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.
Highlights
Rabies is an invariably fatal neurological disease that affects different species of warm-blooded animals, including wild animals, pets, and humans
First successful vaccination against rabies virus infection was performed by Louis Pasteur in the 19th 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
Summary
Rabies is an invariably fatal neurological disease that affects different species of warm-blooded animals, including wild animals, pets, and humans. This infectious disease is caused by a strictly neurotropic virus. Human rabies cases are almost exclusively caused by animal bites, in particular by dogs. Humans first develop a flu-like illness and thereafter severe neurotropic symptoms caused by the ensuing progressive encephalomyelitis. Death commonly follows within an average survival time between 6 and 11 days after first symptomatic onset for furious or paralytic forms, respectively, leaving little time and extremely limited therapeutic options [1,2]
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