Recombinant P. falciparum Circumsporozoite Protein (a.a 19- 424)

Malaria continues to be a significant global health issue, causing substantial morbidity and mortality with 219 million infections and 435,000 deaths annually, predominantly in Africa. The disease is caused by the Plasmodium parasite, with the infective sporozoite stage being a primary target for immune response. Potent humoral immune responses targeting sporozoites can protect murine, simian, and human hosts from malaria-infected mosquito challenges.

Early research on murine models showed that vaccines based on sporozoites or the sporozoite's major surface antigen, the circumsporozoite (CS) protein, could elicit antibodies primarily targeting the central repeat region of the CS protein. Monoclonal antibodies (MABs) specific to CS repeats derived from sporozoite-immunized hosts demonstrated protective effects. Passive transfer of as little as 10 μg of MAB specific to the CS repeats of rodent P. berghei sporozoites protected naïve rodents from sporozoite challenge. Similarly, 2 mg of MAB specific to P. vivax CS repeats protected Saimiri monkeys from homologous sporozoite challenge. Recent studies have further validated these findings. The passive transfer of 100–300 μg of human MAB specific to P. falciparum CS repeats, derived from volunteers immunized with the CS-based RTS,S vaccine, protected mice against challenges with transgenic P. berghei parasites expressing full-length P. falciparum CS protein.

Figure 1. Schematic of the P. falciparum CS proteins and peptides.
(Source: J. Mauricio Calvo-Calle. et al., 2021)

The immunodominant repeat region of the P. falciparum CS protein comprises major and minor tetramer repeat sequences conserved across all isolates. In the P. falciparum NF54 strain, which is widely used in human malaria challenge studies, the CS repeat region predominantly consists of 37 NANP tetramers. Additionally, there is a minor repeat region composed of alternating NVDP and NANP tetramers adjacent to a CS protein proteolytic cleavage site crucial for sporozoite invasion of host cells. These advances highlight the importance of targeting the CS protein in malaria vaccine development. The conservation of the repeat regions across different strains underscores their potential as universal vaccine targets. Continued research and development of CS-based vaccines could significantly improve the efficacy of malaria prevention strategies, ultimately reducing the global burden of this devastating disease.