During a pandemic, there are many situations in which the first available vaccines may not have as high of an effectiveness as vaccines that are still under development or are not yet ready for distribution, raising the question of whether it is better to go with what is available now or wait. Methods: In 2020, the team developed a computational model that represents the U.S. population, coronavirus disease 2019 (COVID-19) spread, and vaccines with different possible efficacies (to prevent infection or reduce severe disease) and vaccination timings to estimate the clinical and economic value of vaccination. Results: Except for a limited number of situations, mainly early on in a pandemic and for a vaccine that prevents infection, when an initial vaccine is available, waiting for a vaccine with a higher efficacy results in additional hospitalizations and costs over the course of the pandemic. For example, if a vaccine with a 50% efficacy in preventing infection becomes available when 10% of the population has already been infected, waiting until 40% are infected for a vaccine with 80% efficacy in preventing infection results in 15.6 million additional cases and 1.5 million additional hospitalizations, costing $20.6 billion more in direct medical costs and $12.4 billion more in productivity losses. Conclusions: This study shows that there are relatively few situations in which it is worth foregoing the first COVID-19 vaccine available in favor of a vaccine that becomes available later on in the pandemic, even if the latter vaccine has a substantially higher efficacy.