Toll-Like Receptor 7/8 (TLR7/8) and TLR9 Agonists Cooperate To Enhance HIV-1 Envelope Antibody Responses in Rhesus Macaques

Abstract

The development of a vaccine that can induce high titers of functional antibodies against HIV-1 remains a high priority. We have developed an adjuvant based on an oil-in-water emulsion that incorporates Toll-like receptor (TLR) ligands to test whether triggering multiple pathogen-associated molecular pattern receptors could enhance immunogenicity. Compared to single TLR agonists or other pairwise combinations, TLR7/8 and TLR9 agonists combined were able to elicit the highest titers of binding, neutralizing, and antibody-dependent cellular cytotoxicity-mediating antibodies against the protein immunogen, transmitted/ founder HIV-1 envelope gp140 (B.63521). We further found that the combination of TLR7/8 and TLR9 agonists was associated with the release of CXCL10 (IP-10), suggesting that this adjuvant formulation may have optimally stimulated innate and adaptive immunity to elicit high titers of antibodies. IMPORTANCECombining TLR agonists in an adjuvant formulation resulted in higher antibody levels compared to an adjuvant without TLR agonists. Adjuvants that combine TLR agonists may be useful for enhancing antibody responses to HIV-1 vaccines.

Beyond antigens and adjuvants: formulating future vaccines

“…Covalent heterodimers of TLR2 and TLR9 agonists have been shown to elicit enhanced NF-κB expression in DCs relative to stimulation with physical mixtures of these ligands in vitro, and this response may be linked to enforced spatial colocalization of TLRs and their associated adaptor molecules (76). The use of particulate or oil-in-water formulations also facilitates combination delivery of danger signals in mouse and NHP models (73,77). PLGA nanoparticles encapsulating TLR4 and TLR7 agonists were found to synergistically promote strong antibody titers and increase the number of GCs following vaccination in mice, while avoiding the toxicity of the free adjuvant compounds (48).…”

“…For example, a cancer vaccine based on irradiated flagellin-and ovalbuminexpressing tumor cells was shown to elicit potent T cell responses in mice, dependent on both TLR5 and the Nod-like receptors NLRC4 and NAIP5 (72). In NHPs, combinations of TLR7/8 and TLR9 agonists enhanced the induction of binding and neutralizing antibody titers against an HIV envelope immunogen (73). High-throughput screening has begun to be applied to the problem of defining optimal danger signal combinations, and in vitro assays predictive of in vivo vaccine performance should enable more facile exploration of the vast parameter space of possible adjuvant combinations (74).…”

Combined HIV-1 Envelope Systemic and Mucosal Immunization of Lactating Rhesus Monkeys Induces a Robust Immunoglobulin A Isotype B Cell Response in Breast Milk

“…The intramuscular (i.m.) component of the combined boost consisted of 100 g HIV Env C.1086 gp120 and 250 l of the adjuvant STR8S-C (squalene-containing STS base adjuvant plus R848 plus oCpGs) (21). i.n.…”

Dietary gluten and the development of celiac disease and type 1 diabetes

“…The evidence is both epidemiologic and genetic. The Toll-like receptors (TLR) 7 and 8 genes, encoding for the innate receptors for single-stranded viral RNA and related to the antiviral responses, 71 have been found to be associated with CD. 72 Similarly, the TLR3 and TLR4 genes, which play an important role in the innate immune response triggered by viral infection, are responsible for the development of both T1DM and CD.…”