Saturday, November 23, 2024
11/23/2024
PROJECT SUMMARY An effective vaccine is likely required to reduce the global burden of tuberculosis (TB). Development of one has been difficult, in part due to the ability for Mycobacterium tuberculosis (Mtb) to reside for long periods within host antigen (Ag) presenting cells (APCs), where it expresses a multitude of Ags, many of which have been targeted for vaccine development. Recombinant Ags have been the focus of numerous vaccines, however outcomes to clinical testing have been less than ideal. This R61/R33 proposal in response to program announcement RFA-AI-21-007: “Innovation for Tuberculosis Vaccine Discovery” will leverage a next- generation, vaccine adjuvant system that induces seamless particle-formation of recombinant Ags to assess a multivalent Mtb vaccine. A new immunization paradigm will be advanced, based on combining (via simple mixing) well-characterized soluble protein Mtb Ags with a vaccine adjuvant that induces spontaneous nanoliposome-Ag particleization. Liposomes that contain small amounts of cobalt porphyrin-phospholipid (CoPoP) bind to his-tagged Ags via spontaneous insertion of the his-tag into the bilayer. This approach gives rise to rapid particleization that is stable in biological media. Recombinant Ags are simply admixed with CoPoP liposomes at the time of vaccination (without further purification) to be fully converted for display on the surface of ~100 nm particles. CoPoP recently completed phase I and entered phase II clinical testing as a key component of a COVID-19 vaccine (NCT04783311). CoPoP also induces potent cellular responses using short MHC-I restricted peptide immunogens at nanogram peptide dosing in mice; multiple orders of magnitude lower dosing compared to Ag doses with conventional vaccine adjuvants. Preliminary data demonstrates that multivalent particles decorated with the established Mtb Ags Ag85A, CFP10, ESAT-6, HSP-X, and Mpt64 induce protective cellular immune responses in mice. The underlying hypothesis is that multivalent, particle- based Mtb Ags will induce a potently protective immune responses more effective than Bacillus Calmette– Guérin (BCG) in multiple small animal models of TB infection. The R61 phase of the proposal will use mouse models of TB infection to: (1) Develop well-characterized, multivalent Mtb Ag particles; (2) Assess how particle parameters impact functional immunogenicity; and (3) Compare the efficacy of intranasal and intramuscular particle administration. Ambitious and quantitative R61-R33 transitional milestones are proposed based on A) generating well-characterized particles with storage stability with B) multivalent Ags providing superior protection relative to the best single Ag particles with C) superiority to conventional BCG immunization in mice. The R33 phase of the project will involve (4) assessing the vaccine in the guinea pig model, and (5) developing and assessing the efficacy and toxicity of a lyophilized thermostable version of the vaccine.
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