COVID-19 vaccine uptake, confidence and hesitancy in rural KwaZulu-Natal, South Africa between April 2021 and April 2022: A continuous cross-sectional surveillance study

High COVID-19 vaccine hesitancy in South Africa limits protection against future epidemic waves. We evaluated how vaccine hesitancy and its correlates evolved April 2021-April 2022 in a well-characterized rural KwaZulu-Natal setting. All residents aged >15 in the Africa Health Research Institute’s surveillance area were invited to complete a home-based, in-person interview. We described vaccine uptake and hesitancy trends, then evaluated associations with pre-existing personal factors, dynamic environmental context, and cues to action using ordinal logistic regression. Among 10,011 respondents, vaccine uptake rose as age-cohorts became vaccine-eligible before levelling off three months post-eligibility; younger age-groups had slower uptake and plateaued faster. Lifetime receipt of any COVID-19 vaccine rose from 3.0% in April-July 2021 to 32.9% in January-April 2022. Among 7,445 unvaccinated respondents, 47.7% said they would definitely take a free vaccine today in the first quarter of the study time period, falling to 32.0% in the last. By March/April 2022 only 48.0% of respondents were vaccinated or said they would definitely would take a vaccine. Predictors of lower vaccine hesitancy included being male (adjusted odds ratio [aOR]: 0.70, 95% confidence interval [CI]: 0.65–0.76), living with vaccinated household members (aOR:0.65, 95%CI: 0.59–0.71) and knowing someone who had had COVID-19 (aOR: 0.69, 95%CI: 0.59–0.80). Mistrust in government predicted greater hesitancy (aOR: 1.47, 95%CI: 1.42–1.53). Despite several COVID-19 waves, vaccine hesitancy was common in rural South Africa, rising over time and closely tied to mistrust in government. However, interpersonal experiences countered hesitancy and may be entry-points for interventions.