4 years ago

Combination Adenovirus and Protein Vaccines Prevent Infection or Reduce Viral Burden after Heterologous Clade C SHIV Mucosal Challenge.

Jason Mendy, Marc Gurwith, David Montefiori, Lo Vang, Ruth M Ruprecht, Celia C LaBranche, Jonathan Smith, James H McLinden, Samir K Lakhashe, Alfred W Legasse, Jeff Alexander, Jinhua Xiang, Byung Park, Donald N Forthal, Johannes S Gach, Jack T Stapleton, Joshua Owuor, Hua-Xin Liao, Delphine C Malherbe, Michael K Axthelm, Philip T Barnette, Nancy L Haigwood, Barton F Haynes, James M Wilson, Jason Reed, Jonah B Sacha
HIV vaccine development is focused on designing immunogens and delivery methods that elicit protective immunity. We evaluated a combination of Ad vectors expressing HIV 1086.C (Clade C) Envelope glycoprotein, SIV Gag p55, and human pegivirus GBV-C E2 glycoprotein. We compared replicating simian (SAd7) with non-replicating 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 ADCVI were readily generated. High Env-specific T cell responses elicited in all vaccinees were significantly greater than responses targeting Gag. Following three intrarectal exposures to heterologous Tier 1 Clade C SHIV, all 10 sham vaccinated controls were infected, while 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 with controls; the lowest plasma viral burden was found in those 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.IMPORTANCE There is a well-acknowledged need for an effective AIDS vaccine that protects against HIV infection and limits in vivo 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 non-replicating format. The current study directly compared the replicating SAd7 to non-replicating Ad4 vectors in macaques and demonstrated that in the SAd7 vaccine group, 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.

Publisher URL: http://doi.org/10.1128/JVI.01092-17

DOI: 10.1128/JVI.01092-17

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