COVID-19 vaccines played a critical role in reducing global health burden during the COVID-19 pandemic, but their rapid development required extraordinary effort. This study aims to evaluate their global return-on-investment (ROI) during the first year of the vaccination programme (8 December 2020–8 December 2021) to provide insights into the economic benefits relative to the costs of vaccine development, manufacturing, and delivery. Public health outcomes of COVID-19 vaccination, including life years and QALYs gained from averted death, infections, and hospitalisations, were estimated. Health benefits were converted to economic benefits using welfarist and extra-welfarist approaches. These benefits were compared to the costs of vaccine development, manufacturing, and delivery to estimate the ROI under both approaches. Probabilistic sensitivity analyses were conducted to assess the impact of parameter uncertainty on ROI estimates. Vaccine development and delivery cost $79.4 billion, but the health and economic benefits of vaccination were valued between $4.83 trillion–$37.8 trillion. High-income countries saw the greatest health benefits per-person vaccinated, and low-income countries gained the greatest non-health benefits per-person vaccinated, when expressed as a proportion of GDP per capita. This estimated ROIs of $59.8–$475 per dollar invested. ROIs ranged between $62.2–$442 across all sensitivity analyses for both approaches. Rapid COVID–19 vaccine development and delivery were an excellent investment. Vaccine development and equitable vaccine distribution globally should be prioritised before and during global health crises.

OJW has received personal consultancy fees from WHO and the Clinton Health Access Initiative for unrelated work on malaria. MJ has received research grants (to his institution) from WHO and Gavi, which are both members of COVAX. HB and GB declare no competing interests. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf.

This study is funded by the National Institute for Health and Care Research (NIHR) Health Protection Research Unit in Modelling and Health Economics, a partnership between the UK Health Security Agency, Imperial College London and LSHTM (grant code NIHR200908). The views expressed are those of the author(s) and not necessarily those of the NIHR, UK Health Security Agency or the Department of Health and Social Care. OJW was supported by an Imperial College and Eric and Wendy Schmidt AI in Science Fellowship, a program of Schmidt Sciences, Centre funding from the UK Medical Research Council (reference MR/X020258/1), and funding from Community Jameel. GB was funded by the Medical Research Council (MR/W006677/1).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors.