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Infection and Immunity, October 2006, p. 5529-5536, Vol. 74, No. 10
0019-9567/06/$08.00+0     doi:10.1128/IAI.00573-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Passive Immunization with a Multicomponent Vaccine against Conserved Domains of Apical Membrane Antigen 1 and 235-Kilodalton Rhoptry Proteins Protects Mice against Plasmodium yoelii Blood-Stage Challenge Infection

David L. Narum,1* Solabomi A. Ogun,2 Adrian H. Batchelor,3 and Anthony A. Holder2

EntreMed, Inc., Rockville, Maryland 20850,1 Division of Parasitology, National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom,2 University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland 212013

Received 6 April 2006/ Returned for modification 10 May 2006/ Accepted 7 July 2006

During malaria parasite invasion of red blood cells, merozoite proteins bind receptors on the surface of the erythrocyte. Two candidate Plasmodium yoelii adhesion proteins are apical membrane antigen 1 (AMA1) and the 235-kDa rhoptry proteins (P235). Previously, we have demonstrated that passive immunization with monoclonal antibodies (MAbs) 45B1 and 25.77 against AMA1 and P235, respectively, protects against a lethal challenge infection with P. yoelii YM. We show that MAb 45B1 recognizes an epitope located on a conserved surface of PyAMA1, as determined by phage display and analysis of the three-dimensional structure of AMA1, in a region similar to that bound by the P. falciparum AMA1-specific inhibitory antibody 4G2. The epitope recognized by 25.77 could not be assigned. We report here that MAbs 45B1 and 25.77 also protect against challenge with the nonlethal parasite line 17X, in which PyAMA1 has a significantly different amino acid sequence from that in YM. When administered together, the two MAbs acted at least additively in providing protection against challenge with the virulent YM parasite. These results support the concept of developing a multicomponent blood-stage vaccine and the inclusion of polymorphic targets such as AMA1, which these results suggest contain conserved domains recognized by inhibitory antibodies.

* Corresponding author. Mailing address: Malaria Vaccine Development Branch/NIH, 5640 Fishers Lane, Twinbrook I, Rockville, MD 20852. Phone: (301) 435-2185. Fax: (301) 480-1962. E-mail: dnarum{at}niaid.nih.gov.

Editor: W. A. Petri, Jr.

Infection and Immunity, October 2006, p. 5529-5536, Vol. 74, No. 10
0019-9567/06/$08.00+0     doi:10.1128/IAI.00573-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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