Unmodified rabies mRNA vaccine elicits high cross-neutralizing antibodies and diverse B cell memory responses

Licensed rabies virus vaccines based on whole inactivated virus are effective in humans. However, there is a lack of detailed investigations of the elicited immune response, and whether responses can be improved with novel vaccine platforms is lacking. Here we show that two doses of a lipid nanoparticle-formulated unmodified mRNA vaccine encoding the rabies virus glycoprotein (RABV-G) induced higher levels of RABV-G specific plasmablasts, memory B cells and T cells in blood, and plasma cells in the bone marrow after intramuscular injection compared to two doses of inactivated vaccine in non-human primates. The mRNA vaccine also generated higher RABV-G binding antibody titers than the inactivated vaccine, while the neutralizing titers, degree of somatic hypermutation and clonal diversity of the response was similar for the two vaccines. The higher overall binding titers induced by the mRNA vaccine translated into improved cross-neutralization of related lyssavirus strains, suggesting that this platform has potential for the development of a broadly protective vaccine against these viruses.