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

Despite higher clinical risk of severe COVID-19, contemporary data on antibody durability and breadth in older adults receiving multiple COVID-19 booster vaccines remain limited amid ongoing evolution of SARS-CoV-2 Omicron JN.1 descendants and the divergent BA.3.2 saltation variant. We studied a clinically vulnerable cohort of 43 older adults (median age = 85 years, IQR 75-88, 40% female). Using pseudotyped and surrogate virus neutralization-based assays, we demonstrate that JN.1 and KP.2 vaccinations six months apart elicit high-potency neutralization across all studied JN.1-lineage variants but not BA.3.2.2, where titers were 2-3-fold lower. Waning of serum neutralizing activity was modest between vaccine doses, suggesting sustained immunity. Importantly, the half-life of serum neutralization against Wu-1 (179 days) was substantially longer than JN.1 subvariants (43.7-70.1 days), consistent with Wu-1-specific imprinted responses. Furthermore, BA.3.2.2 neutralizing antibody half-life was prolonged at 107 days, implicating imprinted ancestral variant-targeting antibodies having some activity against BA.3.2.2. While absolute neutralization titers remained highest against ancestral Wu-1 due to multiple historical exposures, recall responses after the KP.2 vaccine revealed a shift in immunodominance. Neutralization against full-length Wu-1 spike was not boosted, whereas all JN.1 descendants and BA.3.2.2 showed significant boosts, indicating partial alleviation of immune imprinting. These data indicate that in the elderly, protective neutralizing antibody responses against recent variants of concern can be achieved, with reduction of immune imprinting and waning through biannual, strain-updated booster vaccines. Imprinted antibodies against ancestral variants may still be relevant for protection against highly immune evasive variants such as BA.3.2.2, highlighting that careful characterization of population-level COVID-19 humoral immunity remains warranted.