Development of novel malaria vaccine antigen targeting multiple stages of the Plasmodium lifecycle.

About This Grant

Development of a novel malaria vaccine antigen targeting multiple stages of the Plasmodium lifecycle. Project summary Previously, using a phage peptide display library technique, our group identified mimotope peptides that mimic the conformation of Plasmodium sporozoite ligands essential for liver infection. Notably, these small peptides elicit protective immunity by inducing antibodies that neutralize sporozoites. Using a similar approach, we identified two peptides, FG1 and MG1, which structurally mimic ligands employed by male and female gametes to facilitate parasite fertilization in the mosquito midgut. Antibodies generated against each peptide specifically bind to their corresponding gametes and markedly inhibit fertilization, thereby blocking mosquito transmission. Using the anti-MG1 antibody, we further identified the Plasmodium Heat-Shock- Protein 90 N’-terminal ATPase domain (HSP90N’) as the female gamete fertilization ligand and a potential transmission-blocking vaccine (TBV) antigen. We propose to 1) evaluate the transmission-blocking efficacy of the HSP90N’ domain and the MG1 peptide to select an optimal female-targeting antigen, and then fuse it with the male-targeting FG1 peptide to generate a dual-target TBV antigen; and 2) develop a multiple-stage vaccine antigen by linking the dual epitope TBV construct with our recently developed triple-epitope liver-stage vaccine antigen. The final fusion vaccine antigen will comprise: (i) a female gamete antigen (HSP90N’ or MG1), (ii) the FG1 peptide targeting male gametes, (iii) the PfCSP NPNA repeat peptide, (iv) the P39 peptide targeting sporozoite–Kupffer cell traversal, and (v) the HP1 peptide targeting sporozoite–hepatocyte invasion. We anticipate that this strategy will enhance malaria control by eliciting broad protective immunity through a single antigen targeting multiple essential epitopes across the Plasmodium life cycle.