Our previous work has shown that antigens adjuvanted with ligands specific for Toll-like receptor 4 (TLR4) and TLR7/8 encapsulated in poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles (NPs) induce robust and durable immune responses in mice and macaques. We investigated the efficacy of these NP adjuvants in inducing protective immunity against simian immunodeficiency virus (SIV). Rhesus macaques (RMs) were immunized with NPs containing TLR4 and TLR7/8 agonists mixed with soluble recombinant SIVmac239-derived envelope (Env) gp140 and Gag p55 (protein) or with virus-like particles (VLPs) containing SIVmac239 Env and Gag. NPadjuvanted vaccines induced robust innate responses, antigen-specific antibody responses of a greater magnitude and persistence, and enhanced plasmablast responses compared to those achieved with alum-adjuvanted vaccines. NP-adjuvanted vaccines induced antigen-specific, long-lived plasma cells (LLPCs), which persisted in the bone marrow for several months after vaccination. NP-adjuvanted vaccines induced immune responses that were associated with enhanced protection against repeated low-dose, intravaginal challenges with heterologous SIVsmE660 in animals that carried TRIM5α restrictive alleles. The protection induced by immunization with protein-NP correlated with the prechallenge titers of Env-specific IgG antibodies in serum and vaginal secretions. However, no such correlate was apparent for immunization with VLP-NP or alum as the adjuvant. Transcriptional profiling of peripheral blood mononuclear cells isolated within the first few hours to days after primary vaccination revealed that NP-adjuvanted vaccines induced a molecular signature similar to that induced by the live attenuated yellow fever viral vaccine. This systems approach identified early blood transcriptional signatures that correlate with Envspecific antibody responses in vaginal secretions and protection against infection. These results demonstrate the adjuvanticity of the NP adjuvant in inducing persistent and protective antibody responses against SIV in RMs with implications for the design of vaccines against human immunodeficiency virus (HIV).
Bibliographical noteFunding Information:
We thank all animal staff at the Yerkes National Primate Research Center at Emory University, especially Christopher Souder, Robert Sheffield, Stephanie Ehnert, and Elizabeth Strobert, in helping out with the macaque study. We acknowledge Steve Bosinger, Nirav Patel, and Greg Tharp at the Yerkes Genomic Core for help with the microarray assay in the transcriptomics study. We acknowledge Benton Lawson from the CFAR Virology Core for measurement of the SIV load and Kenneth Rogers for TRIM5+ genotyping. We thank Robert L. Wilson for excellent technical assistance in processing the secretions and measuring mucosal antibodies. We thank Tianwei Yu for help with statistical analysis. We thank the CFAR Immunology/Emory Vaccine Center Flow Cytometry Core. We acknowledge the NIH AIDS Reagent Program for Gag and Env peptide pool reagents. The CFAR Immunology/Emory Vaccine Center Flow Cytometry Core is supported by an NIH grant (P30 A050509). This work was supported by grants NIH P51-RR000165 and P51-OD011132 to the Yerkes National Primate Research Center. Studies were also supported by grants P01-AI096187 (principal investigator, Eric Hunter) and R01-AI58706 (principal investigator, Cynthia A. Derdeyn) from the National Institutes of Health and a Collaboration for AIDS Vaccine Discovery (CAVD) grant (principal investigator, Bali Pulendran) from the Bill and Melinda Gates Foundation.
© 2017 American Society for Microbiology.
Copyright 2018 Elsevier B.V., All rights reserved.
- Antibody responses
- HIV vaccines
- Plasma cells
- Rhesus macaques
- TLR ligands