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experienced widespread SARS-CoV-2 infection before vaccine availability. We assessed the association between vaccination and severe COVID-19 in the Western Cape, South Africa, in an observational cohort study of &gt;2 million adults during 2020\u20132022. 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 hospitalization and death, adjusting for demographic characteristics, underlying health conditions, socioeconomic status proxies, and healthcare utilization. We found that by the end of 2022, 41% of surviving adults had completed vaccination and 8% had received a booster dose. Recent vaccination was associated with notable reductions in severe COVID-19 during periods dominated by Delta, and Omicron BA.1\/2 and BA.4\/5 (sub)lineages. During the latest 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\u201394 and 49\u201395, respectively). However, distinct reductions of effectiveness occurred at longer times post completing or boosting vaccination. Results highlight the importance of continued emphasis on COVID-19 vaccination and boosting for those at high risk of severe COVID-19, even in settings with widespread infection-induced immunity.<\/jats:p>","DOI":"10.3390\/vaccines12060628","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T05:59:42Z","timestamp":1717567182000},"page":"628","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["COVID-19 Vaccine Uptake and Effectiveness by Time since Vaccination in the Western Cape Province, South Africa: An Observational Cohort Study during 2020\u20132022"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1200-8726","authenticated-orcid":false,"given":"Reshma","family":"Kassanjee","sequence":"first","affiliation":[{"name":"Centre for Infectious Disease Epidemiology and Research, School of Public Health, Faculty of Health Sciences, University of 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