The effect of Natural Killer cell depletion and inhibition on mRNA vaccine immunogenicity and reactogenicity 3829

Description mRNA vaccines produce highly effective and robust immune responses. However, high symptomatology tends to follow vaccination and antibody response has not been as durable as hoped. In this study we evaluated the role Natural Killer cells play in reactogenicity and durability of immune responses to mRNA vaccination. Mice were depleted of NK cells with anti-NK1.1 antibodies (IgG2a used as control), then vaccinated with 1??g or 0.1??g of LNP with mRNA encoding SARS-CoV2 spike. Proinflammatory cytokines were measured at 6 and 24 hours post vaccination, anti-spike antibodies were measured weekly until week 3, and activated spike-specific T cells were measured by flow cytometry at week 3. NK depletion prior to vaccination led to significant decreases in IFN?? (1ug: p = 0.007, 0.1ug : p = 0.016) and IL1?? (1??g: p = 0.016; 0.1??g: p = 0.024) at 24 hours and no significant differences in spike-specific antibody levels or T cell responses at 3 weeks. We are currently testing novel vaccines that encode for NK inhibitors as well as spike protein. Preliminary data of ongoing studies suggests that while these vaccines do not alter vaccine-induced cytokine responses, durability of IgG responses after co-vaccination with mRNA vaccines encoding spike and Serpin B9 (granzyme B inhibitor) may be enhanced. These findings suggest that NK cells influence both reactogenicity and durability of mRNA vaccines, and may be a novel target for next-generation mRNA vaccines. Funding Sources Supported by Leidos Biomedical Research, Inc. 67510-314307-1.00 Topic Categories Vaccines and Immunotherapy (VAC)