Malaria transmission blocking vaccines (TBV) have been prioritized as an intervention to facilitate malaria elimination, but tools are required to support roll-out and evaluation. This thesis presents research that aids development of pre-fertilization TBV candidate 10C (amino acids 159-428 of Pfs48/45). Gametocytes must be detected to identify the infectious reservoir and support mosquito infectivity studies. I proposed filter papers as a novel, cost effective, practical approach for collection and detection of mRNA in low density gametocytes. Comparing 3 filter papers, 2 RNA extraction methods and 2 molecular detection techniques, I concluded Whatman 903 and Whatman 3MM filter papers, combined with guanidine based nucleic acid extraction and detection using QT-NASBA, were operationally most appealing and most sensitive. To identify natural recognition to 10C and 230CMB (a vaccine candidate including amino acids 444-730 of Pfs230), cross sectional surveys were performed sampling school children (n=510) in 3 countries. I demonstrated naturally exposed individuals had antibodies against 10C and 230CMB which displayed age dependent acquisition (p<0.03). Supportive datasets demonstrated 10C and 230CMB antibodies are significantly associated with >90% transmission reducing activity (TRA) (p<0.003). To assess the TRA of 10C-immunized rats against genetically diverse parasites, I sampled venous blood from naturally infected participants in Burkina Faso (n=53), and performed direct membrane feeding assay combined with serum replacement using European control serum spiked with IgG from 10C vaccinated rats. I demonstrated 10C vaccine induced IgG significantly reduced transmission in 4/5 participants who were infectious and infected >2 mosquitoes. This resulted in 80.9-100% reduction in oocyst prevalence (p<0.042), and 85.2-100% reduction in oocyst density (p<0.023). My research identified an attractive combination of tools for detecting low density gametocytes to facilitate sampling in remote field settings. I advanced progress of 6 10C vaccine candidate by indicating antibodies are acquired following natural malaria exposure and are associated with functional TRA.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:634519 |
| Date | January 2014 |
| Creators | Jones, S. C. P. |
| Publisher | London School of Hygiene and Tropical Medicine (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://researchonline.lshtm.ac.uk/2088685/ |
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