1. A Vaccine Platform against Arenaviruses Based on a Recombinant Hyperattenuated Mopeia Virus Expressing Heterologous Glycoproteins
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Stéphane Barron, Sylvain Baize, Elsie Laban Yekwa, Hervé Raoul, Audrey Page, Stéphanie Reynard, Mathieu Mateo, Xavier Carnec, Audrey Vallve, Laura Barrot, Jimmy Hortion, Caroline Picard, François Ferron, Caroline Carbonnelle, Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections (UBIVE), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Architecture et fonction des macromolécules biologiques (AFMB), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Laboratoire P4 Jean Mérieux-Inserm [Lyon] (Unité de service 3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Européen de Recherche en Virologie et Immunologie [Lyon] (Tour Inserm CERVI), This work was supported by the Fondation pour l'Innovation en Infectiologie (FINOVI) (Lyon, France), the Fondation pour la Recherche Médicale (FRM) (France), French National Research Agency grant ANR-11-BSV_019-02, and the Fondation Méditerranée Infection. This work was also supported by Labex Ecofect (grant ANR-11-LABX-0048, Lyon University) within the program Investissements d'Avenir (grant ANR-11-IDEX-0007, French National Research Agency)., ANR-11-LABX-0048,ECOFECT,Dynamiques eco-évolutives des maladies infectieuses(2011), ANR-11-IDEX-0007,Avenir L.S.E.,PROJET AVENIR LYON SAINT-ETIENNE(2011), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], ANR-11-IDEX-0007-02/11-LABX-0048,ECOFECT,Dynamiques eco-évolutives des maladies infectieuses(2011), and ANR-11-IDEX-0007-02/11-IDEX-0007,Avenir L.S.E.,Avenir L.S.E.(2011)
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0301 basic medicine ,viruses ,MESH: Monkey Diseases/prevention & control ,viral hemorrhagic fevers ,MESH: Cricetinae ,medicine.disease_cause ,MESH: Lassa Fever/prevention & control ,MESH: Lassa Fever/virology ,Cricetinae ,Chlorocebus aethiops ,MESH: Animals ,Arenaviridae ,Lassa fever ,arenavirus ,innate immunity ,MESH: Arenaviridae/genetics ,biology ,MESH: Arenaviridae/immunology ,Viral Vaccine ,Monkey Diseases ,Vaccination ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,3. Good health ,Hemorrhagic Fevers ,MESH: Monkey Diseases/virology ,MESH: HEK293 Cells ,Interferon Type I ,MESH: Lassa virus/immunology ,MESH: Hemorrhagic Fevers, Viral/transmission ,MESH: Lassa Fever/immunology ,MESH: Interferon Type I/immunology ,MESH: Viral Vaccines/immunology ,Hemorrhagic Fevers, Viral ,live-vector vaccines ,Immunology ,MESH: Vero Cells ,MESH: Hemorrhagic Fevers, Viral/pathology ,Vaccines, Attenuated ,Microbiology ,Virus ,Cell Line ,03 medical and health sciences ,Virology ,Vaccines and Antiviral Agents ,medicine ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Lassa virus ,Vero Cells ,Arenavirus ,MESH: Humans ,MESH: Vaccines, Attenuated/immunology ,Viral Vaccines ,MESH: Monkey Diseases/immunology ,MESH: Vaccination ,biology.organism_classification ,medicine.disease ,MESH: Cercopithecus aethiops ,MESH: Hemorrhagic Fevers, Viral/immunology ,MESH: Exoribonucleases/metabolism ,MESH: Cell Line ,Macaca fascicularis ,HEK293 Cells ,030104 developmental biology ,MESH: Macaca fascicularis ,MESH: Hemorrhagic Fevers, Viral/virology ,Insect Science ,Junin virus ,Exoribonucleases - Abstract
Several Old World 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, antivirals, or specific treatments are available, except for Junín virus. However, protection of nonhuman primates against Lassa fever virus (LASV) is possible through the inoculation of the closely related but nonpathogenic Mopeia virus (MOPV) before challenge with LASV. We reasoned that this virus, modified by 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 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 hyperattenuated strain (MOPV ExoN6b ) that is (i) genetically stable over passages, (ii) has increased immunogenic properties compared to those of MOPV, and (iii) still promotes a strong type I interferon (IFN) response. MOPV ExoN6b was further modified to harbor the envelope glycoproteins of heterologous pathogenic arenaviruses, such as LASV or Lujo, Machupo, Guanarito, Chapare, or Sabia virus in order to broaden specific antigenicity while preserving the hyperattenuated characteristics of the parental strain. Our MOPV-based vaccine candidate for LASV, MOPEVAC LASV , was used in a one-shot immunization assay in nonhuman primates and fully protected them from a lethal challenge with LASV. Thus, our hyperattenuated strain of MOPV constitutes a promising new live-attenuated vaccine platform to immunize against several, if not all, pathogenic arenaviruses. IMPORTANCE Arenaviruses 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 and 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 hyperattenuated strain of the nonpathogenic Mopeia virus and showed that the Lassa virus candidate fully protected nonhuman primates from a lethal challenge. These results showed that a rationally designed recombinant MOPV-based vaccine is safe, immunogenic, and efficacious in nonhuman primates.
- Published
- 2018
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