Design of human challenge studies balances scientific validity, efficiency, and study safety. This Perspective explores some advantages and disadvantages of “low-dosage” challenge studies, in the setting of testing second-generation vaccines against COVID-19. Compared to a conventional vaccine challenge, a low-dosage vaccine challenge would be likelier to start, and start earlier. A low-dosage challenge would also be less likely to rule out a vaccine candidate which would have been potentially effective in target usage. A key ethical advantage of a low-dosage challenge over conventional challenge is that both it and its dose escalation process are safer for each participant. Low-dosage studies usually require larger numbers of participants than conventional challenges, but this and other potential disadvantages are less serious than they may initially appear. Overall, low-dosage challenges should be considered for certain roles, such as prioritizing between second-generation vaccines against COVID-19.