Durability and Breadth of Neutralizing Antibodies Against SARS-CoV-2 Variants Following XBB.1.5 Vaccination in a Multiply Exposed Cohort

Abstract Background Widespread immunity from vaccination and infection has reduced COVID-19 morbidity and mortality, but this immunity varies across the population. Understanding how repeated antigenic exposures influence antibody responses helps to inform future vaccination strategies. Methods We characterized neutralizing antibody responses in serum samples collected one and six months after XBB.1.5 vaccination from 25 healthcare workers with varying, complex histories of vaccination and reported infections. Neutralizing activity was assessed against a range of variants, from pre-Omicron to recent Omicron JN.1 sublineage, and divergent BA.3.2 variants using lentiviral pseudoviruses. Participants were stratified into five exposure groups based on their documented vaccination and reported infection history. Results XBB.1.5 vaccination elicited broad neutralizing responses, with strong boosting against previously encountered antigens relative to vaccine-matched XBB.1.5 and newer variants. Geometric mean neutralization titers were generally comparable across exposure groups, though small subgroup sizes and considerable intra-group heterogeneity precluded definitive conclusions about the influence of prior exposure history. At six months, titers declined by 36-62% across all variants. Titers remained highest against pre-Omicron variants and were lowest against JN.1 sublineage variants, with some falling to very low levels. Conclusions In this cohort with extensive prior antigenic exposures, broad neutralizing antibody profiles were observed following XBB.1.5 vaccination, though these responses waned substantially after six months. The observed waning of cross-neutralizing antibodies against emerging variants underscores the challenge of maintaining durable protection and supports the need for continued monitoring of antibody responses to guide evidence-based updates to COVID-19 vaccines.