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Infection and Immunity, December 2002, p. 6948-6960, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6948-6960.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

In Vitro Studies with Recombinant Plasmodium falciparum Apical Membrane Antigen 1 (AMA1): Production and Activity of an AMA1 Vaccine and Generation of a Multiallelic Response

Michael C. Kennedy, Jin Wang, Yanling Zhang, Aaron P. Miles, Farideh Chitsaz, Allan Saul, Carole A. Long, Louis H. Miller, and Anthony W. Stowers*

Malaria Vaccine Development Unit, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852

Received 29 May 2002/ Returned for modification 13 July 2002/ Accepted 24 August 2002

Apical membrane antigen 1 (AMA1) is regarded as a leading malaria blood-stage vaccine candidate. While the overall structure of AMA1 is conserved in Plasmodium spp., numerous AMA1 allelic variants of P. falciparum have been described. The effect of AMA1 allelic diversity on the ability of a recombinant AMA1 vaccine to protect against human infection by different P. falciparum strains is unknown. We characterize two allelic forms of AMA1 that were both produced in Pichia pastoris at a sufficient economy of scale to be usable for clinical vaccine studies. Both proteins were used to immunize rabbits, singly and in combination, in order to evaluate their immunogenicity and the ability of elicited antibodies to block the growth of different P. falciparum clones. Both antigens, when used alone, elicited high homologous anti-AMA1 titers, with reduced strain cross-reactivity. Similarly, sera from rabbits immunized with a single antigen were capable of blocking the growth of homologous parasite strains at levels theoretically sufficient to clear parasite infections. However, heterologous inhibition was significantly reduced, providing experimental evidence that AMA1 allelic diversity is a result of immune pressure. Encouragingly, rabbits immunized with a combination of both antigens exhibited titers and levels of parasite inhibition as good as those of the single-antigen-immunized rabbits for each of the homologous parasite lines, and consequently exhibited a broadening of allelic diversity coverage.

* Corresponding author. Present address: CSL Ltd., 45 Poplar Rd., Parkville, Victoria 3052, Australia. Phone: 61 3 9389 1034. Fax: 61 3 9388 2063. E-mail: anthony_stowers{at}csl.com.au.

Editor: W. A. Petri, Jr.

Infection and Immunity, December 2002, p. 6948-6960, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6948-6960.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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