SBIR/STTR Award attributes
We propose to further enhance Plasmodium falciparum (Pf) Sporozoite (SPZ)-based vaccines against malaria that are the only immunogens proven to induce rt90% short term (3 weeks) and long term (at least 14 months) protection against controlled human malaria infection with Plasmodium falciparum (Pf) in humans. Using a unique glycolipid adjuvant 7DW8-5, the goal is to prolong the duration of vaccine efficacy (VE) and to increase efficacy in endemic settings. In the mouse model using P. yoelii (Py) sporozoites (SPZ) we achieved rt 80% protection at 16 weeks with 2 dose and 4 dose accelerated regimens of irr PySPZ plus 7DW8-5 adjuvant administered by direct venous inoculation (DVI) representing a 2-fold enhancement over irr PySPZ without adjuvant. The adjuvant could be mixed with irr PySPZ. High level (rt80%) protection of mice persisted at 16 weeks with irr PySPZ by DVI, in the presence of 7DW8-5, but not by non-DVI routes. Manufacturing of 7DW8-5 under cGMPs was completed and in a pilot study with P. knowlesi (Pk) SPZ, irr PkSPZ we achieved 50% VE and no improvement with the adjuvant, likely attributable to sub-optimal comparative dose or dosing regimens, or the short-term infectious challenge design. Due to the excellent demonstrable safety record of the combined SPZ-adjuvant vaccine in NHPs, and comparable bioactivity on co- culture human iNKT cells in vitro, we propose further optimization of dosing regimens for durable immunity in pig-tailed macaques, the natural host for Pk, along with protection studies to assess adjuvant effects on chemically attenuated (PySPZ-chemoprophylaxis vaccine CVac) and genetically attenuated (PySPZ-LARC) in mice. Using humanized HISA2/ hCD1d mice possessing functional human CD8+ T cells and human iNKT cells (cellular targets of 7DW8-5) we will investigate whether a PfSPZ-7DW8-5 combination immunogen can enhance the human CD8+ T-cell response to PfSPZ. Adjuvant-associated biomarker discovery studies are also planned in mice. Towards clinical use of the PfSPZ-7DW8-5 combination vaccine, we will establish stability criteria and formulation methodologies for 7DW8-5, and further comparability testing of GMP-grade 7DW8-5 for bioactivity in vitro as a lot release attribute and humanized HISA2/ hCD1d mice in vivo, compile a pre-IND package in preparation for pre-clinical and clinical evaluation of the safety and efficacy of 7DW8-5-PfSPZ combinations, and manufacture GMP 7DW8-5 for clinical use. Because studies outlined in this project will be conducted with clinical grade, well characterized 7DW8-5, a positive outcome in our studies will place us in a position to rapidly design and conduct formal pre-clinical toxicology and/or biodistribution studies in compliance with FDA mandates for a speedier path to the clinic. Completion of this project will mark the first development of an adjuvant for a live eukaryotic parasite vaccine.
