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Infection and Immunity, March 2007, p. 1349-1358, Vol. 75, No. 3
0019-9567/07/$08.00+0     doi:10.1128/IAI.01467-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Enhanced Protection against Malaria by a Chimeric Merozoite Surface Protein Vaccine

Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 19129

Received 13 September 2006/ Returned for modification 26 October 2006/ Accepted 1 December 2006

The 42-kDa processed fragment of Plasmodium falciparum merozoite surface protein 1 (MSP-1₄₂) is a prime candidate for a blood-stage malaria vaccine. Merozoite surface protein 8 contains two C-terminal epidermal growth factor (EGF)-like domains that may function similarly to those of MSP-1₄₂. Immunization with either MSP-1 or MSP-8 induces protection that is mediated primarily by antibodies against conformation-dependent epitopes. In a series of comparative immunogenicity and efficacy studies using the Plasmodium yoelii rodent model, we tested the ability of recombinant P. yoelii MSP-8 (rPyMSP-8) to complement rPyMSP-1-based vaccines. Unlike MSP-1, PyMSP-8-dependent protection required immunization with the full-length protein and was not induced with recombinant antigens that contained only the C-terminal EGF-like domains. Unlike PyMSP-8, the immunogenicity of the PyMSP-1 EGF-like domains was low when present as part of the rPyMSP-1₄₂ antigen. Immunization with a mixture of rPyMSP-1₄₂ and rPyMSP-8 further inhibited the antibody response to protective epitopes of rPyMSP-1₄₂ and did not improve vaccine efficacy. To improve PyMSP-1 immunogenicity, we produced a chimeric antigen containing the EGF-like domains of PyMSP-1 fused to the N terminus of PyMSP-8. Immunization with the chimeric rPyMSP-1/8 antigen induced high and comparable antibody responses against the EGF-like domains of both PyMSP-1 and PyMSP-8. This enhanced MSP-1-specific antibody response and the concurrent targeting of MSP-1 and MSP-8 resulted in improved, nearly complete protection against lethal P. yoelii 17XL malaria. Unexpectedly, immunization with rPyMSP-1/8 failed to protect against challenge infection with reticulocyte-restricted P. yoelii 17X parasites. Overall, these data establish an effective strategy to improve the efficacy of P. falciparum MSP-based vaccines.

Published ahead of print on 11 December 2006.

Editor: W. A. Petri, Jr.