Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5α Restrictive Macaques

Abstract

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 TRIM5␣ 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 persis-

Polymer-based nanoparticles loaded with a TLR7 ligand to target the lymph node for immunostimulation

“…The exclusive presence of the PEG hydrophilic moieties in R848-NPb batches resulted in lower affinity of the drug to the polymer matrix leading therefore to lower encapsulation rates. In the literature, several studies relate the encapsulation of R848 or analogues in polymer nanoparticles either alone or co-encapsulated with antigens or adjuvants (Cruz et al, 2012;Ilyinskii et al, 2014;Kasturi et al, 2017Kasturi et al, , 2011Seth et al, 2017;Tacken et al, 2011;Tel et al, 2013). When encapsulation rates are given by the authors, the values are ranging from 1.2 to 6.4 μg/mg of NP.…”

Modulating the immune system through nanotechnology

“…More recently, Kasturi et al reported enhanced protection of non-human primates against up to 12 low-dose intravaginal challenges with SIVsmE660. Interestingly, these results were achieved using PLGA-based NPs loading TLR 4/7/8 ligands as adjuvants, in a physical mixture either with the soluble immunogens Env and Gag or displayed in virus-like particles [185]. …”

Adjuvants

“…Kasturi and Pulendran (30) investigated nanoparticles that encapsulated TLR4 and TLR 7/8 agonists and combined with SIV Env and Gag expressed as soluble proteins or VLPs. The nanoparticle-TLR formulation, in comparison to alum adjuvant, significantly enhanced the magnitude and persistence of antigen-specific antibody responses.…”