Our U01 project supports NIAID?s mission to better understand, treat, and prevent infectious diseases by focusing on pre-erythrocytic malaria vaccine development. Vaccines that efficiently stop the Plasmodium sporozoite (spz) or liver stage can provide complete protection against malarial disease and will enable eradication efforts. There are currently no FDA-approved malaria vaccines for use in humans although repeated dosing with intravenously-administered attenuated spz has shown sterile protection against challenge in multiple Phase 1-2 clinical trials. Recently, CD8+ T cells that reside in the liver, namely liver resident memory T cells or TRM cells, have been identified as key cell types in protection against liver stage infection. Vaccine strategies that increase liver TRM cells and can be readily adapted to clinical use are therefore critically needed. Such vaccines could bolster CD8+ T cell immunity and may result in T cell-focused vaccines that achieve durable, high-grade protection for persons in endemic and non-endemic regions. Our laboratory has developed a two-dose vaccine that uses a DNA prime followed by an attenuated spz boost or ?trapping dose? that increases liver TRM cells and achieves sterile protection. This project aims to improve upon spz-based trapping by developing an orally-administered nanoparticle-based trapping vaccine. The University of Washington will collaborate with Johns Hopkins University to develop this more easily manufactured, more easily deliverable, and less expensive vaccine. In Project 1, we will define a threshold of Pf antigen-specific TRM cells needed to achieve protection using DNA prime/sporozoite trapping. In Project 2, we will optimize nanoparticles for liver- specific delivery and expression profile in hepatocytes using a variety of nanoparticle compositions, sizes, surface characteristics, and formulation strategies. In Project 3, we will evaluate the optimized nanoparticles in prime-and-trap vaccination in mice and non-human primates for safety, tolerability, immunogenicity, and efficacy. If successful, this project will deliver an optimized prime-and-oral trap vaccine rationally designed to elicit complete protection against the Plasmodium liver stage.
Malaria vaccines that block the parasite lifecycle in the liver depend on cytotoxic T cells that kill infected hepatocytes. This project aims to develop a two-dose vaccine regimen that significantly increases the formation of liver resident memory T cells in the liver using an established mode of priming coupled to a novel, orally-delivered booster vaccine. This project will help improve the efficacy of malaria vaccines and accelerate work toward a protective malaria vaccine.
