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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

2013; American Society for Microbiology; Volume: 20; Issue: 6 Linguagem: Inglês

10.1128/cvi.00066-13

1556-6811

Michael D. Porter, Jennifer Nicki, Christopher Pool, Margot DeBot, Ratish M. Illam, Clara Brando, Brooke A. Bozick, Patricia De La Vega, Divya Angra, Roberta Spaccapelo, Andrea Crisanti, Jittawadee Murphy, Jason W. Bennett, Robert Schwenk, Christian F. Ockenhouse, Sheetij Dutta,

Research on Leishmaniasis Studies

Circumsporozoite 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.