Ceron-Gutierrez, L. | Search bioRxiv

bioRxiv2026

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 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.

microbiology↗

bioRxiv2021

SARS-CoV-2 spike protein arrested in the closed state induces potent neutralizing responses

The majority of SARS-CoV-2 vaccines in use or in advanced clinical development are based on the viral spike protein (S) as their immunogen. S is present on virions as pre-fusion trimers in which the receptor binding domain (RBD) is stochastically open or closed. Neutralizing antibodies have been described that act against both open and closed conformations. The long-term success of vaccination strategies will depend upon inducing antibodies that provide long-lasting broad immunity against evolving, circulating SARS-CoV-2 strains, while avoiding the risk of antibody dependent enhancement as observed with other Coronavirus vaccines. Here we have assessed the results of immunization in a mouse model using an S protein trimer that is arrested in the closed state to prevent exposure of the receptor binding site and therefore interaction with the receptor. We compared this with a range of other modified S protein constructs, including representatives used in current vaccines. We found that all trimeric S proteins induce a long-lived, strongly neutralizing antibody response as well as T-cell responses. Notably, the protein binding properties of sera induced by the closed spike differed from those induced by standard S protein constructs. Closed S proteins induced more potent neutralising responses than expected based on the degree to which they inhibit interactions between the RBD and ACE2. These observations suggest that closed spikes recruit different, but equally potent, virus-inhibiting immune responses than open spikes, and that this is likely to include neutralizing antibodies against conformational epitopes present in the closed conformation. Together with their improved stability and storage properties we suggest that closed spikes may be a valuable component of refined, next-generation vaccines.

immunology↗