Objectives: Amid a pandemic, vaccines represent a promising solution for mitigating public health and economic crises, and an improved understanding of individuals’ vaccination intentions is crucial to design optimal immunization campaigns. This study predicts uptake rates for different COVID-19 vaccine specifications and identifies personal characteristics that moderate an individual’s responsiveness to vaccine attributes. Methods: We developed an online survey with contingent specifications of a COVID-19 vaccine, varying in effectiveness, risks of side effects, duration of immunity, and out-of-pocket cost. Using population-averaged logit models, we estimated vaccine uptake rates that account for uncertainty, heterogeneity across respondents, and interactions between vaccine and personal characteristics. Results: We obtained 3047 completed surveys. The highest uptake rate for an annual vaccine, 62%, is predicted when vaccine effectiveness is 80% to 90%, side effects are minimal, and the vaccine is provided at zero cost, with decreases seen in the uptake rate for less effective vaccines, for example, 50% for 50% to 60% effectiveness. Moreover, we found that Americans’ response to vaccine effectiveness depends on their self-reported concern, that is, concerned respondents report a higher willingness to get vaccinated. Our findings also indicate that COVID-19 vaccine uptake rates decrease with vaccine cost and that responsiveness to vaccine cost is moderated by income. Conclusions: Although providing the COVID-19 vaccine at zero cost will motivate many individuals to get vaccinated, a policy focused exclusively on vaccine cost may not be enough to reach herd immunity thresholds. Although those concerned with COVID-19 will participate, further evidence is needed on how to incentivize participation among the unconcerned (43%) to prevent further pandemic spread.