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Suppression of Lethal Plasmodium yoelii Malaria following Protective Immunization Requires Antibody-, IL-4-, and IFN--Dependent Responses Induced by Vaccination and/or Challenge Infection¹

Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129

Immunization with Plasmodium yoelii merozoite surface protein (PyMSP)-8 protects mice from lethal malaria but does not prevent infection. Using this merozoite surface protein-based vaccine model, we investigated vaccine- and infection-induced immune responses that contribute to protection. Analysis of prechallenge sera from rPyMSP-8-immunized C57BL/6 and BALB/c mice revealed high and comparable levels of Ag-specific IgG, but differences in isotype profile and specificity for conformational epitopes were noted. As both strains of mice were similarly protected against P. yoelii, we could not correlate vaccine-induced responses with protection. However, passive immunization studies suggested that protection resulted from differing immune responses. Studies with cytokine-deficient mice showed that protection was induced by immunization of C57BL/6 mice only when IL-4 and IFN- were both present. In BALB/c mice, the absence of either IL-4 or IFN- led to predictable shifts in the IgG isotype profile but did not reduce the magnitude of the Ab response induced by rPyMSP-8 immunization. Immunized IL-4^–/– BALB/c mice were solidly protected against P. yoelii. To our surprise, immunized IFN-^–/– BALB/c mice initially controlled parasite growth but eventually succumbed to infection. Analysis of cytokine production revealed that P. yoelii infection induced two distinct peaks of IFN- that correlated with periods of controlled parasite growth in intact, rPyMSP-8-immunized BALB/c mice. Maximal parasite growth occurred during a period of sustained TGF-β production. Combined, the data indicate that induction of protective responses by merozoite surface protein-based vaccines depends on IL-4 and IFN--dependent pathways and that vaccine efficacy is significantly influenced by host responses elicited upon infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health-National Institute of Allergy and Infectious Diseases Grant R01AI35661.

² Address correspondence and reprint requests to Dr. James M. Burns, Jr., Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129. E-mail address: jburns{at}drexelmed.edu

³ Abbreviations used in this paper: MSP-1, merozoite surface protein-1; AMA, apical membrane antigen; PyMSP, Plasmodium yoelii merozoite surface protein; R/A, reduced and alkylated; pRBC, parasitized RBC; RT, reverse transcription; rBCG, recombiant bacillus Calmette-Guérin.

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