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.

Abstract

Rapidly evolving viral variants pose challenges for developing vaccines for older adults (aged ≥60 years), who might respond poorly to new antigens because of pre-existing antibody repertoires imprinted by ancestral strains. Repeat infection with divergent GII.4 strains makes norovirus an ideal model for studying the effect of immune imprinting on vaccine neutralising antibody (NAb) responses. The aim of this study was to explore the magnitude, breadth, and durability of GII.4-NAbs in the context of population-based immune imprinting and virus evolution, to inform the design of future vaccines optimised for protection against norovirus variants. In this post-hoc analysis, we evaluated serum samples collected during a phase 2, randomised, controlled, double-blind trial (NOR-204; NCT02661490) conducted at ten centres in the USA evaluating the safety and immunogenicity of a GI.1/GII.4c bivalent virus-like particle norovirus vaccine candidate in healthy adults aged 60 years or older. In this study, we included participants from the NOR-204 trial who had received a single unadjuvanted dose of vaccine, had provided consent for future sample use, were aged 60-74 years and 85 years or older, and for whom sufficient serum volume was available; participants aged 75-84 years were excluded. NAb titre to GII.4 variants (ancestral variants: US95/96, FH2002, and YE2006a; contemporary variants: DH2006b, NO2009, SY2012, SF2017, AL2018, and WI2021) was measured using a surrogate assay in serum collected at days 1 (baseline), 57 (28 days after vaccination), and 393 (365 days after vaccination) to compare the magnitude, breadth, and durability of NAbs. Antigenic relationships among GII.4 variants were visualised by antigenic cartography. Participants were enrolled in the NOR-204 trial between Feb 1, 2016, and Oct 31, 2017. In this study, we included 45 (59%) of 76 participants who received a single unadjuvanted dose of vaccine in the NOR-204 trial; we excluded 25 (100%) of 25 participants aged 75-84 years and included 23 (92%) of 25 participants aged 60-74 years and 22 (85%) of 26 participants aged 85 years or more. 26 (58%) of 45 participants were female and 19 (42%) were male; 41 (91%) participants were White, three (7%) were Asian, and one (2%) was Black or African American. Serum was available for analysis for all participants on days 1 and 57 (n=45) and for 44 participants on day 393. Before vaccination, GII.4 surrogate NAb (sNAb) geometric mean titres (GMTs) were the highest against ancestral variants and lowest against contemporary variants compared with those for US95/96 (p<0·05). On day 57, GII.4 sNAb GMTs were elevated against all the GII.4 variants tested compared with day 1 (p<0·0001), although only GII.4c and DH2006b sNAb titres were as high as the titres of ancestral GII.4 variants (p>0·05, compared with US95/96). At day 393, GII.4 sNAb GMTs were lower than those at day 57, but all ancestral variants, GII.4c, DH2006b, and AL2018 had GMTs higher than those at day 1 (p<0·05); only GII.4c GMT remained as elevated as GMTs targeting ancestral variants (p>0·05, compared with US95/96). Antigenic cartography was used to visualise serum samples cross-reactivity patterns. GII.4 variants that circulated until 2006 (CW1987, US95/96, FH2002, YE2006a, and DH2006b) and GII.4c formed antigenic cluster 1, whereas GII.4 variants that emerged between 2009 and 2021 (NO2009, SY2012, SF2017, AL2018, and WI2021) formed antigenic cluster 2 before vaccination. At days 57 and 393, contemporary variants were further resolved into two subclusters, 2A (DH2006b, SY2012, and AL2018) and 2B (NO2009, WI2021, and SF2017). Analyses support the hypothesis that a vaccine composed of ancestral variant NAb sites boosts sNAb titre imprinted from natural exposures, driving magnitude, breadth, and durability in older adults. Optimal vaccination strategies could combine an ancestral variant able to capitalise on imprinted NAbs to recall breadth and magnitude, and a divergent variant to expand durability to distant contemporary viruses. National Institute of Allergy and Infectious Diseases, HilleVax.