A seven-valent norovirus mRNA vaccine elicits robust humoral responses in preclinical models
Karin Bystol, Gregory O'Donnell, Susanne Hartwig, Courtney David, Jennifer Galli, Christopher Warren, Gwenny Go, Bennett Obed, Athena Lago, Michael Citron, Corey May Fulton, Thienlong Phan, John M. Gaspar, Pratap Singh, Arthur Fridman, Yi Shu, Jiajie WeiABSTRACT
Noroviruses are a leading cause of acute gastroenteritis and impose a substantial global disease burden, particularly in children younger than 5 years and in older adults. Although multiple vaccine candidates are in preclinical and clinical development, no targeted intervention has been approved. We previously reported that a pentavalent mRNA vaccine candidate encoding VP1 proteins from genotypes GI.1, GII.2, GII.3, GII.4, and GII.6 elicited robust humoral and cellular immune responses in mice and nonhuman primates. Because recent surveillance data indicate increasing prevalence of GI.3 and GII.17, we designed mRNAs targeting these genotypes and evaluated an expanded seven-valent formulation in preclinical studies. We first compared candidate GI.3 and GII.17 strains in mice and selected vaccine components based on immunogenicity and cross-reactivity. The resulting seven-valent mRNA vaccine elicited strong humoral responses in mice and African green monkeys, including serum IgG binding to norovirus virus-like particles (VLPs) and functional antibodies that blocked VLP binding to histo-blood group antigens (HBGAs). Importantly, incorporation of GI.3 and GII.17 broadened functional coverage, whereas multivalent formulation introduced only limited evidence of immune interference. These findings support the feasibility of surveillance-guided updating of multivalent norovirus mRNA vaccines and highlight the adaptability of the mRNA platform for addressing emerging variants.
IMPORTANCE
Norovirus is a major cause of vomiting and diarrhea worldwide, but developing a broadly protective vaccine is difficult because many genetically distinct strains circulate, and their prevalence changes over time. This study demonstrates a flexible vaccine strategy in which mRNA components can be selected and added based on disease surveillance and experimental evidence. We expanded a five-component norovirus vaccine to include GI.3 and GII.17, two increasingly important genotypes. The resulting seven-component vaccine generated strong antibody responses in mice and African green monkeys and broadened the range of virus types targeted by functional antibodies. Although additional studies are needed to determine whether these responses protect humans, the findings show how the adaptability of mRNA technology could support periodic updates of multivalent norovirus vaccines as circulating strains change.