This conversation was led by Jeffrey Townsend, Elihu Professor of Biostatistics and Professor of Ecology and Evolutionary Biology at Yale University, Alex Dornburg, Assistant Professor of Bioinformatics and Genomics at University of North Carolina, Charlotte, and Hayley Hassler, Research Associate in Biostatistics at Yale University. Among the most consequential unknowns of the devastating COVID-19 pandemic are the durability of immunity and time to likely reinfection. However, there is limited direct data on SARS-CoV-2 long-term immune responses and reinfection. We obtained from 128 days to 28 years of post-infection antibody optical density data for six human-infecting coronavirus relatives of SARS-CoV-2 to estimate times to reinfection by a comparative evolutionary analysis of related viruses. These data provided a means to estimate profiles of the typical antibody decline and probabilities of reinfection over time under endemic conditions. Reinfection by SARS-CoV-2 under endemic conditions would likely occur between 3 and 63 months, with a median of 16 months. This protection is less than half the duration revealed for the endemic coronaviruses circulating among humans. This time frame for reinfection is fundamental to numerous aspects of public health decision-making. As the pandemic continues, reinfection is likely to become increasingly common. Maintaining public health measures that curb transmission—including among individuals who were previously infected by SARS-CoV-2—coupled with persistent efforts to accelerate vaccination worldwide are critical to prevention of COVID-19 morbidity and mortality.