A Dual TLR Agonist Adjuvant Enhances the Immunogenicity and Protective Efficacy of the Tuberculosis Vaccine Antigen ID93

Abstract

With over eight million cases of tuberculosis each year there is a pressing need for the development of new vaccines against Mycobacterium tuberculosis. Subunit vaccines consisting of recombinant proteins are an attractive vaccine approach due to their inherent safety compared to attenuated live vaccines and the uniformity of manufacture. Addition of properly formulated TLR agonist-containing adjuvants to recombinant protein vaccines enhances the antigen-specific CD4+ T cell response characterized by IFN-γ and TNF, both of which are critical for the control of TB. We have developed a clinical stage vaccine candidate consisting of a recombinant fusion protein ID93 adjuvanted with the TLR4 agonist GLA-SE. Here we examine whether ID93+GLA-SE can be improved by the addition of a second TLR agonist. Addition of CpG containing DNA to ID93+GLA-SE enhanced the magnitude of the multi-functional TH1 response against ID93 characterized by co-production of IFN-γ, TNF, and IL-2. Addition of CpG also improved the protective efficacy of ID93+GLA-SE. Finally we demonstrate that this adjuvant synergy between GLA and CpG is independent of TRIF signaling, whereas TRIF is necessary for the adjuvant activity of GLA-SE in the absence of CpG.

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).…”

Nanoparticle approaches against bacterial infections

“…More importantly, nanoparticles allow for programmable presentation of adjuvants and antigens to immune cells for desirable responses. For example, combinations of TLR agonists, as opposed to a single adjuvant, have been concurrently loaded into nanoparticles to mimic the combinatorial TLR activation that occurs in natural infections, therefore resulting in more vigorous immune responses 126–128 . In addition, nanoparticles allow for the sequential presentation of antigens and adjuvants to be programmed for optimal immune responses.…”

Tuberculosis Vaccine Types and Timings

“…When delivered in a potent glucopyranosyl lipid adjuvant (GLA), this fusion vaccine gives excellent protection in animal models (38,39).…”