Many individuals possess B cells capable of recognizing epitopes on the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this issue of the JCI, Paschold and Simnica et al. interrogated the frequency of SARS-CoV-2-specific B cell receptor rearrangements in healthy subjects based on age and cancer status. The authors found that while SARS-CoV-2-specific antibody signatures can be identified in the repertoires of young, healthy individuals, such sequences are less frequent in elderly subjects or patients with cancer. Overall, this study sheds light on B cell repertoire restrictions that might lead to an unfavorable clinical course of coronavirus disease 2019 infection in at-risk populations.