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Infection and Immunity, August 2003, p. 4749-4758, Vol. 71, No. 8
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.8.4749-4758.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Induction of Parasite Growth-Inhibitory Antibodies by a Virosomal Formulation of a Peptidomimetic of Loop I from Domain III of Plasmodium falciparum Apical Membrane Antigen 1

Molecular Immunology, Swiss Tropical Institute, CH-4002 Basel,¹ Institute of Organic Chemistry, University of Zurich, CH-8057 Zurich,² Pevion Biotech Ltd., CH-3018 Bern, Switzerland³

Received 2 December 2002/ Returned for modification 11 February 2003/ Accepted 14 May 2003

Apical membrane antigen 1 (AMA-1) of Plasmodium falciparum is a leading candidate antigen for inclusion in a malaria subunit vaccine. Its ectodomain can be divided into three subdomains, each with disulfide bond-stabilized structures. Since the majority of antibodies raised against the ectodomain appear to recognize strain-specific epitopes in domain I, we attempted to develop a vaccine formulation which directs the immune response to a region that contains more conserved epitopes. Here we demonstrate that a virosomal formulation of a peptide that mimics the semiconserved loop I of domain III elicits parasite growth-inhibitory antibodies. A synthetic peptide comprising residues 446 to 490 of AMA-1 (AMA-1^446-490) was conjugated through the N terminus to a derivative of phosphatidylethanolamine and the phosphatidylethanolamine-peptide conjugate was incorporated into immunopotentiating reconstituted influenza virosomes as a human-compatible antigen delivery system. Both cyclized and linear versions of the peptide antigen elicited antibodies which specifically bound to parasite-expressed AMA-1 in Western blotting with parasite lysates as well as in immunofluorescence assays with blood stage parasites. All 11 peptidomimetic-specific monoclonal antibodies generated were cross-reactive with parasite-expressed AMA-1. Antigen binding assays with a library of overlapping cyclic peptides covering the target sequence revealed differences in the fine specificity of these monoclonal antibodies and provided evidence that at least some of them recognized discontinuous epitopes. The two immunodominant epitopes comprised the conserved linear sequences K⁴⁵⁹RIKLN⁴⁶⁴ and D⁴⁶⁷DEGNKKII⁴⁷⁵. A key feature of the synthetic vaccine formulation proposed here is the display of the peptide antigen in a native-like state on the surface of the virosome.

Editor: S. H. E. Kaufmann

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