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Infection and Immunity, December 2002, p. 6606-6613, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6606-6613.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Immunization with a Combination of Merozoite Surface Proteins 4/5 and 1 Enhances Protection against Lethal Challenge with Plasmodium yoelii

Lukasz Kedzierski,^1, Casilda G. Black,¹ Matthew W. Goschnick,¹ Anthony W. Stowers,² and Ross L. Coppel^1*

Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia,¹ Malaria Vaccine Development Unit, The Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20852²

Received 18 April 2002/ Returned for modification 24 May 2002/ Accepted 22 August 2002

It is widely believed that subunit vaccines composed of multiple components will offer greater protection against challenge by malaria, and yet there is little experimental evidence to support this view. We set out to test this proposition in the Plasmodium yoelii challenge system in rodents by comparing the degree of protection conferred by immunization with a mixture of merozoite surface proteins to that conferred by single proteins. We therefore examined a defined protein mixture made of the epidermal growth factor-like domains of P. yoelli merozoite surface protein 1 (MSP1) and MSP4/5, the homologue of P. falciparum MSP4 and MSP5. In the present study we demonstrate that this combination of recombinant proteins dramatically enhances protection against lethal malaria challenge compared to either protein administered alone. Many mice immunized with the MSP4/5 plus MSP1₁₉ combination did not develop detectable parasitemia after challenge. Combined immunization with MSP1₁₉ and yMSP4/5, a product characterized by lower protective efficacy, also greatly enhanced protection by reducing peak parasitemias and increasing the numbers of survivors. In some combination trials, levels of antibodies to MSP1₁₉ were elevated compared to the MSP1₁₉ alone group; however, improved protection occurred regardless of whether boosting of the anti-MSP1₁₉ response was observed. Boosting of anti-MSP1₁₉ did not appear to be due to contaminating endotoxin in the EcMSP4/5 material since enhanced protection was observed in C3H/HeJ mice, which are endotoxin insensitive. Collectively, these experiments show that multiantigen combinations offer enhanced levels of protection against asexual stage infection and suggest that combinations of MSP1, MSP4, and MSP5 should be evaluated further for use in humans.

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* Corresponding author. Mailing address: Department of Microbiology, P.O. Box 53, Monash University, Clayton, Victoria 3800, Australia. Phone: 61-3-9905-4822. Fax: 61-3-9905-4811. E-mail: ross.coppel{at}med.monash.edu.au.

Editor: S. H. E. Kaufmann

Present address: Walter and Eliza Hall Institute of Medical Research, Post Office, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.

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Infection and Immunity, December 2002, p. 6606-6613, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6606-6613.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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