Complex Genetic Traits Regulate the Kinetics, Magnitude and Durability of Norovirus mRNA LNP Vaccine Performance in Outbred Populations.

Ralph Baric, UNC 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, , Martin T. Ferris3, Drew Weissman2, Elena N. Atochina-Vasserman2, Alexandra Schäfer1 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 are powerful countermeasures for pandemic preparedness and global health. We have developed a modified mRNA-LNP vaccine candidate comprised of human norovirus GI.1/GII.4 capsids (GI.1/GII.4 mRNA-LNP). The vaccine induced high titer neutralizing antibodies (nAb) in standard laboratory mice strains with limited genetic variation. In comparison, heterogeneity in human responses to mRNA-LNP vaccination suggestthat host genetic variation may influence nAb responses and vaccine performance. To test this hypothesis, we vaccinated the Collaborative Cross (CC) Genetic Reference Population with GI.1/GII.4 mRNA-LNP to identify strains that elicited nAb responses, phenocopying responses seen in human populations. High-low responsive lines differed in the total numbers of B, but not TFH cell numbers in the spleen. To identify susceptibility loci that regulate nAb responses, we designed an F2 genetic intercross between high- and low- nAb response lines (n=300). The F2 cohort was primed and boosted with GI.1/GII.4 mRNA-LNP and nAb (ligand-blocking) responses were followed for ~10 months. After genotyping the F2 cohort, we conducted quantitative trait locus mapping to identify loci associated with nAb responses to mRNA-LNP vaccination. We identified multiple loci impacting nAb titer (prime/boost), breadth/durability, immunogen-specific, and mRNA LNP platform specific. We validated several mRNA-LNP platform loci using vaccines encoding SARS-CoV2_S2P immunogens. Priority genes under associated loci include regulators of immune cell activation, somatic hypermutation and antibody production. Further studies of the specific genes under targeted loci willidentify potential allele variants, immune pathways and mechanisms that regulate mRNA-LNP vaccine performance and safety in models of outbred populations.
Funding: National Institute of Allergy and Infectious Disease R01 AI148260 and U01-AI149644-03.