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
| Autor: | Divya Angra, Ratish M. Illam, Christopher D. Pool, Jason W. Bennett, Robert Schwenk, Brooke A. Bozick, Margot DeBot, Andrea Crisanti, Roberta Spaccapelo, Clara Brando, Jennifer Nicki, Sheetij Dutta, Patricia De La Vega, Christian F. Ockenhouse, Michael D. Porter, Jittawadee Murphy |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Microbiology (medical)
Plasmodium berghei Clinical Biochemistry Immunology Plasmodium falciparum Protozoan Proteins Antibodies Protozoan Enzyme-Linked Immunosorbent Assay Parasitemia transgenic parasites vaccine Mice Antigen parasitic diseases Malaria Vaccines medicine Immunology and Allergy Animals Avidity Vaccines Vaccines Synthetic biology Malaria vaccine fungi Vaccination Antibody titer biology.organism_classification medicine.disease Virology Malaria Circumsporozoite protein Mice Inbred C57BL Disease Models Animal Culicidae |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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