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Abstract BackgroundCOVID-19 booster vaccinations mitigate transmission and reduce the morbidity and mortality associated with infection. However, the optimal date for booster administration remains uncertain. Geographic variation in infection rates throughout the year makes it challenging to intuit the best yearly booster administration date to effectively prevent infection, and also challenging to provide best guidance on how to alter booster administration in response to a breakthrough infection. MethodsWe leveraged longitudinal antibody and reinfection probabilities with spatiotemporal projections of COVID-19 incidence to develop a geographically informed approach to optimizing the timing of booster vaccination. We assessed the delay in booster vaccination that is warranted following breakthrough infections whenever they occur during the year, enabling a personalized assessment of optimal timing that acknowledges and respects diversity of COVID-19 immune status, addressing a substantial barrier to uptake. ResultsYearly booster vaccination on any date is beneficial to prevention of infection. However, each location exhibits as much as a 3–4-fold range in degree of protection by date of uptake. Optimal COVID-19 booster vaccination dates are location-specific, typically in early autumn in the Northern Hemisphere. Infection late in the interval between boosts substantially alters the optimal boosting date. ConclusionsConsiderable benefit accrues from aptly timing COVID-19 booster vaccination campaigns, which can be tailored to specific locations. Individuals can acquire the greatest benefit from booster vaccination by timing it optimally, including delaying in cases of infection late in the interval between boosts. These results provide location-specific guidance for public health policy, healthcare provider recommendations, and individual decision-making.