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

The first exposure to a pathogen or an antigen profoundly impacts immune responses upon subsequent encounter with related pathogens. This immune imprinting explains that infection or vaccination with currently circulating SARS-CoV-2 variants primarily recalls cross-reactive memory B cells and antibodies induced by prior Wu spike (S) glycoprotein exposure rather than priming de novo responses. The magnitude and persistence of immune imprinting in mRNA vaccinated populations and the prospect to overcome it are not understood. To understand the impact of immune imprinting, we investigated memory B cell and plasma antibody responses after administration of multiple doses of XBB.1.5 and JN.1/KP.2 updated COVID-19 vaccine boosters. We found that administration of the JN.1/KP.2 booster elicited broadly neutralizing antibody responses against recently circulating SARS-CoV-2 variants that were accounted for by recall of Wu S-induced immunity. We detected an increased fraction of serum antibodies and particularly memory B cells recognizing XBB.1.5 S and KP.2 S, but not Wu S, relative to individuals who received a single XBB.1.5 booster a year prior. These findings suggest that repeated exposures to antigenically divergent S trimers contribute to progressively overcoming immune imprinting and support vaccine updates and innovation to provide continued protection against COVID-19.