Significance Shortages of COVID-19 vaccines hampered efforts to fight the current pandemic, leading experts to argue for delaying the second dose to provide earlier first-dose protection to twice as many people. We designed a model-based strategy for identifying the optimal second-dose delay using the hospitalization rate as the key metric. While epistemic uncertainties apply to our modeling, we found that the optimal delay was dependent on first-dose efficacy and vaccine mechanism of action. For infection-blocking vaccines, the second dose could be delayed ≥ 8 weeks if the first-dose efficacy was ≥ 50%. For symptom-alleviating vaccines, this delay duration is recommended if the first-dose efficacy was ≥ 70%. These results suggest that delaying the second vaccine dose is a feasible option.