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 March 1, 2019; First published February 18, 2019
Citation Information: J Clin Invest. 2019;129(3):1314-1328. https://doi.org/10.1172/JCI122110.
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Categories: Research Article Vaccines

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 3

The mucosal vaccine mediated delay of viral acquisition against repeated low-dose SHIV challenges in the absence of anti-Env antibody responses in the third cohort study.

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The mucosal vaccine mediated delay of viral acquisition against repeated...
(A) Schematic illustration of mucosal vaccination and challenge protocol of the third cohort study. Twenty-eight macaques were distributed into either a vaccine group (n = 21) or naive group (n = 7). MVA-SIV with adjuvant combination of triple TLR (TLR2, -3, and -9) agonists plus IL-15 was given intrarectally, while FLSC with mLT in nanoparticle format was given orally. (B) Infection-free curves for the vaccinated and naive groups. A Kaplan-Meier curve analysis was performed after a series of 8 weekly intrarectal challenges. (C and D) The plasma VLs of each of the infected animals (C) and the geometric mean and SEM of the vaccinated and naive groups. (E) Anti-HIV humoral responses in the colorectal samples (rectal swab, rectal pinches, MLNs) 4 weeks after the last vaccination were measured. No gp120-specific IgG or IgA was detected. HIV Env–specific B cell responses in the rectal pinches 4 weeks after the last vaccination did not change. Mann-Whitney test was used to compare the 2 groups (n = 6, and 12 for naive and vaccinated groups). †MVA, modified vaccinia Ankara, plus adjuvant (triple TLR [TLR2, -3, and -9] agonists) plus IL-15. ††FLSC, full-length single chain, cross-linked gp120-CD4 complexes. IR, intrarectal; mLT, mutant heat-labile E. coli toxin (R192G); NS, not significant.