Reproducing SIVDnef vaccine correlates of protection: Trimeric gp41 antibody concentrated at mucosal front lines

James E. Voss, Matthew S. Macauley, Kenneth A. Rogers, Francois Villinger, Lijie Duan, Liang Shang, Elizabeth A. Fink, Raiees Andrabi, Arnaud D. Colantonio, James E. Robinson, Paul P. Johnson, Dennis R. Burton, Ashley T. Haase

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2427-2438
Number of pages12
JournalAIDS
Volume30
Issue number16
DOIs
StatePublished - Oct 23 2016

Bibliographical note

Funding Information:
was produced by the NIH Nonhuman Primate Reagent Resource funded by NIH grant OD010976 and NIAID contract HHSN272200130031C.

Keywords

  • Mucosal concentration
  • SIV VACCINE
  • Trimeric gp41 antibodies

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