BackgroundLassa fever is an emerging zoonotic disease endemic to west Africa. Several vaccines aimed at preventing Lassa fever are currently under development, creating a need to assess how best to administer them once licensed for human use. We aimed to project the health-economic burden of Lassa fever from 2025 to 2037 across age and sex groups in subnational administrative divisions of west Africa with endemic Lassa mammarenavirus transmission and to estimate the cost-effectiveness of targeting Lassa vaccination to different risk groups.MethodsIn this vaccine-impact modelling study, we developed a mathematical model using a zoonosis risk map and epidemiological data from recent and ongoing cohort studies to predict the health-economic burden of Lassa fever across age and sex groups in endemic regions. We simulated vaccination campaigns targeting different risk groups to estimate the cost-effectiveness of various strategies for Lassa vaccine administration. Threshold vaccine costs (TVCs), which represent the break-even price per dose of vaccine administered, were estimated in international dollars (INT$ 2023), accounting for health-care costs, productivity losses, and monetised disability-adjusted life-years (DALYs) averted by vaccination.FindingsLassa fever was estimated to cause 6·23 (95% uncertainty interval (UI) 4·21-8·42) hospitalisations, 0·75 (0·48-1·10) deaths and 31·1 (17·7-52·2) DALYs per 100 000 person-years. Vaccine strategies targeting adolescents-adults aged 15-49, older adults aged 50 years and older, and women of childbearing age (WCBA) aged 15-49 years prevented, respectively, the most hospitalisations, deaths, and DALYs per 100 000 vaccine doses. Under base case assumptions, the most cost-effective strategy (greatest net monetary benefit) was untargeted vaccination for a vaccine costing INT$2 per dose, and targeting adolescents-adults at $5 per dose. At $10 per dose or more, none of the considered strategies were cost-effective. The highest TVC for a single-dose vaccine was estimated at $7·39 (95% UI 4·33-11·60) when targeting adolescents-adults, followed by $6·69 (4·17-9·85) when targeting older adults, $6·10 (3·56-9·74) when targeting WCBA, and $1·94 (1·10-3·10) when targeting children.InterpretationTargeting of adolescents-adults appears to generate the greatest health-economic value per vaccine dose. However, the most cost-effective vaccination strategy will depend on vaccine price.FundingCoalition for Epidemic Preparedness Innovations.