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J Virol. 2018 Jan 2;92(2). pii: e01092-17. doi: 10.1128/JVI.01092-17. Print 2018 Jan 15.

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

Author information

1
Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA.
2
PaxVax, Inc., San Diego, California, USA.
3
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA.
4
Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, Texas, USA.
5
Southwest National Primate Research Center, San Antonio, Texas, USA.
6
Division of Infectious Diseases, Department of Medicine, University of California, Irvine School of Medicine, Irvine, California, USA.
7
Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA.
8
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
9
Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
10
The Iowa City Veterans Affairs Medical Center, Iowa City, Iowa, USA.
11
The University of Iowa, Iowa City, Iowa, USA.
12
Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA.
13
Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
14
Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA haigwoon@ohsu.edu jalexander@paxvax.com.
15
PaxVax, Inc., San Diego, California, USA haigwoon@ohsu.edu jalexander@paxvax.com.

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.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 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.

KEYWORDS:

HIV vaccine; SHIV challenge; V1V2-specific antibody; adenovirus; adenovirus vector; correlate of protection; neutralizing antibody; rhesus macaque; simian human immunodeficiency virus; vaccine

PMID:
29093095
PMCID:
PMC5752948
DOI:
10.1128/JVI.01092-17
[Indexed for MEDLINE]
Free PMC Article

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