Friday, April 4, 2025
4/4/2025
Species-transcending prevention of mosquito vector infection - Malaria remains a leading cause of human disease and suffering worldwide, with more than 249 million cases of malaria resulting in approximately 608,000 deaths in 2022. The majority of cases are caused by several species of vector-borne parasites of the genus Plasmodium, with Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) accounting for nearly all human infections worldwide. The development of effective vaccines faces significant hurdles from the diversity inherent to multiple species of causative agents, along with diversity existing within species. Vaccines that can provide efficacy against more than one species of Plasmodium do not exist, therefore accounting for the diversity of malaria currently requires a multi-antigen or multi-vaccine approach. Given the infrastructure and economic constraints of delivering a vaccine in endemic areas, a bespoke vaccine approach local to an area is not feasible and remains a significant roadblock to global eradication efforts. Our recent work on vector transmission biology has led to the discovery of a novel vaccine target called HAP2p which, together with its known paralog HAP2, opened a new path for vector stage vaccine development. HAP2 and HAP2p vaccines would block infection of the mosquito vector, breaking the life cycle, and thus, would be powerful tools for eradication. Importantly, we provide experimental proof of concept that antibodies against these two targets can mediate transmission reducing activity (TRA) across the species divide and are active against both Pf and Pv, raising the possibility of developing a universal transmission blocking vaccine (TBV) with worldwide coverage and overcoming the major barriers noted above. We propose an integrated research program that combines world-class expertise in antigen and mAb technologies, malaria vector stage biology, and structure-guided vaccinology. We aim to develop potent TRA-mediating monoclonal antibodies (mAbs) defined by their ability to block vector infection with species-transcending activity. In parallel, we will characterize human naturally acquired immunity against these mosquito stage targets in subjects with previous malaria infection. Potent mAbs, derived from both humans and mice, will serve as prototypes for structure-guided vaccine design. We will define the structural features of epitope recognition which we will use to optimize our antigens, culminating in new structurally designed HAP2 and HAP2p vaccines that elicit exceptionally potent species transcending vector transmission blocking. This comprehensive approach has proven exceptionally powerful in developing potent vaccine candidates in a variety of species, and we hypothesize that this structural vaccinology approach can optimize HAP2 and HAP2p vaccine candidates with superior stability, antigenicity, and vaccine efficacy. If successful, this research will culminate in the first pan- Plasmodium species vaccine candidate, one that can be deployed worldwide. A single optimal universal transmission blocking vaccine would provide an extraordinarily powerful eradication tool which would be transformational in the fight to eradicate malaria.
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