An mRNA Vaccine Encoding Rabies Virus Glycoprotein Induces Protection against Lethal Infection in Mice and Correlates of Protection in Adult and Newborn Pigs

Abstract

Rabies is a zoonotic infectious disease of the central nervous system (CNS). In unvaccinated or untreated subjects, rabies virus infection causes severe neurological symptoms and is invariably fatal. Despite the long-standing existence of effective vaccines, vaccine availability remains insufficient, with high numbers of fatal infections mostly in developing countries. Nucleic acid based vaccines have proven convincingly as a new technology for the fast development of vaccines against newly emerging pathogens, diseases where no vaccine exists or for replacing already existing vaccines. We used an optimized non-replicating rabies virus glycoprotein (RABV-G) encoding messenger RNA (mRNA) to induce potent neutralizing antibodies (VN titers) in mice and domestic pigs. Functional antibody titers were followed in mice for up to one year and titers remained stable for the entire observation period in all dose groups. T cell analysis revealed the induction of both, specific CD4+ as well as CD8+ T cells by RABV-G mRNA, with the induced CD4+ T cells being higher than those induced by a licensed vaccine. Notably, RABV-G mRNA vaccinated mice were protected against lethal intracerebral challenge infection. Inhibition of viral replication by vaccination was verified by qRT-PCR. Furthermore, we demonstrate that CD4+ T cells are crucial for the generation of neutralizing antibodies. In domestic pigs we were able to induce VN titers that correlate with protection in adult and newborn pigs. This study demonstrates the feasibility of a non-replicating mRNA rabies vaccine in small and large animals and highlights the promises of mRNA vaccines for the prevention of infectious diseases.

Author Summary

Although first successful vaccination against rabies virus infection was performed by Louis Pasteur in the 19 ^th century, every year about 50,000 patients, predominantly children, succumb to rabies infection because of insufficient availability of effective low-cost vaccines worldwide. The work presented here describes the protective capacity of such a vaccine candidate based on a non-replicating messenger RNA (mRNA). Here we highlight the efficacy of this type of vaccine in a highly fatal viral infection mouse model and demonstrate the induction of accepted correlates of protection in domestic pigs. The results extend and strengthen our previous work on mRNA-based vaccines protecting against Influenza. The data from Rabies and Influenza studies, together with the increased thermostability (manuscript in preparation) and the conceived cost-effectiveness of production suggest that non-replicating mRNA-based vaccines are an attractive and promising format for the development of protective vaccines against a wide range of infectious diseases.