Vaccine induction of antibodies and tissue-resident CD8+ T cells enhances protection against mucosal SHIV-infection in young macaques
Caroline Petitdemange, … , David Masopust, Bali Pulendran
Caroline Petitdemange, … , David Masopust, Bali Pulendran
Published February 21, 2019
Citation Information: JCI Insight. 2019;4(4):e126047. https://doi.org/10.1172/jci.insight.126047.
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Research Article AIDS/HIV Vaccines

Vaccine induction of antibodies and tissue-resident CD8+ T cells enhances protection against mucosal SHIV-infection in young macaques

Abstract

Antibodies and cytotoxic T cells represent 2 arms of host defense against pathogens. We hypothesized that vaccines that induce both high-magnitude CD8+ T cell responses and antibody responses might confer enhanced protection against HIV. To test this hypothesis, we immunized 3 groups of nonhuman primates: (a) Group 1, which includes sequential immunization regimen involving heterologous viral vectors (HVVs) comprising vesicular stomatitis virus, vaccinia virus, and adenovirus serotype 5–expressing SIVmac239 Gag; (b) Group 2, which includes immunization with a clade C HIV-1 envelope (Env) gp140 protein adjuvanted with nanoparticles containing a TLR7/8 agonist (3M-052); and (c) Group 3, which includes a combination of both regimens. Immunization with HVVs induced very high–magnitude Gag-specific CD8+ T cell responses in blood and tissue-resident CD8+ memory T cells in vaginal mucosa. Immunization with 3M-052 adjuvanted Env protein induced robust and persistent antibody responses and long-lasting innate responses. Despite similar antibody titers in Groups 2 and 3, there was enhanced protection in the younger animals in Group 3, against intravaginal infection with a heterologous SHIV strain. This protection correlated with the magnitude of the serum and vaginal Env-specific antibody titers on the day of challenge. Thus, vaccination strategies that induce both CD8+ T cell and antibody responses can confer enhanced protection against infection.

Authors

Caroline Petitdemange, Sudhir Pai Kasturi, Pamela A. Kozlowski, Rafiq Nabi, Clare F. Quarnstrom, Pradeep Babu Jagadeesh Reddy, Cynthia A. Derdeyn, Lori M. Spicer, Parin Patel, Traci Legere, Yevgeniy O. Kovalenkov, Celia C. Labranche, François Villinger, Mark Tomai, John Vasilakos, Barton Haynes, C. Yong Kang, James S. Gibbs, Jonathan W. Yewdell, Dan Barouch, Jens Wrammert, David Montefiori, Eric Hunter, Rama R. Amara, David Masopust, Bali Pulendran

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Figure 1

Vaccination that induces both antibody and tissue-resident CD8+ T cell responses confer enhanced protection against mucosal SHIV infection in young macaques.

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(A) Vaccination groups and immunogens: 65 female RMs of ages 5–15 years were divided into 3 experimental groups. Animals in Group 1 were sequentially immunized with replication competent recombinant heterologous viral vectors (HVV) VSV, VV, and Ad5 each encoding SIVmac239 Gag protein. Animals in Group 2 were immunized with recombinant gp140 C.1086 K160N trimeric Env protein adjuvanted with the TLR7/8 agonist, 3M-052, encapsulated in PLGA nanoparticles (NP). Group 3 animals received immunizations with both HVV and adjuvanted Env protein, according to schedule indicated. (B) Study overview. Animals were bled 4 weeks before primary immunization for baseline analysis. Immunization was performed with each viral vector or adjuvanted Env protein on the weeks indicated by arrows. At week 54, 4 animals in each group were sacrificed to evaluate prechallenge immune responses. Starting at week 58, the remaining animals were challenged weekly by the intravaginal route a total of 10 times or until infected with SHIV-1157ipd3N4, which expresses a heterologous Clade C Env. (C) Rate of infection acquisition in all vaccinated animals in comparison with the 15 unvaccinated controls. The gray section highlights SHIV acquisition up to 5 challenges. (D) Acquisition of infection in animals <8 years old (dotted line) and animals >8 years old (solid line). When compared with young unvaccinated controls, younger animals (<8 years) given the HVV, Env + NP vaccine regimen were found to be significantly protected using the Mantel-Cox Log-rank test or Gehan-Breslow Wilcoxon test for early time points.