. We recruited participants in the long-running Doetinchem Cohort Study (DCS) who underwent vaccination as part of the national COVID-19 program, and measured antibody concentrations to SARS-CoV-2 Spike protein (S1) and Nucleoprotein (N) at baseline (T0), and a month after both the first vaccination (T1), and the second vaccination (T2). Associations between the antibody concentrations and demographic variables, including age, sex, socio-economic status (SES), comorbidities (cardiovascular diseases and immune mediated diseases), various health parameters (cardiometabolic markers, inflammation markers, kidney- and lung function) and a composite measure of frailty ('frailty index', ranging from 0 to 1) were tested using multivariate models. Results: We included 1457 persons aged 50 to 92 years old. Of these persons 1257 were infection naïve after their primary vaccination series. The majority (N = 954) of these individuals were vaccinated with two doses of BNT162b2 (Pfizer) and their data were used for further analysis. A higher frailty index was associated with lower anti-S1 antibody responses at T1 and T2 for both men (RT1 = -0.095, PT1 = 0.05; RT2 = -0.11, PT2 = 0.02) and women (RT1 = -0.24, PT1 < 0.01; RT2 = -0.15, PT2 < 0.01). After correcting for age and sex the frailty index was also associated with the relative increase in anti-S1 IgG concentrations between the two vaccinations (β = 1.6, P < 0.01). Within the construct of frailty, history of a cardiac catheterization, diabetes, gastrointestinal disease, a cognitive speed in the lowest decile of the population distribution, and impaired lung function were associated with lower antibody responses after both vaccinations. Conclusions: Components of frailty play a key role in the primary vaccination response to the BNT162b2 vaccine within an ageing population. Older persons with various comorbidities have a lowered immune response after their first vaccination, and while frail and sick older persons see a stronger increase after their second vaccination compared to healthy people, they still have a lower antibody response after their second vaccination. [ABSTRACT FROM AUTHOR]