Mucosal vaccine efficacy against intrarectal SHIV is independent of anti-Env antibody response
Yongjun Sui, … , Robert C. Gallo, Jay A. Berzofsky
Yongjun Sui, … , Robert C. Gallo, Jay A. Berzofsky
Published February 18, 2019
Citation Information: J Clin Invest. 2019;129(3):1314-1328. https://doi.org/10.1172/JCI122110.
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Mucosal vaccine efficacy against intrarectal SHIV is independent of anti-Env antibody response

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.

Authors

Yongjun Sui, George K. Lewis, Yichuan Wang, Kurt Berckmueller, Blake Frey, Amiran Dzutsev, Diego Vargas-Inchaustegui, Venkatramanan Mohanram, Thomas Musich, Xiaoying Shen, Anthony DeVico, Timothy Fouts, David Venzon, James Kirk, Robert C. Waters, James Talton, Dennis Klinman, John Clements, Georgia D. Tomaras, Genoveffa Franchini, Marjorie Robert-Guroff, Giorgio Trinchieri, Robert C. Gallo, Jay A. Berzofsky

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Figure 6

Gut microbiome correlated with viral exposure, Tfh in MLNs, and newly migrated monocytes in the IELs of the colorectal tissues in the third study.

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Gut microbiome correlated with viral exposure, Tfh in MLNs, and newly mi...
(A) The diversity of the gut microbiome at the genus level was lower in the vaccinated animals compared with that of the naive controls. Mann-Whitney test was used for comparison. (B) Bacterial richness inversely correlated with viral acquisition. (C) The total plasma cells were lower in the rectal pinches 4 weeks after the last vaccination compared with those of the naive controls. (D) Bacterial richness positively correlated with Tfh cells in the MLNs. (E and F) Principal component analysis (PCA) plot of the gut microbiome at the genus level 1 month before vaccination (E) and 7 weeks after the last vaccination (F). The blue dots indicate vaccinated animals, while the yellow ones indicate the naive animals. (G and H) PCA-1 of the gut microbiome at the genus level was exported for each animal. The bacterial PCA-1 showed associations with the number of viral exposures (G), and Tfh in the MLNs (H). (I and J) CD14+DR– cells in the IELs of the colorectal tissues correlated with bacterial richness (I) and bacterial PCA-1 at the genus level (J). Spearman’s test was used to calculate the r and P values of the correlations.