A vaccine platform against arenaviruses based on a recombinant hyper-attenuated Mopeia virus expressing heterologous glycoproteins.

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A vaccine platform against arenaviruses based on a recombinant hyper-attenuated Mopeia virus expressing heterologous glycoproteins.

J Virol. 2018 Mar 28;:

Authors: Carnec X, Matéo M, Page A, Reynard S, Hortion J, Picard C, Yekwa E, Ferron F, Baize S

Abstract
Several Old and New-World arenaviruses are responsible for severe endemic and epidemic hemorrhagic fevers, whereas other members of the Arenaviridae family are nonpathogenic. To date, no approved vaccines, antiviral or specific treatments are available, except for Junín virus. Protection in non-human primates against Lassa fever virus (LASV) is however possible through the inoculation of the closely related but nonpathogenic Mopeia virus (MOPV) before challenge with LASV. We reasoned that this virus, modified using reverse genetics, would represent the basis for the generation of a vaccine platform against LASV and other pathogenic arenaviruses. After showing evidence of exoribonuclease (ExoN) activity in the NP of MOPV, we found that this activity was essential for multiplication in antigen presenting cells. The introduction of multiple mutations in the ExoN site of MOPV NP generated a hyper-attenuated strain (MOPVExoN6b) which is (i) genetically stable over passages, (ii) has increased immunogenic properties compared to MOPV and (iii) still promotes a strong type I IFN response. The MOPVExoN6b virus was further modified to harbor the envelope glycoproteins of heterologous pathogenic arenaviruses, such as LASV, Lujo, Machupo, Guanarito, Chapare, or Sabia viruses in order to broaden specific antigenicity while preserving the hyper-attenuated characteristics of the parental strain. Our MOPV based vaccine candidate for LASV, MOPEVACLASV, was used in a one-shot immunization assay in non-human primates and fully protected them from a lethal challenge with LASV. Thus, our hyper-attenuated strain of MOPV constitutes a promising new live-attenuated vaccine platform to immunize against several, if not all, pathogenic arenaviruses.ImportanceArenaviruses are emerging pathogens transmitted to humans by rodents and responsible for endemic and epidemic hemorrhagic fevers of global concern. Nonspecific symptoms associated with the onset of infection make these viruses difficult to distinguish from other endemic pathogens. Moreover, the unavailability of rapid diagnosis in the field delays the identification of the virus, early care for treatment, and favors spreading. The vaccination of exposed populations would be of great help to decrease morbidity and human-to-human transmission. Using reverse genetics, we generated a vaccine platform for pathogenic arenaviruses based on a modified and hyper-attenuated strain of the nonpathogenic Mopeia virus and showed that the Lassa virus candidate fully protected non-human primates from a lethal challenge. These results showed that a rationally designed recombinant MOPV-based vaccine is safe, immunogenic and efficacious in non-human primates.

PMID: 29593043 [PubMed - as supplied by publisher]

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