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Infection and Immunity, October 2003, p. 5700-5713, Vol. 71, No. 10
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.10.5700-5713.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Analysis of Immunological Nonresponsiveness to the 19-Kilodalton Fragment of Merozoite Surface Protein 1 of Plasmodium yoelii: Rescue by Chemical Conjugation to Diphtheria Toxoid (DT) and Enhancement of Immunogenicity by Prior DT Vaccination

Danielle I. Stanisic,^1,2 Laura B. Martin,^1,2, Xue Q. Liu,¹ David Jackson,^2,3 Juan Cooper,¹ and Michael F. Good^1,2*

The Queensland Institute of Medical Research,¹ The CRC for Vaccine Technology, Brisbane 4029 ,² Department of Microbiology, The University of Melbourne, Parkville 3052, Australia³

Received 17 March 2003/ Returned for modification 26 May 2003/ Accepted 18 July 2003

The Plasmodium merozoite surface protein 1 (MSP1) is a leading vaccine candidate for protecting against the blood stage of malaria. Previous studies have shown that the 19-kDa carboxyl terminus of this protein is able to induce protective immunity in some monkey and mouse strains. We show that immunization with the recombinant Plasmodium yoelii 19-kDa fragment of MSP1 (MSP1₁₉) expressed in Saccharomyces cerevisiae (yMSP1₁₉) can induce protective antibodies in several inbred mouse strains and one outbred mouse strain. However, mice expressing the H-2^s major histocompatibility complex haplotype are unable to generate yMSP1₁₉-specific antibodies. While synthetic peptides derived from MSP1₁₉ are immunogenic in B10.S mice, they cannot function as helper epitopes, and immunization with yMSP1₁₉ does not induce T cells that recognize the recombinant protein or synthetic peptides corresponding to its sequence. Nonresponsiveness could be overcome by using chemical linkers to conjugate yMSP1₁₉ to diphtheria toxoid (DT), resulting in immunogens capable of inducing protective yMSP1₁₉-specific antibodies in both MSP1₁₉-responsive and otherwise nonresponsive mouse strains. The ability of sera from mice immunized with the conjugate to inhibit binding of a protective monoclonal antibody (MAb 302) to yMSP1₁₉ correlated strongly with a delay in the prepatent period. Chemical conjugation of yMSP1₁₉ to DT may be a preferred method to enhance immunogenicity, as carrier priming experiments demonstrated that an existing immune response to DT enhanced a subsequent antibody response to yMSP1₁₉ after vaccination with yMSP1₁₉-DT. These results have important implications for the development of a malaria vaccine to protect a population with diverse HLAs.

Editor: S. H. E. Kaufmann

Present address: Malaria Vaccine Development Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.

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