Mitigation of imprinted antibody responses against COVID-19 in highly vaccinated older adults

SARS-CoV-2 continues to evolve from the Omicron serotype, with BA.2.86 sublineage JN.1 and descendants predominating in 2025-26 and recent emergence of the highly divergent BA.3.2 saltation variant. Elderly individuals continue to be at greatest risk of clinical complications from COVID-19, yet contemporary data on kinetics of immune potency and breadth following multiple vaccinations remain limited in this group. We studied a cohort of forty-three healthy older adults (median age = 85 years, IQR 75-88, 40% female). Using both pseudotyped virus (PVNT) and surrogate virus (SVNT) neutralization-based assays, we demonstrate that JN.1 and KP.2 vaccinations six months apart elicit high potency neutralization across all studied variants except BA.3.2.2, where titres were around 2-3 fold lower. Waning of serum neutralizing activity was modest between vaccine doses, suggesting sustained immunity following multiple vaccines. Importantly, the half-life of serum neutralization against Wu-1 (179 days) was substantially longer compared to JN.1 subvariants (43.7-70.1days), consistent with imprinted and longer-lived Wu-1-specific responses. Furthermore, half-life for BA.3.2.2 neutralisation was prolonged at 107 days compared to JN.1 subvariants, implicating imprinted ancestral variant targeting antibodies in neutralization of this saltation variant. While absolute neutralization titers remained highest against ancestral Wu-1 at all timepoints due to multiple historical exposures and accumulation, the recall responses after the recent KP.2 vaccine revealed a shift in immunodominance: neutralization against full-length Wu-1 spike was not boosted, whereas all tested JN.1 descendants and BA.3.2.2 showed significant boosts, indicating that immune imprinting against ancestral Wu-1 was partially overcome. These data indicate that in the elderly, protective neutralizing antibody responses against recent VOC can be achieved, with alleviation of immune imprinting and reduction of waned responses through biannual, strain-updated booster vaccines. Imprinted antibodies against ancestral pre Omicron variants may still be relevant for protection against further highly immune evasive variants such as BA.3.2.2, highlighting that careful characterisation of population level COVID-19 humoral immunity is still warranted.