Tawny Chandler, Baker Institute for Animal Health, Cornell University

Tawny L. Chandler 1, Sarah Woodyear 1, Valerie Chen 1, Tom M. Lonergan 1, Natalie Baker 1, Katherine Harcourt 2, Simon Clare 2, Faraz Ahmed 3, and Sarah L. Caddy 1,4 1 Baker Institute for Animal Health, Cornell University, Ithaca, NY, United States 2 Department of Medicine, University of Cambridge, Cambridge, UK 3 Genomics Innovation Hub and TREx Facility, Institute of Biotechnology, Cornell University, Ithaca, NY, United States 4 Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States

Vaccines

Maternal antibodies (MatAbs) are transferred transplacentally and during lactation to provide protection whilst the neonatal immune response is immature. However, MatAbs also suppress the development of neonatal B cell responses via mechanisms that are poorly defined. This is a significant problem for current rotavirus vaccines, which are live-attenuated strains administered orally to infants at 8 weeks of age. High MatAbs titers have been correlated with poor seroconversion in several clinical trials. To investigate mechanisms of MatAb-mediated interference we developed a mouse model of neonatal oral rotavirus vaccination in the presence and absence of MatAbs. Vaccination with attenuated murine rotavirus induced robust neonatal antibody responses, whereas vaccination failed to induce seroconversion in the presence of MatAbs. In fact, live vaccine replication was blocked in the presence of MatAbs and more rapid waning of MatAbs was observed following vaccination suggesting premature vaccine clearance. Single-cell RNA sequencing of mesenteric lymph nodes revealed diminished plasma and germinal center B cell subpopulations as well as global reduction of interferon-stimulated genes in the presence of MatAbs, consistent with decreased vaccine replication and neonatal antibody responses. We used FcRIIB knock-out mice to investigate its role in MatAb interference and observed no effect after high transfer of MatAbs but consistent IgA interference at low MatAb transfer. Our data supports the conclusion that MatAb-mediated vaccine clearance is a key mechanism of interference with oral rotavirus vaccination, and that IgG and IgA blockade can be separated. This must be taken into consideration for development and optimization of future rotavirus vaccination.