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

PLoS Negl Trop Dis. 2016 Jun 23;10(6):e0004746. doi: 10.1371/journal.pntd.0004746. eCollection 2016 Jun.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Base Sequence
  • Dose-Response Relationship, Immunologic
  • Female
  • Glycoproteins / immunology*
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Peptide Fragments / immunology*
  • Pregnancy
  • RNA, Messenger / chemistry
  • RNA, Messenger / immunology*
  • Rabies / mortality
  • Rabies / prevention & control
  • Rabies / veterinary*
  • Rabies Vaccines* / genetics
  • Rabies Vaccines* / immunology
  • Swine
  • Swine Diseases / prevention & control*
  • T-Lymphocytes
  • Vaccines, Synthetic / immunology
  • Viral Proteins / immunology*

Substances

  • Glycoproteins
  • Peptide Fragments
  • RNA, Messenger
  • Rabies Vaccines
  • Vaccines, Synthetic
  • Viral Proteins
  • rabies virus glycoprotein peptide

Grant support

The work was supported by the followig KMU-innovativ grants: 0315802, 031A061A and 031A061C. KMU-innovativ is an Innovation Programme of the Bundes-Ministerium für Bildung und Forschung (BMBF; Germany) for SMEs (Website: https://www.bmbf.de/de/kmu-innovativ-561.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.