ABSTRACTBackgroundFew studies have assessed the benefits of COVID-19 vaccines in settings where most of the population had been exposed to SARS-CoV-2 infection.MethodsWe conducted a cost-effectiveness analysis of COVID-19 vaccine in Kenya from a societal perspective over a 1.5-year time frame. An age-structured transmission model assumed at least 80% of the population to have prior natural immunity when an immune escape variant was introduced. We examine the effect of slow (18 months) or rapid (6 months) vaccine roll-out with vaccine coverage of 30%, 50% or 70% of the adult (> 18 years) population prioritizing roll-out in over 50-year olds (80% uptake in all scenarios). Cost data were obtained from primary analyses. We assumed vaccine procurement at $7 per dose and vaccine delivery costs of $3.90-$6.11 per dose. The cost-effectiveness threshold was USD 919.FindingsSlow roll-out at 30% coverage largely targets over 50-year-olds and resulted in 54% fewer deaths (8,132(7,914 to 8,373)) than no vaccination and was cost-saving (ICER=US$-1,343 (-1,345 to - 1,341) per DALY averted). Increasing coverage to 50% and 70%, further reduced deaths by 12% (810 (757 to 872) and 5% (282 (251 to 317) but was not cost-effective, using Kenya’s cost-effectiveness threshold ($ 919.11). Rapid roll-out with 30% coverage averted 63% more deaths and was more cost-saving (ICER=$-1,607 (-1,609 to -1,604) per DALY averted) compared to slow roll-out at the same coverage level, but 50% and 70% coverage scenarios were not cost-effective.InterpretationWith prior exposure partially protecting much of the Kenyan population, vaccination of young adults may no longer be cost-effective.KEY QUESTIONSWhat is already known?The COVID-19 pandemic has led to a substantial number of cases and deaths in low-and middle-income countries.COVID-19 vaccines are considered the main strategy of curtailing the pandemic. However, many African nations are still at the early phase of vaccination.Evidence on the cost-effectiveness of COVID-19 vaccines are useful in estimating value for money and illustrate opportunity costs. However, there is a need to balance these economic outcomes against the potential impact of vaccination.What are the new findings?In Kenya, a targeted vaccination strategy that prioritizes those of an older age and is deployed at a rapid rollout speed achieves greater marginal health impacts and is better value for money.Given the existing high-level population protection to COVID-19 due to prior exposure, vaccination of younger adults is less cost-effective in Kenya.What do the new findings imply?Rapid deployment of vaccines during a pandemic averts more cases, hospitalisations, and deaths and is more cost-effective.Against a context of constrained fiscal space for health, it is likely more prudent for Kenya to target those at severe risk of disease and possibly other vulnerable populations rather than to the whole population.