Characterisation of Plasmodium Sexual Stage Antigens as Targets of Transmission Blocking Immunity

Muthui, Michelle Kathini (2021). Characterisation of Plasmodium Sexual Stage Antigens as Targets of Transmission Blocking Immunity. PhD thesis The Open University.



A promising strategy to achieve malaria elimination is by interrupting transmission using transmission-blocking vaccines (TBVs). TBVs target the sexual or mosquito stages of the malaria parasite to inhibit parasite development within the mosquito. To date, however, there are only three lead TBV candidate antigens Pfs230, Pfs48/45 and Pfs25 in various stages of clinical development. This project sought to identify novel antigens expressed on gametocytes, gametes and ookinetes with potential as TBV candidates. Furthermore, naturally acquired immune responses (NAI) to gametocytes have been described and have the potential to guide the development and the implementation of TBVs Therefore, this work also sought to improve our understanding of NAI to gametocytes. This was achieved by (1) carrying out a systematic review and meta-analysis of studies investigating NAI to the lead gametocyte-stage TBV candidates, and (2) assessing the changing patterns of gametocyte carriage at the Kenyan coast over time.

Key indicators of gametocytaemia and anti-gametocyte immunity were identified and evaluated against a novel panel of gametocyte antigens. These antigens, together with a separate set of gamete and ookinete stage antigens, were identified as potential TBV candidates using a combination of bioinformatic tools and laboratory investigations. Immunoprofiling of the identified gametocyte candidates provided evidence that stable responses can be generated to sexual stage antigens. Moreover, antigens that could serve as serological markers of recent gametocyte exposure, in particular PEB-P (PF3D7_0303900), were also identified. The ability of the sexual stage antigens to induce transmission-blocking immunity was also assessed. Promising candidates identified included PBCPP2 (PBANKA_0719100), a novel conserved and uncharacterised P. berghei protein), and SOAP (PBANKA_1037800). Further characterisation of these antigens may yield new candidates to add to the TBV development pipeline.

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