IMMUNE imprinting from earlier norovirus infections may influence how older adults respond to vaccination, according to new research that could help inform the design of future vaccines against emerging strains.

Norovirus is a leading cause of acute gastroenteritis worldwide, but the virus evolves rapidly, creating challenges for vaccine development. In older adults, repeated exposure to circulating strains over a lifetime may leave lasting immunological signatures that affect responses to new vaccines.

Vaccine Boosts Responses to Historical Strains

Researchers explored this phenomenon through a post-hoc analysis of a Phase II trial evaluating a GI.1/GII.4c bivalent virus-like particle vaccine in adults aged 60 years and older. The study examined neutralising antibody responses against a panel of historical and contemporary GII.4 norovirus variants before vaccination, 28 days after vaccination, and one year later.

Prior to vaccination, participants showed the strongest antibody responses against older GII.4 variants that circulated decades ago, while responses to more recent strains were comparatively lower. Following vaccination, neutralising antibody levels increased significantly across all variants tested. However, the highest responses were seen against ancestral strains and the closely related GII.4c vaccine component, suggesting that vaccination preferentially boosted pre-existing immunity established through previous exposures.

Although antibody titres declined over the course of a year, several responses remained above baseline at the final follow-up. Notably, antibody levels against the GII.4c strain remained comparable to those observed against ancestral variants, indicating durable immune responses to the vaccine-matched strain.

Findings Support Role of Immune Imprinting

To further investigate these patterns, the researchers used antigenic cartography to map relationships between circulating GII.4 variants. The analysis identified distinct clusters of older and more contemporary strains, with vaccination enhancing cross-reactive responses across both groups. Nevertheless, differences in antibody recognition between variant clusters persisted, reflecting the continued impact of viral evolution on immune protection.

The findings support the concept of immune imprinting, whereby prior exposure to earlier norovirus strains shapes vaccine-induced antibody responses later in life. According to the researchers, future vaccine strategies may benefit from combining ancestral strains that recall broad pre-existing immunity with antigenically distinct contemporary variants capable of extending protection against newly emerging viruses.

The study provides new insight into how immune history influences vaccine responses in older adults and may help guide the development of next-generation norovirus vaccines designed to offer broader and more durable protection.

Reference

Lindesmith LC et al. Norovirus GII.4 serological repertoire in older adults after GII.4 ancestral variant vaccination: a post-hoc analysis of a randomised, double-blind, phase 2 trial. Lancet. 2026;7(6):101337.

Image credit: Adobestock/N Lawrencen