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Objectives: This study aims to identify the factors influencing vaccine hesitancy, willingness and its variation over time in order to inform more responsive strategies for increasing vaccination uptake. The specific objectives are: (1) to describe and compare levels of COVID-19 vaccine hesitancy among the general population in rural and urban settings in West Africa over time and (2) to identify factors associated with COVID-19 vaccination willingness and hesitancy among the general population across five West African countries over time., Design: Following a baseline survey (Wave I), three serial cross-sectional surveys (Waves II-IV) were implemented., Setting: The study was conducted in Burkina Faso, Guinea, Mali, Senegal and Sierra Leone from November 2021 to July 2022., Participants: A total of 13 571 study participants were included in the study (n=4373, n=4593 and n=4605 for survey Waves II, III and IV, respectively). Inclusion criteria were being 18 years or older, living in the study area and willing to provide informed consent. A two-stage sampling strategy was used to select the sample from among the general population., Primary and Secondary Outcomes: Primary outcomes were the variability of vaccine hesitancy over time and across the five West African countries. Secondary outcomes were factors associated with vaccine willingness., Results: A small but steady increase in hesitancy to COVID-19-vaccination can be observed across countries, with an upward trend of vaccine hesitancy reported by 952 participants (33.9 %) in Wave II, 1055 (37.3%) in Wave III and 1089 (38.1%) in Wave IV. Among the countries included, Senegal shows the highest level of vaccine hesitancy ('Definitely no' and 'Probably no' ranging from 50.2% to 56.0% and 26.2 to 28.3%, respectively). At the same time, Senegal has the lowest vaccination coverage overall. Across all five countries and survey waves, the primary factor associated with vaccination willingness is fear of experiencing severe COVID-19 disease (Wave II: OR 0.42, 95% CI 0.34 to 0.51, Wave III: OR 0.48, 95% CI 0.40 to 0.59 and Wave IV: OR 0.54, 95% CI 0.44 to 0.66). Perceived improved financial status seems to influence willingness to get vaccinated negatively (OR 0.57, 95% CI 0.40 to 0.81) and unlike in Western, Educated, Industrialised, Rich and Democratic countries, men seem more reluctant to get vaccinated than women (OR 0.77, 95%, CI 0.65 to 0.93)., Conclusions: Our findings suggest that vaccine hesitancy should be monitored over time to inform communication strategies, which are responsive to changes in vaccination-related public sentiments. Additionally, a focus on social solidarity and the importance of women in vaccination advocacy can help improve COVID-19 vaccination coverage in West Africa., Trial Registration Number: The general protocol is registered on clinicaltrial.gov (protocol number: NCT04912284)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)