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Background: There are few data on the real-world effectiveness of COVID-19 vaccines and boosting in Africa, which experienced high levels of SARS-CoV-2 infection in a mostly vaccine-naïve population, and has limited vaccine coverage and competing health service priorities. We assessed the association between vaccination and severe COVID-19 in the Western Cape, South Africa., Methods: We performed an observational cohort study of >2 million adults during 2020-2022. We described SARS-CoV-2 testing, COVID-19 outcomes, and vaccine uptake over time. We used multivariable cox models to estimate the association of BNT162b2 and Ad26.COV2.S vaccination with COVID-19-related hospitalisation and death, adjusting for demographic characteristics, underlying health conditions, socioeconomic status proxies and healthcare utilisation., Results: By end 2022, only 41% of surviving adults had completed vaccination and 8% a booster dose, despite several waves of severe COVID-19. Recent vaccination was associated with notable reductions in severe COVID-19 during distinct analysis periods dominated by Delta, Omicron BA.1/2 and BA.4/5 (sub)lineages: within 6 months of completing vaccination or boosting, vaccine effectiveness was 46-92% for death (range across periods), 45-92% for admission with severe disease or death, and 25-90% for any admission or death. During the Omicron BA.4/5 wave, within 3 months of vaccination or boosting, BNT162b2 and Ad26.COV2.S were each 84% effective against death (95% CIs: 57-94 and 49-95, respectively). However, there were distinct reductions of VE at larger times post completing or boosting vaccination., Conclusions: Continued emphasis on regular COVID-19 vaccination including boosting is important for those at high risk of severe COVID-19 even in settings with widespread infection-induced immunity., Competing Interests: Conflicts of interest MD reports grants from Viiv Healthcare, outside the submitted work. CC reports grants from Sanofi Pasteur, US Centers for Disease Control and Prevention (CDC), Wellcome Trust, South African Medical Research Council (SAMRC) and the Bill & Melinda Gates Foundation. NW reports grants from the Bill and Melinda Gates Foundation and Sanofi. SW reports grants from US CDC and Bill and Melinda Gates Foundation. AvG reports grants from the World Health Organisation Regional Office for Africa (WHO-AFRO), US CDC, SAMRC, Fleming Fund, Africa Centres for Disease Control / African Society for Laboratory Medicine. AB reports grants from the US National Institutes for Health, Bill and Melinda Gates Foundation and the Wellcome Trust.