Integrating human and non-human primate data to understand the acquisition of pre-erythrocytic immunity

This project investigates the impact of prior malaria exposure on the immune response to malaria vaccination, hypothesizing that this pre-existing malaria immunity is responsible for the hyporesponsiveness to vaccination seen in malaria-endemic areas. Using P. knowlesi in rhesus macaques as a model for acute malaria infection we can sample multiple tissues and analyze the immune response by flow cytometry, RNAseq, and scRNA-seq. Combining these technologies with readouts of immunogenicity and efficacy, we are identifying the cell types critical to the establishment of antimalarial immunity with the goal of identifying possible mechanisms of vaccine hyporesponsiveness after malaria exposure that could be overcome in malaria-exposed populations. This project pairs this tissue-specific non-human primate work with analysis of blood samples from human vaccine trials. This allows us to bridge the immunology taking place in the liver, spleen, and bone marrow of non-human primates with that taking place in the peripheral blood of humans, with the goal of getting a window into tissues inaccessible in humans. This project is a collaboration between several VGTI labs, ONPRC, University of Washington, Indiana University, and Seattle Children's Research Institute, and Fred Hutch.

A universal malaria T cell vaccine based on HLA-E presentation (NIH R01)

This project capitalizes on two recent discoveries by co-PI Caroline Junquiera (Institute for Research in Biomedicine, Switzerland): 1) that CD8 T cells can kill reticulocytes infected with the blood stages of P. vivax and; 2) the first immunopeptidomic analysis of Plasmodium CD8⁺ T cell antigens. This project pairs Dr. Junqueira’s mechanistic studies in difficult-to-obtain human samples with a unique CMV vector platform that elicits unconventional T cell responses in non-human primates and the P. cynomolgi model of malaria that closely recapitulates the unique lifecycle characteristics of P. vivax. Working between these systems we aim to understand the mechanistic minutiae of CD8⁺ T cell-mediated killing of Plasmodium at multiple stages and use this to develop a CD8⁺ T cell-based malaria vaccine that spans Plasmodium species and parasite lifecycle stages. This project is a collaboration with co-PI Caroline Junquiera and VGTI co-I's Drs. Daniel Malouli and Klaus Fruh.

Intracellular-acting antibodies for the prevention of malaria liver stage infection (NIH R21)

This project builds on a novel discovery that antibodies against a Plasmodium protein expressed at the liver stage (UIS3) are functional when administered after the sporozoite-stage parasites have established an intracellular infection in liver hepatocytes. We aim to understand the mechanism of this unconventional action by using monoclonal antibodies and active vaccination. These findings will support the rational design of superior vaccines and monoclonal antibody treatments that integrate a liver-stage protective component.

Testing anti-malarial monoclonal antibodies in a preclinical mouse model (BMGF)

This project with the Bill and Melinda Gates Foundation uses a humanized liver mouse model to test P. falciparum antibodies with the goal of advancing the best individual and combinations of antibodies to clinical trials. Key questions include: 1) What are the limits of anti-circumsporozoite (CSP) monoclonal antibody efficacy?; 2) Is there a benefit to combining non-CSP antibodies targeting various lifecycle stages of the parasite? and; 3) What is the predictive value of this model when translating results to controlled human malaria infection and field studies? This work involves many collaborations including with Dr. Simon Draper at Oxford University, Drs. Robert Seder and Joshua Tan at the National Institutes of Health, and the Gates Medical Research Institute.

Supporting the development of new tools for antimalarial drug discovery

In collaboration with scientists at the Novartis Institute of Tropical Disease, our team helps create and test transgenic P. cynomolgi parasites for functionality in rhesus and Japanese macaques. Notably, our partnership has developed a P. cynomolgi parasite that expresses the P. vivax version of the circumsporozoite protein, a primary vaccine target, allowing us to test human vaccine constructs in a non-human primate model.

Collaborations with MalarVx, Inc

We work closely with partners at MalarVx, Inc, a Seattle-based bio-pharmaceutical company aiming to address the myriad of challenges to creating a safe, affordable, and effective malaria vaccine. We utilize our expertise in malaria immunology and the humanized mouse model to advance our shared goals of interventions that allow sustainable control or elimination of malaria.