Defining targets of protective immunity to plasmodium vivax using human monoclonal antibodies

The National Institute of Allergy and Infectious Diseases awarded Case Western Reserve University $631,401 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to develop human monoclonal antibodies targeting Plasmodium vivax malaria.

The research focuses on isolating and optimizing monoclonal antibodies (MAbs) that target the parasite's apical membrane protein 1 (AMA1) and circumsporozoite protein (CSP) to prevent and treat vivax malaria, which affects 3.3 billion people worldwide and causes at least 15 million documented clinical cases annually. The work includes screening phage display single-chain variable fragment libraries, applying AI-guided targeted mutations to improve binding affinity based on crystal structures, and modifying the Fc region of MAbs to enhance effector functions. Optimized MAbs will be tested in nonhuman primates before advancing to human clinical trials. The research aims to develop a cost-effective therapeutic that could provide protection for up to six months through a single subcutaneous injection, targeting high-risk populations including children, pregnant women, migrant workers, travelers, and military personnel.

Performance occurs in Cleveland, Ohio, with a period of performance from September 1, 2026, through August 31, 2027. The award is classified as a Project Grant, a standard assistance type under the program supporting innovative research addressing infectious disease threats.

Abstract

Our proposal aims to develop new methods for preventing and treating human malaria caused by the parasite plasmodium vivax (PV) by focusing on the use of human monoclonal antibodies (mabs). PV is the most widely distributed type of malaria, with 3.3 billion people at risk worldwide, resulting in at least 15 million documented clinical cases each year. PV can cause severe illness and death. We have isolated and characterized mabs that target the parasite's apical membrane protein 1 (AMA1) and protect against both liver and blood-stage infections. Our plan includes testing these mabs in nonhuman primates (NHP) before advancing to human trials in subsequent studies. To enhance the potency of mabs, we will implement several strategies: 1) screening a phage display single-chain variable fragment (SC-FV) library based on the VH and VL regions from this MAB, 2) applying targeted mutations guided by advanced AI algorithms to improve binding to PVAMA1, based on crystal structures of PVAMA1 with its ligand, RON2, and 3) modifying the FC region of the MAB to boost its effector functions. Additionally, we aim to isolate mabs that target the PV circumsporozoite (CSP) protein, which is essential for infecting human liver cells. The optimized or newly developed mabs targeting PVAMA1 or pvcsp will also be tested in NHP to identify those mabs with high efficacy at low concentrations. This will lay the groundwork for human clinical trials to develop a cost-effective, efficacious human mabs to protect people living in endemic areas and travelers to these regions. These mabs could be used for treating severely ILL patients or for prophylaxis against vivax malaria, where a single subcutaneous injection could provide protection for up to six months for high-risk groups, such as children, pregnant women, migrant workers, travelers, and military personnel.