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

Mon, 04/30/2018 - 10:24am -- dana
TitleCombination Adenovirus and Protein Vaccines Prevent Infection or Reduce Viral Burden after Heterologous Clade C Simian-Human Immunodeficiency Virus Mucosal Challenge.
Publication TypeJournal Article
Year of Publication2018
AuthorsMalherbe DC, Mendy J, Vang L, Barnette PT, Reed J, Lakhashe SK, Owuor J, Gach JS, Legasse AW, Axthelm MK, Labranche CC, Montefiori D, Forthal DN, Park B, Wilson JM, McLinden JH, Xiang J, Stapleton JT, Sacha JB, Haynes BF, Liao H-X, Ruprecht RM, Smith J, Gurwith M, Haigwood NL, Alexander J
JournalJ Virol
Date Published2018 01 15
KeywordsAdenoviridae, Animals, Antibodies, Neutralizing, Antibodies, Viral, Antibody Specificity, CD4 Lymphocyte Count, Cell Line, Genetic Vectors, Genotype, HIV, Humans, Immunity, Humoral, Immunization, Kaplan-Meier Estimate, Macaca mulatta, Male, Protein Binding, SAIDS Vaccines, Simian Acquired Immunodeficiency Syndrome, Simian immunodeficiency virus, T-Lymphocytes, Vaccines, Synthetic, Viral Envelope Proteins, Viral Load

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.

Alternate JournalJ. Virol.
PubMed ID29093095
PubMed Central IDPMC5752948
Grant ListP51 OD011092 / OD / NIH HHS / United States
I01 BX000207 / BX / BLRD VA / United States
R01 AI118581 / AI / NIAID NIH HHS / United States
R01 AI100703 / AI / NIAID NIH HHS / United States
R44 AI091546 / AI / NIAID NIH HHS / United States