Reproducing SIVnef vaccine correlates of protection: trimeric gp41 antibody concentrated at mucosal front lines

• Type of Material: Article
• Authors: James E. Voss, Scripps Research Institute; Matthew S. Macauley, Scripps Research Institute; Kenneth A. Rogers, Emory University; Francois Villinger, Emory University; Lijie Duan, University of Minnesota; Liang Shang, University of Minnesota; Elizabeth A. Fink, University of California San Diego; Raiees Andrabi, Scripps Research Institute; Arnaud D. Colantonio, Harvard Medical School; James E. Robinson, Tulane University; Robert Johnson, Emory University; Dennis R. Burton, Scripps Research Institute; Ashley T. Haase, University of Minnesota
• Language: English
• Date: 2016-10-23
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Wolters Kluwer Health, Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1097/QAD.0000000000001199
• Title of Journal or Parent Work: AIDS
• ISSN: 0269-9370
• Volume: 30
• Issue: 16
• Start Page: 2427
• End Page: 2438
• Grant/Funding Information: The 4.9C antibody used in the passive immunization studies was produced by the NIH Nonhuman Primate Reagent Resource funded by NIH grant OD010976 and NIAID contract HHSN272200130031C.; Portions of this work were facilitated by the Protein Expression and Proteomics Core of the University of California, San Diego, Center for AIDS Research (CFAR).; This work was supported by National Institutes of Health Grants R01 AI102625 and P30 AI036214.
• Keywords: SIV VACCINE; Science & Technology; Life Sciences & Biomedicine; INFECTION; TYPE-1; MACAQUES; LIVE; SIMIAN IMMUNODEFICIENCY VIRUS; CONTROL REPLICATION; Virology; SIVMAC239-DELTA-NEF; Infectious Diseases; Immunology; mucosal concentration; ATTENUATED SIV; trimeric gp41 antibodies; TRANSMEMBRANE PROTEIN; IMMUNE-RESPONSES
• Research Categories: Biology, Microbiology; Health Sciences, Immunology; Biology, Virology

Abstract

Vaccination with SIV mac239 δnef 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 SIV mac239 δnef 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 SIV mac239 δnef vaccinated and protected animals. Although this strategy did not reproduce the system of local production of antibody in SIV mac239 δnef-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.