title: Protective efficacy of centralized and polyvalent envelope immunogens in an attenuated equine lentivirus vaccine.
abstract: Lentiviral Envelope (Env) antigenic variation and related immune evasion present major hurdles to effective vaccine development. Centralized Env immunogens that minimize the genetic distance between vaccine proteins and circulating viral isolates are an area of increasing study in HIV vaccinology. To date, the efficacy of centralized immunogens has not been evaluated in the context of an animal model that could provide both immunogenicity and protective efficacy data. We previously reported on a live-attenuated (attenuated) equine infectious anemia (EIAV) virus vaccine, which provides 100% protection from disease after virulent, homologous, virus challenge. Further, protective efficacy demonstrated a significant, inverse, linear relationship between EIAV Env divergence and protection from disease when vaccinates were challenged with viral strains of increasing Env divergence from the vaccine strain Env. Here, we sought to comprehensively examine the protective efficacy of centralized immunogens in our attenuated vaccine platform. We developed, constructed, and extensively tested a consensus Env, which in a virulent proviral backbone generated a fully replication-competent pathogenic virus, and compared this consensus Env to an ancestral Env in our attenuated proviral backbone. A polyvalent attenuated vaccine was established for comparison to the centralized vaccines. Additionally, an engineered quasispecies challenge model was created for rigorous assessment of protective efficacy. Twenty-four EIAV-naïve animals were vaccinated and challenged along with six-control animals six months post-second inoculation. Pre-challenge data indicated the consensus Env was more broadly immunogenic than the Env of the other attenuated vaccines. However, challenge data demonstrated a significant increase in protective efficacy of the polyvalent vaccine. These findings reveal, for the first time, a consensus Env immunogen that generated a fully-functional, replication-competent lentivirus, which when experimentally evaluated, demonstrated broader immunogenicity that does not equate to higher protective efficacy.
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Jodi K
authors.initials: JK
authors.lastname: Craigo
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Corin
authors.initials: C
authors.lastname: Ezzelarab
authors.affiliation: Department of Veterinary Science, Gluck Equine Research Center, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Sheila J
authors.initials: SJ
authors.lastname: Cook
authors.affiliation: Department of Veterinary Science, Gluck Equine Research Center, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Chong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Veterinary Science, Gluck Equine Research Center, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Horohov
authors.affiliation: Department of Veterinary Science, Gluck Equine Research Center, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Issel
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Montelaro
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000940:Antigenic Variation / Q000276:immunology; D001483:Base Sequence; D004859:Equine Infectious Anemia / Q000517:prevention & control*; D014644:Genetic Variation; D006736:Horses / Q000276:immunology*; D004860:Infectious Anemia Virus, Equine / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D010802:Phylogeny; D016896:Treatment Outcome; D014613:Vaccines, Attenuated / Q000627:therapeutic use*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*; D014765:Viral Vaccines / Q000627:therapeutic use
chemical_list: D014613:Vaccines, Attenuated; D014759:Viral Envelope Proteins; D014765:Viral Vaccines