| Summary: | <p><em>Plasmodium falciparum</em> malaria continues to evade control efforts in part through the complexity of its life cycle. While asexual parasites cause clinical illness in the human host, the highly specialized sexual stages transmit infection by uptake as intra-erythrocytic gametocytes from peripheral blood into a mosquito vector. Evidence from endemic settings suggests that naturally acquired immunity to sexual stage parasites may disrupt this cycle. Indeed in a vaccination model, antibodies to sexual stage antigens, ingested in the mosquito blood meal, can inhibit parasite growth in the insect midgut as judged by functional <em>ex vivo</em> experiments such as the standard membrane feeding assay (SMFA). To date, only a fraction of sexual stage antigens have been screened by this methodology; the list of proteins capable of eliciting the robust inhibitory responses required of a transmission-blocking vaccine (TBV) has changed little over the past 30 years. This thesis aims to strengthen the pre-clinical TBV pipeline by improving the characterization of known and novel candidate antigens. This study first establishes an independent and unbiased performance ranking of historical TBV antigens, and then uses this ranking as a benchmark to evaluate a diverse set of sexual stage proteins by heterologous expression and functional prioritization in SMFA. Finally, both known and novel proteins with exposure to human immunity are evaluated for seroreactivity in malaria-endemic Burkina Faso and Mali to better assess longitudinal antibody responses to potential TBVs. Proteins of little interest to vaccine development are considered as possible markers of gametocyte exposure in a Malian cohort with defined gametocyte positivity.</p>
|
|---|