Vaccines are a crucial tool for controlling infectious diseases, yet rarely offer perfect protection. "Vaccine efficacy" describes a population-level effect measured in clinical trials, but mathematical models used to evaluate the impact of vaccination campaigns require specifying how vaccines fail at the individual level, which is often impossible to measure. Does 90% efficacy imply perfect protection in 90% of people and no protection in 10% ("all-or-nothing"), or that the per-exposure risk is reduced by 90% in all vaccinated individuals ("leaky"), or somewhere in between? Here we systematically investigate the role of vaccine failure mode in controlling ongoing epidemics. We find that the difference in population-level impact between all-or-nothing and leaky vaccines can be substantial when R0 is higher, vaccines efficacy is intermediate, and vaccines slow but can't curtail an outbreak. Comparing COVID-19 pandemic phases, we show times when model predictions would have been most sensitive to assumptions about vaccine failure mode. When determining the optimal risk group to prioritize for limited vaccines, we find that modeling a leaky vaccine as all-or-nothing (or vice versa) can change the recommended target group. Overall, we conclude that models of vaccination campaigns should include uncertainty about vaccine failure mode in their design and interpretation.

The authors have declared no competing interest.

Funding for this work was supported by the Centers for Disease Control and Prevention (75D30121F00005 - ALH and 6NU38FT000012 - ALH, AAN) and the National Institutes of Health (DP5OD019851 - ALH, AAN, TA, DAL and R01AI146129 - MZL). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the funding agencies.

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confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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