title: Reproducing SIVΔnef vaccine correlates of protection: trimeric gp41 antibody concentrated at mucosal front lines.
abstract: Vaccination with SIVmac239Δnef provides robust protection against subsequent challenge with wild-type simian immunodeficiency virus (SIV), but safety issues have precluded designing an HIV-1 vaccine based on a live-attenuated virus concept. Safe immunogens and adjuvants that could reproduce identified immune correlates of SIVmac239Δnef protection therefore offer an alternative path for development of an HIV vaccine. Here we describe SIV envelope trimeric gp41 (gp41t) immunogens based on a protective correlate of antibodies to gp41t concentrated on the path of virus entry by the neonatal Fc receptor (FcRn) in cervical vaginal epithelium. We developed a gp41t immunogen-monophosphoryl lipid A adjuvant liposomal nanoparticle for intramuscular (i.m.) immunization and a gp41t-Fc immunogen for intranasal immunization for pilot studies in mice, rabbits, and rhesus macaques. Repeated immunizations to mimic persistent antigen exposure in infection elicited gp41t antibodies in rhesus macaques that were detectable in FcRn+ cervical vaginal epithelium, thus recapitulating one key feature of SIVmac239Δnef vaccinated and protected animals. Although this strategy did not reproduce the system of local production of antibody in SIVmac239Δnef-vaccinated animals, passive immunization experiments supported the concept that sufficiently high levels of antibody can be concentrated by the FcRn at mucosal frontlines, thus setting the stage for assessing protection against vaginal challenge by gp41t immunization.
authors.affiliation: aDepartment of Immunology and Microbial Science, IAVI Neutralizing Antibody Center, and Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery bDepartment of Chemical Physiology, The Scripps Research Institute, La Jolla, California cDepartment of Pathology and Laboratory Medicine and Emory Vaccine Center, Emory University, Atlanta, Georgia dDepartment of Microbiology and Immunology, Medical School, University of Minnesota, Minneapolis, Minnesota eProtein Expression and Proteomics Core of the Center for AIDS Research, University of California San Diego, La Jolla, California fNew England Primate Research Center, Harvard Medical School, Southborough, Massachusetts gDepartment of Pediatrics, Tulane University Health Sciences Center, New Orleans, Louisiana hInfectious Disease Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts iYerkes National Primate Research Center, Emory University, Atlanta, Georgia jRagon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts, USA. *Current address: New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, Louisiana, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Voss
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Macauley
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Rogers
authors.forename: Francois
authors.initials: F
authors.lastname: Villinger
authors.forename: Lijie
authors.initials: L
authors.lastname: Duan
authors.forename: Liang
authors.initials: L
authors.lastname: Shang
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Fink
authors.forename: Raiees
authors.initials: R
authors.lastname: Andrabi
authors.forename: Arnaud D
authors.initials: AD
authors.lastname: Colantonio
authors.forename: James E
authors.initials: JE
authors.lastname: Robinson
authors.forename: R Paul
authors.initials: RP
authors.lastname: Johnson
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Ashley T
authors.initials: AT
authors.lastname: Haase
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000281:Administration, Intranasal; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D004848:Epithelium / Q000276:immunology; D015686:Gene Products, env / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D018928:Immunity, Mucosal; D007273:Injections, Intramuscular; D008050:Lipid A / Q000008:administration & dosage; D008253:Macaca mulatta; D008807:Mice, Inbred BALB C; D011817:Rabbits; D011961:Receptors, Fc / Q000276:immunology; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000276:immunology*; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D014760:Viral Fusion Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D015686:Gene Products, env; D015395:Histocompatibility Antigens Class I; D008050:Lipid A; D011961:Receptors, Fc; D015682:Retroviridae Proteins, Oncogenic; D018449:SAIDS Vaccines; D014760:Viral Fusion Proteins; C059580:transmembrane protein, Simian immunodeficiency virus; C100688:Fc receptor, neonatal