Designing a PfRIPR-based blood stage malaria vaccine: from understanding human antibody responses to structure-guided design

Malaria is regarded as one of the deadliest diseases of humanity, with over 600,000 deaths and two hundred million cases reported each year. The treatment and prevention of malaria rely on various measures, but progress has been hampered by the absence of a vaccine. In a significant advancement, the first two malaria vaccines, RTS,S and R21, have been licensed. However, the administration of multiple doses is required, and only 30-50% protection was achieved in phase III trials, with immunity waning over a few years. Therefore, the development of new vaccines is imperative. The parasites responsible for malaria first invade liver cells before progressing into the bloodstream. While current vaccines are designed to prevent liver invasion, targeting the blood stage has been identified as highly promising. Symptoms and transmission of malaria occur when parasites replicate in the blood, and these processes could be prevented by a vaccine that blocks red blood cell (RBC) invasion. The most deadly malaria parasite, Plasmodium falciparum, requires a five-component protein complex, PfPCRCR, to invade RBCs. Among these, PfRH5 has been studied extensively. An essential interaction is formed between PfRH5 and human basigin, and RBC invasion can be prevented by antibodies targeting PfRH5. In phase I clinical trials, vaccines based on PfRH5 have been shown to slow parasite growth in vaccinated volunteers, but the level of protective antibodies induced has not been sufficient to prevent malaria. Consequently, other PfPCRCR components must also be evaluated as potential blood-stage malaria vaccines.

This proposal is centered on PfRIPR, which is the central component of PfPCRCR. This large and complex protein has been identified as essential for RBC invasion and as a target for highly neutralizing antibodies. However, until recently, little information has been available regarding its structure and function. In 2023, the structure of PfRIPR was revealed, demonstrating its complex molecular architecture, which consists of a compact ‘core’ and an elongated ‘tail.’ It was also demonstrated that PfRIPR connects the PfRH5 protein, which interacts with the RBC membrane, to the PfCSS:PfPTRAMP complex located on the parasite surface. These insights now enable the application of structure-guided vaccine design techniques to PfRIPR. Structure-guided reverse vaccinology is used to design vaccine immunogens that elicit only neutralizing antibody responses. When vaccination is performed with a complex immunogen, antibodies are induced to bind to multiple regions of the immunogen. In the case of PfRIPR, only a subset of these antibodies has been found to prevent RBC invasion. Through structure-guided vaccinology, the regions of PfRIPR that induce the most effective antibodies will be identified, and these PfRIPR fragments will be tested as vaccine immunogens. To accomplish this, the latest methods will be employed to produce the first-ever panel of human PfRIPR-targeting monoclonal antibodies, which will be isolated from volunteers who have previously suffered from malaria. The antibodies that prevent RBC invasion by parasites will be identified, and structural studies will be conducted to determine where these neutralizing antibodies bind to PfRIPR and how they function. Finally, PfRIPR-based vaccine immunogens will be tested using a validated preclinical model involving rodent immunization, and the effectiveness of the induced antibodies in preventing RBC invasion will be assessed. The human-compatible vaccine adjuvant that induces the strongest immune response in combination with PfRIPR will be determined. Additionally, structure-guided rational design will be employed to generate the 15 individual modules that constitute PfRIPR as separate proteins. Those that bind neutralizing antibodies will be tested in the preclinical model alongside the most effective PfRH5-based vaccine immunogen. The outcomes of this study will include the development of the first human PfRIPR-targeting neutralizing monoclonal antibodies and the first fully tested PfRIPR-based vaccine immunogens, which will be ready for clinical testing in future malaria vaccines.

Project details

Immunology
Vaccines

Sep 2024 — Sep 2027

$1.28M

United Kingdom

mAbs for malaria vaccine development