1. Michael Heidelberger Division of Immunology, Department of Pathology, New York University School of Medicine, New York, New York 10016, USA
2. Department of Microbiology and Immunology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
3. Laboratory of Molecular Immunology and Howard Hughes Institute, Rockefeller University, New York, New York 10021, USA
4. Department of Medical and Molecular Parasitology, and Department of Pathology, New York University School of Medicine, New York, New York 10016, USA
5. Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA
6. These authors contributed equally to this work.

Correspondence to: Kota Arun Kumar^1,6 Correspondence and requests for materials should be addressed to A.K. (Email: arun.kumar@med.nyu.edu).

Malaria infection starts when mosquitoes inject sporozoites into the skin. The parasites enter the blood stream and make their way to the liver where they develop into the exo-erythrocytic forms (EEFs). Immunization with irradiated sporozoites (IrSp) leads to robust protection against malaria infection in rodents¹, monkeys² and humans³ by eliciting antibodies to circumsporozoite protein (CS) that inhibit sporozoite infectivity, and T cells that destroy the EEFs⁴. To study the role of non-CS antigens in protection, we produced CS transgenic mice that were tolerant to CS T-cell epitopes. Here we show that in the absence of T-cell-dependent immune responses to CS, protection induced by immunization with two doses of IrSp was greatly reduced. Thus, although hundreds of other Plasmodium genes are expressed in sporozoites⁵ and EEFs⁶, CS is a dominant protective antigen. Nevertheless, sterile immunity could be obtained by immunization of CS transgenics with three doses of IrSp.

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