Last Updated: 27/05/2025
Identification & evaluation of novel malaria anti-gametocyte transmission blocking vaccine candidate antigens
Objectives
The overall goal of this application is to identify and describe novel candidate antigens for an anti-gametocyte transmission blocking vaccine (TBV) for human falciparum malaria. This proposal will apply the whole proteome differential screening platform to interrogate the gametocyte proteome with already collected plasma from Kenyan adolescents/adults with and without resistance to peripheral microscopic gametocytemia (as well as from a second cohort of Kenyan children in which will enable the quantification of sub-microscopic gametocytemia) to identify parasite genes that encode proteins uniquely recognized by the plasma of individuals resistant but not susceptible to gametocytemia.
The development of malaria vaccines that reduce transmission of the parasite and thereby substantially reduce the incidence of human malaria (parasite) infection has been widely recognized as a pivotal determinant of the success of future malaria control efforts. Vaccines to interrupt transmission have classically focused on interrupting gamete fertilization and ookinete invasion events in the mosquito vector. However, an alternative target exists, ie, the reduction of gametocytes (the transmissible form of malaria) in the human host. Evidence to support the feasibility of developing an anti- gametocyte as compared to an anti-gamete TBV springs from longitudinal field studies that have documented the acquisition of antibodies to gametocyte-infected erythrocytes in children and adults, and critically these antibodies were correlated with decreased gametocyte densities. Mosquito infection prevalence has also been found to decrease at low gametocyte densities, suggesting that vaccine-induced decreases in human gametocytemia may contribute to transmission blocking efforts by decreasing mosquito infection. The hypothesis is that a subset of these antigens, elicit antibodies that regulate gametocyte density. In preliminary data generated for this grant, a unique gametocyte antigen, antibodies to which (measured at the start of the high transmission season) predict significantly lower gametocytemia over the 18- week transmission season (P = 0.021) has already been identified in the Adolescent-Adult Kenyan cohort (JID, 2018). To complete the anti-gametocyte vaccine antigen discovery and validation process, following specific aims are proposed; 1) To identify additional novel anti-gametocyte TBV candidate antigens using our differential whole gametocyte proteome screening platform and relate antigen specific IgG responses to resistance to gametocytemia in two independent Kenyan cohorts, and in 2) the study will validate antigens identified in SA1 as suitable TBV candidates based on cellular location, surface expression and ability to elicit gametocyte controlling immune responses in in vitro assays. The deliverables of this application will include the identification of gametocyte specific antigens which are the targets antibodies that control gametocytemia. The discovery and validation of these antigens, will represent a landmark achievement on the path towards the development of an anti-gametocyte TBV.
Aug 2019 — Jul 2024
$2.65M
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