Combination Adenovirus and Protein Vaccines Prevent Infection or Reduce Viral Burden after Heterologous Clade C Simian-Human Immunodeficiency Virus Mucosal Challenge

Abstract

HIV vaccine development is focused on designing immunogens and delivery methods that elicit protective immunity. We evaluated a combination of adenovirus (Ad) vectors expressing HIV 1086.C (clade C) envelope glycoprotein (Env), SIV Gag p55, and human pegivirus GBV-C E2 glycoprotein. We compared replicating simian (SAd7) with nonreplicating human (Ad4) adenovirus-vectored vaccines paired with recombinant proteins in a novel prime-boost regimen in rhesus macaques, with the goal of eliciting protective immunity against SHIV challenge. In both vaccine groups, plasma and buccal Env-specific IgG, tier 1 heterologous neutralizing antibodies, and antibody-dependent cell-mediated viral inhibition were readily generated. High Env-specific T cell responses elicited in all vaccinees were significantly greater than responses targeting Gag. After three intrarectal exposures to heterologous tier 1 clade C SHIV, all 10 sham-vaccinated controls were infected, whereas 4/10 SAd7- and 3/10 Ad4-vaccinated macaques remained uninfected or maintained tightly controlled plasma viremia. Time to infection was significantly delayed in SAd7-vaccinated macaques compared to the controls. Cell-associated and plasma virus levels were significantly lower in each group of vaccinated macaques compared to controls; the lowest plasma viral burden was found in animals vaccinated with the SAd7 vectors, suggesting superior immunity conferred by the replicating simian vectors. Furthermore, higher V1V2-specific binding antibody titers correlated with viral control in the SAd7 vaccine group. Thus, recombinant Ad plus protein vaccines generated humoral and cellular immunity that was effective in either protecting from SHIV acquisition or significantly reducing viremia in animals that became infected, consequently supporting additional development of replicating Ad vectors as HIV vaccines. There is a well-acknowledged need for an effective AIDS vaccine that protects against HIV infection and limits viral replication and associated pathogenesis. Although replicating virus vectors have been advanced as HIV vaccine platforms, there have not been any direct comparisons of the replicating to the nonreplicating format. The present study directly compared the replicating SAd7 to nonreplicating Ad4 vectors in macaques and demonstrated that in the SAd7 vaccine group, the time to infection was significantly delayed compared to the control group, and V1V2 Env-specific binding antibodies correlated with viral outcomes. Viral control was significantly enhanced in vaccinated macaques compared to controls, and in infected SAd7-vaccinated macaques compared to Ad4-vaccinated macaques, suggesting that this vector may have conferred more effective immunity. Because blocking infection is so difficult with current vaccines, development of a vaccine that can limit viremia if infection occurs would be valuable. These data support further development of replicating adenovirus vectors.

Multimeric Epitope-Scaffold HIV Vaccines Target V1V2 and Differentially Tune Polyfunctional Antibody Responses

“…A total of seven vaccine groups, each comprised of six adult rhesus macaques, were immunized according to the schedules shown in Figure 1A using single or multiple V1V2-scaffold proteins formulated in Adjuplex adjuvant. Simultaneously, all animals received either clade C gp120(ZM109) or gp120(ZM53) plasmid DNA intradermally via gene gun, a procedure used previously for optimal immunogenicity in animal models (Hessell et al, 2016; Jaworski et al, 2012; Krebs et al, 2014; Malherbe et al, 2014, 2018; Pissani et al, 2014). The immunization regimens, summarized in Figure 1B, varied in the choice and number of V1V2 scaffolds to examine (1) DNA and protein co-immunization priming followed by a protein-only boost (groups 1–3), (2) subcutaneous (s.c.) versus intramuscular (i.m.)…”

Simian-Human Immunodeficiency Virus SHIV.CH505 Infection of Rhesus Macaques Results in Persistent Viral Replication and Induces Intestinal Immunopathology

“…ELISA antibody assays. HIV-1 Env binding antibody titers were measured in plasma samples collected at regular intervals against autologous CAP257 54wpi_D gp140 according to methods previously established (61,62).…”

Passive and active antibody studies in primates to inform HIV vaccines

“…Another solution was to develop Ad vectors based on Ads from other species (chimpanzees and rhesus macaques), but these vectors do not replicate in humans and may not confer immunity that is as potent. There was evidence for significantly better viral control in a recent study that combined either human Ad4 or simian Ad7 expressing Gag and Env with recombinant Env protein [146].…”