Abstract Background The ongoing COVID-19 pandemic has placed an unprecedented health and economic burden on countries at all levels of socioeconomic development, emphasizing the need to evaluate the most effective vaccination strategy in multiple, diverse environments. The high reported efficacy, low cost, and long shelf-life of the ChAdOx1 nCoV-19 vaccine positions it well for evaluation in different settings. Methods Using data from the ongoing ChAdOx1 nCoV-19 clinical trials, an individual-based model was constructed to predict the 6-month population-level impact of vaccine deployment. A detailed probabilistic sensitivity analysis (PSA) was developed to evaluate the importance of epidemiological, demographic, immunological, and logistical factors in determining vaccine effectiveness. Using representative countries, logistical plans for vaccination rollout at various levels of vaccine availability and delivery speed, conditional on vaccine efficacy profiles (efficacy of the booster dose, time interval between doses, and relative efficacy of the first dose) were explored.Findings and Interpretation Our results highlight how expedient vaccine delivery to high-risk groups is critical in mitigating COVID-19 disease and mortality. In scenarios where the number of vaccine doses available is insufficient for high-risk groups (those aged more than 65 years) to receive two vaccine doses, administration of a single dose of vaccine is optimal. This effect is consistent even when vaccine efficacy after one dose is just 75% of the levels achieved after two doses. These findings offer a nuanced perspective of the critical drivers of COVID-19 vaccination effectiveness and can inform optimal allocation strategies. These are relevant to high-income countries with a large high-risk group population as well as to low-income countries with younger populations, where the cost and logistical challenges of procuring and delivering two doses for each citizen represent a significant challenge.