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J Virol. 2018 Jul 17;92(15). pii: e00281-18. doi: 10.1128/JVI.00281-18. Print 2018 Aug 1.

Control of Heterologous Simian Immunodeficiency Virus SIVsmE660 Infection by DNA and Protein Coimmunization Regimens Combined with Different Toll-Like-Receptor-4-Based Adjuvants in Macaques.

Author information

1
Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.
2
Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.
3
AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
4
Duke Human Vaccine Institute, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
5
Duke Human Vaccine Institute, Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA.
6
Duke Human Vaccine Institute, Department of Molecular Genetics, Duke University Medical Center, Durham, North Carolina, USA.
7
Duke Human Vaccine Institute, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
8
Ragon Institute of MGH, MIT, and Harvard University, Cambridge, Massachusetts, USA.
9
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
10
Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
11
Inovio Pharmaceuticals, Inc., Plymouth Meeting, Pennsylvania, USA.
12
Infectious Disease Research Institute, Seattle, Washington, USA.
13
Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA.
14
Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
15
Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA George.pavlakis@nih.gov Barbara.felber@nih.gov.
16
Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA George.pavlakis@nih.gov Barbara.felber@nih.gov.

Abstract

We developed a method of simultaneous vaccination with DNA and protein resulting in robust and durable cellular and humoral immune responses with efficient dissemination to mucosal sites and protection against simian immunodeficiency virus (SIV) infection. To further optimize the DNA-protein coimmunization regimen, we tested a SIVmac251-based vaccine formulated with either of two Toll-like receptor 4 (TLR4) ligand-based liposomal adjuvant formulations (TLR4 plus TLR7 [TLR4+7] or TLR4 plus QS21 [TLR4+QS21]) in macaques. Although both vaccines induced humoral responses of similar magnitudes, they differed in their functional quality, including broader neutralizing activity and effector functions in the TLR4+7 group. Upon repeated heterologous SIVsmE660 challenge, a trend of delayed viral acquisition was found in vaccinees compared to controls, which reached statistical significance in animals with the TRIM-5α-resistant (TRIM-5α R) allele. Vaccinees were preferentially infected by an SIVsmE660 transmitted/founder virus carrying neutralization-resistant A/K mutations at residues 45 and 47 in Env, demonstrating a strong vaccine-induced sieve effect. In addition, the delay in virus acquisition directly correlated with SIVsmE660-specific neutralizing antibodies. The presence of mucosal V1V2 IgG binding antibodies correlated with a significantly decreased risk of virus acquisition in both TRIM-5α R and TRIM-5α-moderate/sensitive (TRIM-5α M/S) animals, although this vaccine effect was more prominent in animals with the TRIM-5α R allele. These data support the combined contribution of immune responses and genetic background to vaccine efficacy. Humoral responses targeting V2 and SIV-specific T cell responses correlated with viremia control. In conclusion, the combination of DNA and gp120 Env protein vaccine regimens using two different adjuvants induced durable and potent cellular and humoral responses contributing to a lower risk of infection by heterologous SIV challenge.IMPORTANCE An effective AIDS vaccine continues to be of paramount importance for the control of the pandemic, and it has been proven to be an elusive target. Vaccine efficacy trials and macaque challenge studies indicate that protection may be the result of combinations of many parameters. We show that a combination of DNA and protein vaccinations applied at the same time provides rapid and robust cellular and humoral immune responses and evidence for a reduced risk of infection. Vaccine-induced neutralizing antibodies and Env V2-specific antibodies at mucosal sites contribute to the delay of SIVsmE660 acquisition, and genetic makeup (TRIM-5α) affects the effectiveness of the vaccine. These data are important for the design of better vaccines and may also affect other vaccine platforms.

KEYWORDS:

A/K variant; ADCC; ADCD; ADNP; Ab glycosylation structures; DNA; HIV; QS21; SIVmac251; SIVsmE660; SIVsmE660 T/F; T cell responses; TLR4; TLR7; TRIM-5α; V2 responses; acquisition delay; adjuvant; binding antibody; correlate of viremia control; cyclic V2; humoral responses; immunization; linear peptide; mucosal responses; neutralizing antibody; protein; reduced risk of infection; repeated low-dose rectal challenge; rhesus macaque; scaffolded gp70-V1V2; systems serology; vaccination; vaccine; viremia control

PMID:
29793957
PMCID:
PMC6052320
DOI:
10.1128/JVI.00281-18
[Indexed for MEDLINE]
Free PMC Article

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