title: Preclinical Development of Inactivated Rabies Virus-Based Polyvalent Vaccine Against Rabies and Filoviruses.
abstract: We previously described the generation of a novel Ebola virus (EBOV) vaccine based on inactivated rabies virus (RABV) containing EBOV glycoprotein (GP) incorporated in the RABV virion. Our results demonstrated safety, immunogenicity, and protective efficacy in mice and nonhuman primates (NHPs). Protection against viral challenge depended largely on the quality of the humoral immune response against EBOV GP.Here we present the extension and improvement of this vaccine by increasing the amount of GP incorporation into virions via GP codon-optimization as well as the addition of Sudan virus (SUDV) and Marburg virus (MARV) GP containing virions. Immunogenicity studies in mice indicate similar immune responses for both SUDV GP and MARV GP compared to EBOV GP. Immunizing mice with multiple antigens resulted in immune responses similar to immunization with a single antigen. Moreover, immunization of NHP with the new inactivated RABV EBOV vaccine resulted in high titer neutralizing antibody levels and 100% protection against lethal EBOV challenge when applied with adjuvant.Our results indicate that an inactivated polyvalent vaccine against RABV filoviruses is achievable. Finally, the novel vaccines are produced on approved VERO cells and a clinical grade RABV/EBOV vaccine for human trials has been produced.
authors.affiliation: Department of Microbiology and Immunology.
authors.forename: Mallory
authors.initials: M
authors.lastname: Willet
authors.affiliation: Department of Microbiology and Immunology.
authors.forename: Drishya
authors.initials: D
authors.lastname: Kurup
authors.affiliation: Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda.
authors.forename: Amy
authors.initials: A
authors.lastname: Papaneri
authors.affiliation: Department of Microbiology and Immunology.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wirblich
authors.affiliation: US Army Medical Research Institute of Infectious Diseases.
authors.forename: Jay W
authors.initials: JW
authors.lastname: Hooper
authors.affiliation: US Army Medical Research Institute of Infectious Diseases.
authors.forename: Steve A
authors.initials: SA
authors.lastname: Kwilas
authors.affiliation: Department of Microbiology and Immunology.
authors.forename: Rohan
authors.initials: R
authors.lastname: Keshwara
authors.affiliation: Department of Microbiology and Immunology.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hudacek
authors.affiliation: IDT Biologika GmbH, Am Pharmapark, Dessau-Rosslau, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Beilfuss
authors.affiliation: IDT Biologika GmbH, Am Pharmapark, Dessau-Rosslau, Germany.
authors.forename: Grit
authors.initials: G
authors.lastname: Rudolph
authors.affiliation: IDT Biologika GmbH, Am Pharmapark, Dessau-Rosslau, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Pommerening
authors.affiliation: IDT Biologika GmbH, Am Pharmapark, Dessau-Rosslau, Germany.
authors.forename: Adriaan
authors.initials: A
authors.lastname: Vos
authors.affiliation: IDT Biologika GmbH, Am Pharmapark, Dessau-Rosslau, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Neubert
authors.affiliation: Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Maryland.
authors.forename: Peter
authors.initials: P
authors.lastname: Jahrling
authors.affiliation: Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Blaney
authors.affiliation: Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda.
authors.forename: Reed F
authors.initials: RF
authors.lastname: Johnson
authors.affiliation: Department of Microbiology and Immunology Jefferson Vaccine Center, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Schnell
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical / Q000379:methods; D046129:Ebola Vaccines / Q000276:immunology; D029043:Ebolavirus / Q000276:immunology; D016563:Filoviridae / Q000276:immunology*; D006023:Glycoproteins / Q000276:immunology; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology / Q000821:virology; D008252:Macaca fascicularis; D029024:Marburgvirus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011818:Rabies / Q000276:immunology* / Q000821:virology; D011819:Rabies Vaccines / Q000276:immunology*; D011820:Rabies virus / Q000276:immunology*; D013397:Sudan; D014611:Vaccination / Q000379:methods; D015164:Vaccines, Inactivated / Q000276:immunology*; D014709:Vero Cells
chemical_list: D000914:Antibodies, Viral; D046129:Ebola Vaccines; D006023:Glycoproteins; D011819:Rabies Vaccines; D015164:Vaccines, Inactivated
keywords: Ebola virus; Marburg virus; Sudan virus; filovirus; polyvalent vaccine; rabies virus; vaccine