Recombinant Isfahan Virus and Vesicular Stomatitis Virus Vaccine Vectors Provide Durable, Multivalent, Single-Dose Protection against Lethal Alphavirus Challenge.
The demonstrated clinical efficacy of a recombinant vesicular stomatitis virus (rVSV) vaccine vector has stimulated the investigation of additional serologically distinctVesiculovirusvectors as therapeutic and/or prophylactic vaccine vectors to combat emerging viral diseases. Among these viral threats are the encephalitic alphaviruses Venezuelan equine encephalitis virus (VEEV) and Eastern equine encephalitis virus (EEEV), which have demonstrated potential for natural disease outbreaks, yet no licensed vaccines are available in the event of an epidemic. Here we report the rescue of recombinant Isfahan virus (rISFV) from genomic cDNA as a potential new vaccine vector platform. The rISFV genome was modified to attenuate virulence and express the VEEV and EEEV E2/E1 surface glycoproteins as vaccine antigens. A single dose of the rISFV vaccine vectors elicited neutralizing antibody responses and protected mice from lethal VEEV and EEEV challenges at 1 month postvaccination as well as lethal VEEV challenge at 8 months postvaccination. A mixture of rISFV vectors expressing the VEEV and EEEV E2/E1 glycoproteins also provided durable, single-dose protection from lethal VEEV and EEEV challenges, demonstrating the potential for a multivalent vaccine formulation. These findings were paralleled in studies with an attenuated form of rVSV expressing the VEEV E2/E1 glycoproteins. Both the rVSV and rISFV vectors were attenuated by using an approach that has demonstrated safety in human trials of an rVSV/HIV-1 vaccine. Vaccines based on either of these vaccine vector platforms may present a safe and effective approach to prevent alphavirus-induced disease in humans.IMPORTANCEThis work introduces rISFV as a novel vaccine vector platform that is serologically distinct and phylogenetically distant from VSV. The rISFV vector has been attenuated by an approach used for an rVSV vector that has demonstrated safety in clinical studies. The vaccine potential of the rISFV vector was investigated in a well-established alphavirus disease model. The findings indicate the feasibility of producing a safe, efficacious, multivalent vaccine against the encephalitic alphaviruses VEEV and EEEV, both of which can cause fatal disease. This work also demonstrates the efficacy of an attenuated rVSV vector that has already demonstrated safety and immunogenicity in multiple HIV-1 phase I clinical studies. The absence of serological cross-reactivity between rVSV and rISFV and their phylogenetic divergence within theVesiculovirusgenus indicate potential for two stand-alone vaccine vector platforms that could be used to target multiple bacterial and/or viral agents in successive immunization campaigns or as heterologous prime-boost agents.
Institute for Human Infections and Immunity, Center for Tropical Diseases, and Departments of Pathology and Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA fanasar@icloud.com sweaver@utmb.edu.
Farooq
F
Nasar
Profectus BioSciences Inc., Tarrytown, New York, USA.
Demetrius
D
Matassov
Institute for Human Infections and Immunity, Center for Tropical Diseases, and Departments of Pathology and Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
Robert L
RL
Seymour
Profectus BioSciences Inc., Tarrytown, New York, USA.
Theresa
T
Latham
Department of Pediatrics, Section of Tropical Medicine, Baylor College of Medicine, Houston, Texas, USA.
Rodion V
RV
Gorchakov
Profectus BioSciences Inc., Tarrytown, New York, USA.
Rebecca M
RM
Nowak
Institute for Human Infections and Immunity, Center for Tropical Diseases, and Departments of Pathology and Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
Grace
G
Leal
Profectus BioSciences Inc., Tarrytown, New York, USA.
Stefan
S
Hamm
Profectus BioSciences Inc., Tarrytown, New York, USA.
John H
JH
Eldridge
Institute for Human Infections and Immunity, Center for Tropical Diseases, and Departments of Pathology and Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
Robert B
RB
Tesh
Profectus BioSciences Inc., Tarrytown, New York, USA.
David K
DK
Clarke
Institute for Human Infections and Immunity, Center for Tropical Diseases, and Departments of Pathology and Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA fanasar@icloud.com sweaver@utmb.edu.
Scott C
SC
Weaver
D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D004195:Disease Models, Animal; D004337:Drug Carriers; D004663:Encephalitis Virus, Eastern Equine / Q000235:genetics / Q000276:immunology*; D004666:Encephalitis Virus, Venezuelan Equine / Q000235:genetics / Q000276:immunology*; D004683:Encephalomyelitis, Equine / Q000517:prevention & control*; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D016019:Survival Analysis; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology; D018116:Vesiculovirus / Q000235:genetics*; D014765:Viral Vaccines / Q000235:genetics / Q000276:immunology*
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D004337:Drug Carriers; D006023:Glycoproteins; D008565:Membrane Proteins; D014614:Vaccines, Synthetic; D014765:Viral Vaccines
Eastern equine encephalitis virus; Isfahan virus; Venezuelan equine encephalitis virus; vesicular stomatitis virus