In order to stay circulating in the human population over many years, viruses need to adapt to the environment, mainly to the host’s immune response, allowing for reinfection despite preexisting immunity. These different viral strategies are clearly important for guiding vaccine design. SARS-CoV-2 is no exception, using three main strategies to avoid protective and long-lived antibody responses: one very common and two rather unique tactics, consisting of 1) random mutation to partially escape existing antibody responses, 2) increasing affinity of the receptor-binding domain (RBD) of the spike protein to it’s receptor Angiotensin-converting enzyme 2 (ACE 2), and 3) diluting out neutralizing epitopes on the viral surface to avoid strong and enduring antibody responses. As the correlate of protection from SARS-CoV-2 is neutralizing antibody response, this review focuses on B cells, the major player in protecting against COVID-19.

© 2025 The Author(s). Published by Elsevier Ltd.