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

• Published in: PLoS neglected tropical diseases Vol. 10; no. 6; p. e0004746
• Main Authors: Schnee, Margit, Vogel, Annette B., Voss, Daniel, Petsch, Benjamin, Baumhof, Patrick, Kramps, Thomas, Stitz, Lothar
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.06.2016; Public Library of Science (PLoS)
• Subjects: Animal bites; Animals; Animals, Newborn; Base Sequence; Biology and Life Sciences; Central nervous system; Developing countries; Domestic animals; Dose-Response Relationship, Immunologic; Drug therapy; Female; Flow cytometry; Genetic aspects; Genetic code; Glycoproteins; Glycoproteins - immunology; Health aspects; HeLa Cells; Humans; Immunoglobulins; Infections; Infectious diseases; Influenza; LDCs; Lymphocytes; Medicine and Health Sciences; Messenger RNA; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nucleic acids; Peptide Fragments - immunology; Pregnancy; Properties; Proteins; Rabies; Rabies - mortality; Rabies - prevention & control; Rabies - veterinary; Rabies Vaccines - genetics; Rabies Vaccines - immunology; RNA polymerase; RNA, Messenger - chemistry; RNA, Messenger - immunology; Swine; Swine Diseases - prevention & control; T-Lymphocytes; Tropical diseases; Vaccines; Vaccines, Synthetic - immunology; Viral infections; Viral Proteins - immunology
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0004746

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.