Repeated COVID-19 vaccine boosters elicit variant-specific memory B cells in humans

The first exposure to a pathogen impacts subsequent immune responses toward related pathogens. This immune imprinting explains that infection or vaccination with circulating SARS-CoV-2 variants primarily recalls cross-reactive memory B cells induced by prior Wuhan-Hu-1 (Wu) spike (S) exposure. The magnitude and persistence of immune imprinting in mRNA vaccinees are not understood. We investigate serum antibody and memory B cell responses after administration of multiple XBB.1.5 and JN.1/KP.2 COVID-19 vaccine boosters. We find that the JN.1/KP.2 booster elicits broadly neutralizing antibody responses against recent SARS-CoV-2 variants by recalling Wu S-induced immunity in all but one individual. We detect an increased fraction of serum antibodies, and particularly memory B cells, recognizing XBB.1.5 and KP.2, but not Wu, relative to individuals who received a single XBB.1.5 booster. Repeated exposures to antigenically divergent S thus contribute to overcoming immune imprinting and support vaccine updates for continued protection.