More than two years into the COVID-19 pandemic, there are still many questions that we sort of think we know the answers to, and many others we don’t. We do know vaccine effectiveness wanes, and that vaccines need to be updated to keep pace with an evolving virus. We don’t know if next-generation vaccines will be as effective against current variants as the original shots were against COVID Classic. We do know that the virus is substantially less deadly now that we’ve built up a big wall of immunity, but it still manages to infect most people, sometimes even multiple times a year. Is this a level of disruption we’re just going to have to tolerate indefinitely? Would anyone really be satisfied with the existing level of COVID risk continuing in perpetuity? And is our healthcare equipped to deal with the ongoing and compounding effects of long COVID? Dr. Peter Hotez, professor of pediatrics and molecular biology at Baylor College of Medicine and co-director of Texas Children’s Hospital Center for Vaccine Development, joins Brian to discuss the known knowns, known unknowns, and the unknown unknowns of COVID—and whether ongoing research can provide the answers we need.