South Africa launched a mass COVID-19 vaccination campaign in May 2021, targeting 40 million adults. Understanding predictors of COVID-19 vaccine intentions was required to achieve this goal. We conducted a population-based survey in June–July 2021 using the WHO Behavioral and Social Drivers (BeSD) of COVID-19 Vaccination tool to determine predictors of vaccine hesitancy, defined as intention to refuse or uncertainty whether to accept COVID-19 vaccination. There were 1193 participants, mean age 39 (standard deviation 15) years, and 53% women, of whom 58% trusted information provided by healthcare workers and 32% were vaccine hesitant. Independent predictors of vaccine hesitancy included concerns about side effects (odds ratio (OR) 11.41; 95% confidence interval (CI) 3.5–50.80), lack of access to the online vaccine registration platform (OR 4.75; CI 2.15–10.37), distrust of government (OR 3.0; CI 1.33–6.77), belief in conspiracy theories (OR 3.01; CI 1.32–6.77), having no monthly income (OR 1.84; CI 1.12–3.07), and depending on someone else to make vaccination decision (OR 2.47; CI 1.06–5.77). We identified modifiable predictors of vaccine hesitancy at the start of South Africa’s COVID-19 vaccination rollout. These factors should be addressed by different stakeholders involved in the national immunization program through tailored communication and other effective strategies that increase vaccine literacy, reach low-income households, and engender confidence in government.

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Background South Africa has reported more than half of all COVID-19 cases and deaths in Africa. The South African government has launched a large COVID-19 immunization campaign with the goal of reaching more than 40 million individuals. Nonetheless, certain international, largely internet-based surveys have shown a significant proportion of vaccine hesitancy in South Africa. This study aims to determine and co-create with local stakeholders a comprehensive understanding of vaccine hesitancy and opportunities to support the promotion of other COVID-19 health-promoting behaviours at community level. Methods and design A mixed-methods, multiple case-study design; informed by the socio-ecological model of behaviour change. Four socio-economically diverse communities across South Africa will be selected and data collection will take place concurrently through three iterative phases. Phase 1 will provide insights into community experiences of COVID-19 (response) through desktop mapping exercises, observations, in-depth interviews, and focus group discussions (FGDs) designed as expression sessions with local stakeholders. Phase 2 will explore the extent and drivers of community acceptance of COVID-19 vaccines. This phase will comprise a quantitative survey based on WHO’s Behavioural and Social Drivers of Vaccination tool as well as further FGDs with community members. Phase 3 will involve cross-case study syntheses and presentation of findings to national role-players. Discussion This study will provide ground up, locally responsive, and timeous evidence on the factors influencing COVID-19 health-seeking behaviours to inform ongoing management and mitigation of COVID-19 in South Africa. It will also provide insights into the applicability of a novel vaccine hesitancy model in Africa.