Qualitative trait loci mapping identifies host alleles that influence norovirus mRNA LNP vaccine neutralizing antibody responses.

Ralph Baric, University of North Carolina Chapel Hill

Lisa C. Lindesmith1, Mark R. Zweigart1, Miranda Hubbard1, Nathan Ona2, Paul D. Brewer-Jensen1, Yaoska I. Reyes1, Samantha R. May1, Michael L. Mallory1, Lily Parsons1, Alexandra Schäfer1, Martin T. Ferris3, Drew Weissman2, Elena N. Atochina-Vasserman2, and Ralph S. Baric1 1Department of Epidemiology, University of North Carolina, Chapel Hill, NC 2Department of Medicine, University of Pennsylvania, Philadelphia, PA 3Department of Genetics, UNC Chapel Hill, NC

Vaccines and immunity

Modified mRNA LNP vaccines were powerful tools in containing the COVID-19 pandemic. The success of the platform ignited interest in developing mRNA LNP vaccines for other high burden diseases caused by rapidly evolving pathogens, including norovirus. We have developed a modified mRNA LNP vaccine candidate comprised of GI.1/GII.4 capsids. The bivalent vaccine induced high titer neutralizing antibodies (nAb) in standard laboratory mice strains with limited variation in their genetic backgrounds. In comparison, human populations vary widely in their nAb response to SARS-CoV-2 vaccination, indicating host genetic variation may influence nAb responses to mRNA LNP vaccination. To test this hypothesis, here we evaluated nAb to GI.1/GII.4 norovirus mRNA LNP vaccine in the Collaborative Cross (CC) resource, a mouse genetic reference population with comparable diversity to outbred populations. CC lines showed variability in nAb responses, phenocopying the range of responses observed in humans. An F2 genetic mapping intercross between high- and low- nAb response lines (n=300) was genome-wide genotyped, then primed, and boosted with vaccine. nAb (ligand-blocking) responses were followed for >6 months. We conducted quantitative trait locus (QTL) mapping to identify alleles associated with differential nAb responses to mRNA LNP vaccination. We identified loci impacting nAb titer at prime and boost, nAb breadth and durability, vaccine immunogen-specific nAb, and mRNA LNP platform. Genes under associated loci encode regulators of immune cell activation and antibody production. Further honing of the specific genes under targeted loci will inform potential pathways to improve nAb responses across populations leading to improved mRNA LNP vaccine performance.