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IntroductionVaccine uptake is influenced by a variety of factors. Behavioral Insights (BI) can be used to address vaccine hesitancy to understand the factors that influence the decision to take or refuse a vaccine.MethodologyThis two-part study consisted of a survey designed to identify the influence of various drivers of people’s COVID-19 vaccination status and their intention to take the vaccine in Ghana, as well as an experiment to test which of several behaviorally informed message frames had the greatest effect on vaccine acceptance. Data was collected from a total of 1494 participants; 1089 respondents (73%) reported already being vaccinated and 405 respondents (27%) reported not being vaccinated yet. The mobile phone-based surveys were conducted between December 2021 and January 2022 using Random Digit Dialing (RDD) to recruit study participants. Data analysis included regression models, relative weights analyses, and ANOVAs.ResultsThe findings indicated that vaccine uptake in Ghana is influenced more by social factors (what others think) than by practical factors such as ease of vaccination. Respondents’ perceptions of their family’s and religious leaders’ attitudes towards the vaccine were among the most influential drivers. Unexpectedly, healthcare providers’ positive attitudes about the COVID-19 vaccine had a significant negative relationship with respondents’ vaccination behavior. Vaccine intention was positively predicted by risk perception, ease of vaccination, and the degree to which respondents considered the vaccine effective. Perceptions of religious leaders’ attitudes also significantly and positively predicted respondents’ intention to get vaccinated. Although perceptions of religious leaders’ views about the vaccine are an important driver of vaccine acceptance, results asking respondents to rank-order who influences them suggest that people may not be consciously aware—or do not want to admit—the degree to which they are affected by what religious leaders think. Message frames that included fear, altruism, social norms were all followed by positive responses toward the vaccine, as were messages with three distinct messengers: Ghana Health Services, a doctor, and religious leaders.ConclusionsWhat drives COVID-19 vaccine intentions does not necessarily drive behaviors. The results of this study can be used to develop appropriate COVID-19 vaccine uptake strategies targeting the most important drivers of COVID-19 vaccine acceptance, using effective message frames.