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Infection and Immunity, June 2008, p. 2660-2670, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.00170-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Diversity-Covering Approach to Immunization with Plasmodium falciparum Apical Membrane Antigen 1 Induces Broader Allelic Recognition and Growth Inhibition Responses in Rabbits{triangledown}

Edmond J. Remarque,{dagger} Bart W. Faber,{dagger} Clemens H. M. Kocken, and Alan W. Thomas*

Biomedical Primate Research Centre, Department of Parasitology, Lange Kleiweg 139, 2288 GJ Rijswijk, The Netherlands

Received 8 February 2008/ Returned for modification 9 March 2008/ Accepted 19 March 2008

Plasmodium falciparum apical membrane antigen 1 (PfAMA1), a candidate malaria vaccine, is polymorphic. This polymorphism is believed to be generated predominantly under immune selection pressure and, as a result, may compromise attempts at vaccination. Alignment of 355 PfAMA1 sequences shows that around 10% of the 622 amino acid residues can vary between alleles and that linkages between polymorphic residues occur. Using this analysis, we have designed three diversity-covering (DiCo) PfAMA1 sequences that take account of these linkages and, when taken together, on average incorporate 97% of amino acid variability observed. For each of the three DiCo sequences, a synthetic gene was constructed and used to transform the methylotrophic yeast Pichia pastoris, allowing recombinant expression. All three DiCo proteins were reactive with the reduction-sensitive monoclonal antibody 4G2, suggesting the DiCo sequences had conformations similar to those of naturally occurring PfAMA1. Rabbits were immunized with FVO strain PfAMA1 or with the DiCo proteins either individually or as a mixture. Antibody titers and the ability to inhibit parasite growth in vitro were determined. Animals immunized with the DiCo mix performed similarly to animals immunized with FVO AMA1 when measured against FCR3 strain parasites but outperformed animals immunized with FVO AMA1 when assessed against other strains. The levels of growth inhibition (~70%) induced by the mix of three DiCo proteins were comparable for FVO, 3D7, and HB3, suggesting that a considerable degree of diversity in AMA1 is adequately covered. This suggests that vaccines based upon the DiCo mix approach provide a broader functional immunity than immunization with a single allele.

* Corresponding author. Mailing address: Department of Parasitology, Biomedical Primate Research Centre, Lange Kleiweg 139, 2288 GJ Rijswijk, The Netherlands. Phone: 31 15 284 2640. Fax: 31 15 284 2601. E-mail: Thomas{at}BPRC.nl

{triangledown} Published ahead of print on 31 March 2008.

Editor: W. A. Petri, Jr.

{dagger} Edmond J. Remarque and Bart W. Faber contributed equally to this work.

Infection and Immunity, June 2008, p. 2660-2670, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.00170-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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