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J Clin Invest. 2019 Mar 1;129(3):1314-1328. doi: 10.1172/JCI122110. Epub 2019 Feb 18.

Mucosal vaccine efficacy against intrarectal SHIV is independent of anti-Env antibody response.

Author information

1
Vaccine Branch, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA.
2
Institute of Human Virology, University of Maryland, Baltimore, Maryland, USA.
3
Cancer and Inflammation Program, Center for Cancer Research, NCI, Frederick, Maryland, USA.
4
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
5
Profectus, Inc., Sarasota, Florida, USA.
6
Biostatistics and Data Management Section, NCI, Rockville, Maryland, USA.
7
Nanotherapeutics, Inc., Alachua, Florida, USA.
8
Alchem Laboratories, Alachua, Florida, USA.
9
Tulane University, New Orleans, Louisiana, USA.

Abstract

It is widely believed that protection against acquisition of HIV or SIV infection requires anti-envelope (anti-Env) antibodies, and that cellular immunity may affect viral loads but not acquisition, except in special cases. Here we provide evidence to the contrary. Mucosal immunization may enhance HIV vaccine efficacy by eliciting protective responses at portals of exposure. Accordingly, we vaccinated macaques mucosally with HIV/SIV peptides, modified vaccinia Ankara-SIV (MVA-SIV), and HIV-gp120-CD4 fusion protein plus adjuvants, which consistently reduced infection risk against heterologous intrarectal SHIVSF162P4 challenge, both high dose and repeated low dose. Surprisingly, vaccinated animals exhibited no anti-gp120 humoral responses above background and Gag- and Env-specific T cells were induced but failed to correlate with viral acquisition. Instead, vaccine-induced gut microbiome alteration and myeloid cell accumulation in colorectal mucosa correlated with protection. Ex vivo stimulation of the myeloid cell-enriched population with SHIV led to enhanced production of trained immunity markers TNF-α and IL-6, as well as viral coreceptor agonist MIP1α, which correlated with reduced viral Gag expression and in vivo viral acquisition. Overall, our results suggest mechanisms involving trained innate mucosal immunity together with antigen-specific T cells, and also indicate that vaccines can have critical effects on the gut microbiome, which in turn can affect resistance to infection. Strategies to elicit similar responses may be considered for vaccine designs to achieve optimal protective efficacy.

KEYWORDS:

AIDS vaccine; Vaccines

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