Research Project
10086740
ABSTRACT Plasmodium falciparum (Pf) sporozoite (SPZ)-based vaccines have shown excellent safety and vaccine efficacy (VE) in more than 25 clinical trials in Africa, Europe, and the US; Phase 3 assessment will begin in mid-2020. Our goal during the next decade is to develop, license, and deploy next generation SPZ vaccines with increased breadth, magnitude, and/or durability of VE and decreased cost of goods. Current assays and animal models do not offer an alternative to clinical trials for demonstrating whether a vaccine candidate exhibits superior performance to current SPZ vaccines. In this project we aim to develop in vitro assays and/or non-human primate (NHP) models that indicate a vaccine recipient will be protected against Pf malaria by a SPZ vaccine, and use them to show superiority of new SPZ vaccines. Success could come from increased understanding of the 1) immunological effector mechanisms of protective immunity (PI), 2) antigenic targets of PI, and/or 3) organs and cells involved in induction of the PI. Despite many studies, our understanding of these 3 areas has only modestly improved in the last 2 decades. In 2000 it was hypothesized that antigen-specific, tissue resident CD8+ T cells in the liver that recognized Pf peptides bound to class I HLA molecules on the surface of Pf-infected hepatocytes were the key cells mediating PI. This hypothesis led to a seminal study that demonstrated subcutaneous administration of PfSPZ Vaccine did not lead to induction of PfSPZ-specific, CD8+ T cells in the livers of immunized NHPs, but intravenous (IV) administration did. Based in large part on these results, a clinical trial of IV administration was initiated, and the trial showed 100% VE. Subsequently, >25 clinical trials of PfSPZ vaccines have shown that empirical alteration of PfSPZ/dose, number of doses, interval between doses, and method of attenuation can improve performance of PfSPZ vaccines. However, we have learned little about mechanisms and targets of PI, or the tissues involved in induction of PI. We believe this is because the effector activity takes place in the liver, and induction of PI also takes place in the central compartment, which is inaccessible in humans. Since our last major advance came from studying the livers of immunized NHPs, we think much more information can be gleaned from this approach, including elucidation of immunological effectors and targets, and comparison and down-selection of vaccine candidates. Therefore, in this project we will develop 3 models in outbred NHPs to study SPZ vaccine-induced immunity, and use the data generated in the models and systems biology assays to establish biomarkers and groups of assays (signature) that consistently predict whether a NHP will be protected, and establish blood surrogates of tissue markers. The best assays/ biomarkers/signatures will be assessed using serum, plasma, and PBMCs from protected/unprotected subjects assessed in clinical trials of PfSPZ vaccines. Finally, we will use the assays/biomarkers/signatures and model systems to screen newly developed SPZ vaccines, especially genetically altered vaccines, to down-select which should move to process development and clinical testing.
