Transgenic Parasites Stably Expressing Full-Length Plasmodium falciparum Circumsporozoite Protein as a Model for Vaccine Down-Selection in Mice Using Sterile Protection as an Endpoint

Abstract

dCircumsporozoite protein (CSP) of Plasmodium falciparum is a protective human malaria vaccine candidate. There is an urgent need for models that can rapidly down-select novel CSP-based vaccine candidates. In the present study, the mouse-mosquito transmission cycle of a transgenic Plasmodium berghei malaria parasite stably expressing a functional full-length P. falciparum CSP was optimized to consistently produce infective sporozoites for protection studies. A minimal sporozoite challenge dose was established, and protection was defined as the absence of blood-stage parasites 14 days after intravenous challenge. The specificity of protection was confirmed by vaccinating mice with multiple CSP constructs of differing lengths and compositions. Constructs that induced high NANP repeat-specific antibody titers in enzyme-linked immunosorbent assays were protective, and the degree of protection was dependent on the antigen dose. There was a positive correlation between antibody avidity and protection. The antibodies in the protected mice recognized the native CSP on the parasites and showed sporozoite invasion inhibitory activity. Passive transfer of anti-CSP antibodies into naive mice also induced protection. Thus, we have demonstrated the utility of a mouse efficacy model to down-select human CSP-based vaccine formulations.

A prime-boost immunization regimen based on a simian adenovirus 36 vectored multi-stage malaria vaccine induces protective immunity in mice

“…Furthermore, all immunization regimens induced antibodies with avidity indices above 0.85. These results are promising as previous reports have cited that antibody avidity above 0.80 is correlated with sterilizing immunity to Plasmodium infection [50]. …”

Optimization of aPlasmodium falciparumcircumsporozoite protein repeat vaccine using the tobacco mosaic virus platform

“…Functionality of antisera in mice was determined by challenge with Plasmodium berghei FL-CSP transgenic sporozoites (45). Protection was defined as an absence of parasites in the mouse blood (46). Vaccines were formulated in the oil-in-water adjuvant, AddaVax (InvivoGen) or in the ALFQ that contains the immune-modulators, 3D-PHAD and QS21 (43).…”

Seroprevalence of Antibodies against Plasmodium falciparum Sporozoite Antigens as Predictive Disease Transmission Markers in an Area of Ghana with Seasonal Malaria Transmission

“…falciparum and were expressed and purified under GMP conditions. The near full-length CSP protein containing 19 of the 38 NANP repeats was expressed in an Escherichia coli system [23]. The CelTOS protein is comprised of 174 amino acids including an N-terminal six-histidine tag within a 16-amino acid linker [24].…”