Mitigation of imprinted antibody responses in elderly COVID-19 highly vaccinated individuals

SARS-CoV-2 continues to evolve from the Omicron serotype, with BA.2.86 sublineage JN.1 and descendants such as KP.2 predominating in 2025-26. By early 2026, the JN.1-derived NB.1.8.1 and XFG variants had largely replaced other variants globally, with a more 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 very 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 (PV) and surrogate virus neutralisation (SVNT) based assays, we demonstrate that JN.1 and KP.2 vaccinations six months apart elicit high potency neutralisation across all studied variants except BA.3.2.2, which escaped neutralisation almost completely in all individuals. Waning of neutralising activity in serum was observed to be modest in the [~]6 months between vaccine doses, suggesting sustained immunity following multiple vaccines. While absolute neutralisation titres remained highest against ancestral Wu-1 at all timepoints due to multiple historical exposures and accumulation, the recall responses revealed a shift in immunodominance. After the recent KP.2 vaccine dose, neutralisation 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. Interestingly, RBD-specific neutralising responses experienced a boost following KP.2 vaccination, suggesting that RBD responses remain imprinted but that they constitute a small proportion in the overall Wu-1 neutralising response as immune imprinting is alleviated.