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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)803-810
Number of pages8
JournalClinical and Vaccine Immunology
Volume20
Issue number6
DOIs
StatePublished - Jun 2013
Externally publishedYes

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