Structural characterisation of antigens for malaria transmission-blocking vaccines

Thesis

Malaria is a deadly infectious disease caused by Plasmodium parasites. These have a complex life cycle involving both sexual and asexual stages in the human host and the mosquito vector. Transmission-blocking vaccines target the parasite at the sexual stage, aiming to reduce its infectivity and prevent the spread of the disease. The two leading candidates, Pfs48/45 and Pfs230, are essential for parasite fertilisation and capable of inducing potent transmission-blocking antibody responses. In this study, the full-length structure of Pfs48/45 was determined. It adopts a triangular, disc-like architecture on the surface membrane of gametocytes and is dynamic in solution, with its conformation altered by interdomain movements. All three domains of Pfs48/45 induce transmission-blocking antibodies, and the accessibility of their epitopes correlates with their transmission-blocking activity. Strategies for studying polyclonal antibody responses using electron microscopy are also explored, which will help identify conserved and novel epitopes on Pfs48/45 using human sera from clinical trials. Additionally, a Plasmodium falciparum gametocyte culture system was established for protein purification. Various approaches were employed to isolate the intact Pfs230-Pfs48/45 complex from gametocytes. A low-resolution cryo-EM map of the complex was obtained, revealing that Pfs230 adopts a two-lobed structure: the N-terminal lobe contains domains D1-D8, while the C-terminal lobe comprises domains D9-D14. It is likely that Pfs48/45 interacts with the C-terminal lobe of Pfs230. These studies provide crucial structural information on both leading candidates for developing transmission-blocking vaccines.

Authors: Ko, K-T

• DOI: 10.5287/ora-nymmzrpyn
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: malaria; Pfs48/45; transmission-blocking vaccine; plasmodium falciparum gametocyte; Pfs230
• Subjects: Structural biology; Vaccine; Parasitology