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Generation of Cross-Protective Antibodies against Plasmodium falciparum Sequestration by Immunization with an Erythrocyte Membrane Protein 1-Duffy Binding-Like 1 Domain ^,

Microbiology and Tumorbiology Center, Karolinska Institutet,¹ Swedish Institute for Infectious Disease Control, 171 77 Stockholm, Sweden,² Department of Nuclear Medicine, Karolinska University Hospital, Solna, Sweden,³ Parasite Molecular Immunology Unit, CNRS URA 2851, Pasteur Institute, Paris, France,⁴ Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom⁵

Received 10 May 2006/ Returned for modification 3 July 2006/ Accepted 23 October 2006

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is an important virulence factor on the surface of infected erythrocytes. Naturally acquired antibodies to PfEMP1 expressed by parasites causing severe malaria are suggested to be protective and of major interest for the development of a vaccine against severe disease. In this study, the PfEMP1 expressed by a parasite clone displaying a multiadhesive phenotype associated with severe malaria was well recognized by sera of malaria semi-immune children. The efficiency of the Duffy binding-like 1 (DBL1) domain of this PfEMP1 was therefore, alone or in combination with two additional DBL1 domains, evaluated as a potential vaccine candidate using both a rodent model and a primate model. Antibodies against the DBL1 domain were generated by immunization with recombinant DBL1-Semliki Forest virus particles and recombinant protein and analyzed in vitro. The immunized animals were challenged in vivo with various parasite strains or clones. Immunization with the PfEMP1-DBL1 domain abolished the PfEMP1-dependent sequestration of the homologous strain in immunized rats and substantially inhibited parasite adhesion in immunized monkeys. Protection against sequestration of heterologous parasite strains was also confirmed by direct or indirect challenge in the rat model. These results strongly support the use of the DBL1 domain in the development of a vaccine targeting severe malaria.

Published ahead of print on 30 October 2006.

Editor: J. F. Urban, Jr.

Supplemental material for this article may be found at http://iai.asm.org/.

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