ABSTRACT
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.