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.

Concerns regarding the safety of COVID-19 vaccination have caused hesitancy and lowered uptake globally. While vaccine hesitancy is documented globally, some continents, countries, ethnic groups and age groups are disproportionately affected, resulting in significant global inequities. To date, Africa has the lowest COVID-19 coverage globally, with only 22% of its population completely vaccinated. It might be argued that the difficulty with COVID-19 vaccine acceptance in Africa was triggered by the anxiety created by misinformation on social media platforms, particularly with the misinformation regarding depopulating Africa, given the significance of maternity in the continent. In this work, we examine numerous determinants of poor vaccination coverage that have received little attention in primary research and that may need to be considered by various stakeholders engaged in the COVID-19 vaccine strategy at the national and continental levels. Our study also emphasizes the importance of a multidisciplinary team when introducing a new vaccine, for people to trust that the vaccine is truly helpful to them and to be convinced that immunization is, all things considered, worthwhile.