title: BoHV-4-Based Vector Single Heterologous Antigen Delivery Protects STAT1(-/-) Mice from Monkeypoxvirus Lethal Challenge.
abstract: Monkeypox virus (MPXV) is the etiological agent of human (MPX). It is an emerging orthopoxvirus zoonosis in the tropical rain forest of Africa and is endemic in the Congo-basin and sporadic in West Africa; it remains a tropical neglected disease of persons in impoverished rural areas. Interaction of the human population with wildlife increases human infection with MPX virus (MPXV), and infection from human to human is possible. Smallpox vaccination provides good cross-protection against MPX; however, the vaccination campaign ended in Africa in 1980, meaning that a large proportion of the population is currently unprotected against MPXV infection. Disease control hinges on deterring zoonotic exposure to the virus and, barring that, interrupting person-to-person spread. However, there are no FDA-approved therapies against MPX, and current vaccines are limited due to safety concerns. For this reason, new studies on pathogenesis, prophylaxis and therapeutics are still of great interest, not only for the scientific community but also for the governments concerned that MPXV could be used as a bioterror agent. In the present study, a new vaccination strategy approach based on three recombinant bovine herpesvirus 4 (BoHV-4) vectors, each expressing different MPXV glycoproteins, A29L, M1R and B6R were investigated in terms of protection from a lethal MPXV challenge in STAT1 knockout mice. BoHV-4-A-CMV-A29LgD106ΔTK, BoHV-4-A-EF1α-M1RgD106ΔTK and BoHV-4-A-EF1α-B6RgD106ΔTK were successfully constructed by recombineering, and their capacity to express their transgene was demonstrated. A small challenge study was performed, and all three recombinant BoHV-4 appeared safe (no weight-loss or obvious adverse events) following intraperitoneal administration. Further, BoHV-4-A-EF1α-M1RgD106ΔTK alone or in combination with BoHV-4-A-CMV-A29LgD106ΔTK and BoHV-4-A-EF1α-B6RgD106ΔTK, was shown to be able to protect, 100% alone and 80% in combination, STAT1(-/-) mice against mortality and morbidity. This work demonstrated the efficacy of BoHV-4 based vectors and the use of BoHV-4 as a vaccine-vector platform.
authors.affiliation: Department of Medical-Veterinary Science, University of Parma, Parma, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Franceschi
authors.affiliation: Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Parker
authors.affiliation: Department of Medical-Veterinary Science, University of Parma, Parma, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Jacca
authors.affiliation: Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Crump
authors.affiliation: Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Doronin
authors.affiliation: Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Edguardo
authors.initials: E
authors.lastname: Hembrador
authors.affiliation: Department of Medical-Veterinary Science, University of Parma, Parma, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pompilio
authors.affiliation: Department of Medical-Veterinary Science, University of Parma, Parma, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Tebaldi
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Estep
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Wong
authors.affiliation: Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Buller
authors.affiliation: Department of Medical-Veterinary Science, University of Parma, Parma, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Donofrio
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology*; D001483:Base Sequence; D002417:Cattle; D002460:Cell Line; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D026021:Herpesvirus 4, Bovine / Q000276:immunology / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D045908:Mpox, Monkeypox / Q000517:prevention & control*; D008993:Monkeypox virus / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014765:Viral Vaccines / Q000235:genetics / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014765:Viral Vaccines