Immune imprinting and vaccine interval determine antibody responses to monovalent XBB.1.5 COVID-19 vaccination

As COVID-19 becomes endemic and vaccines are annually adapted, exposure intervals and immune imprinting become critical considerations for vaccination strategy. Imprinting by the ancestral spike protein affected bivalent Wuhan-Hu-1/BA.4-5 vaccine responses. We assess the persistence of imprinting in antibody responses to the more recent XBB.1.5 monovalent formulation. We quantified live virus-neutralizing antibodies by focus reduction neutralization test and ancestral spike receptor-binding isotype titers by immunosorbent assay in individuals before and after XBB.1.5 vaccination. We compared responses between those who previously received three to four doses of Wuhan-Hu-1 vaccine and one dose of bivalent Wuhan-Hu-1/BA.4-5 (bivalent recipients) and those who received three to four doses of Wuhan-Hu-1 (bivalent non-recipients). We report that before XBB.1.5 vaccination, bivalent non-recipients have decreased breadth and potency of neutralization. At post-vaccination, non-recipients exhibit greater boosting of neutralizing antibodies against XBB.1.5 (18.4X versus 6.2X), EG.5.1 (30.9X versus 7.0X), and JN.1 (9.2X versus 3.7X) variants with comparable breadth and trends toward greater potency. Greater boosting in non-recipients is similarly observed for spike-binding IgA and total IgG/A/M but not IgG nor IgM. Bivalent non-recipients had longer intervals between vaccination, which may enhance antibody responses; however, bivalent receipt and interval are tightly linked, preventing isolation of individual contributions to boosting. Nonetheless, back-boosting of ancestral SARS-CoV-2 titers in both participant groups provides interval-independent evidence that imprinting persists. Our findings indicate that immune imprinting continues to affect humoral immunity elicited by the XBB.1.5 vaccine. Both imprinting and exposure intervals are important phenomena underlying immunogenicity of future variant-adapted COVID-19 vaccines. Wrynla et al. assess humoral immunity elicited by the monovalent XBB.1.5 COVID-19 vaccine in participants who did or did not previously receive the bivalent Wuhan-Hu-1/BA.4-5 vaccine. They find that immune imprinting and vaccination interval affect XBB.1.5 vaccine immunogenicity. COVID-19 vaccines help us produce antibodies, which are protective proteins that can recognize and neutralize viruses. However, the immune system tends to strongly remember the first version of the virus it saw, which can limit how well it responds to new variants—a phenomenon called “immune imprinting.” We studied how people responded to a COVID-19 vaccine that targeted a newer variant, XBB.1.5. We found that it still boosted antibodies against the original virus, showing that imprinting remains a concern. People with fewer previous vaccines that targeted older variants responded better, possibly because of less imprinting or longer time since their last dose. Our findings suggest that vaccine history and timing between doses affect how well updated COVID-19 vaccines work.