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J. Biol. Chem., Vol. 282, Issue 23, 17148-17156, June 8, 2007

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Epitope Analysis of the Malaria Surface Antigen Pfs48/45 Identifies a Subdomain That Elicits Transmission Blocking Antibodies^*

Nikolay Outchkourov¹, Adriaan Vermunt¹, Josephine Jansen, Anita Kaan, Will Roeffen, Karina Teelen, Edwin Lasonder, Anneke Braks, Marga van de Vegte-Bolmer, Li Yan Qiu, Robert Sauerwein, and Hendrik G. Stunnenberg²

From the Department of Molecular Biology, NCMLS, Radboud University Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Medical Microbiology, Radboud University Nijmegen Medical Center, 268, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands

Pfs48/45, a member of a Plasmodium-specific protein family, displays conformation-dependent epitopes and is an important target for malaria transmission-blocking (TB) immunity. To design a recombinant Pfs48/45-based TB vaccine, we analyzed the conformational TB epitopes of Pfs48/45. The Pfs48/45 protein was found to consist of a C-terminal six-cysteine module recognized by anti-epitope I antibodies, a middle four-cysteine module recognized by anti-epitopes IIb and III, and an N-terminal module recognized by anti-epitope V antibodies. Refolding assays identified that a fragment of 10 cysteines (10C), comprising the middle four-cysteine and the C-terminal six-cysteine modules, possesses superior refolding capacity. The refolded and partially purified 10C conformer elicited antibodies in mice that targeted at least two of the TB epitopes (I and III). The induced antibodies could block the fertilization of Plasmodium falciparum gametes in vivo in a concentration-dependent manner. Our results provide important insight into the structural organization of the Pfs48/45 protein and experimental support for a Pfs48/45-based subunit vaccine.

Received for publication, February 1, 2007 , and in revised form, April 9, 2007.

^* This study was financially supported by European Malaria Vaccine Initiative Grant 041222 and by EuroMalvac II Contract QLK2-CT-2002-01197. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to the presented work.

² To whom correspondence should be addressed: Dept. of Molecular Biology, NCMLS M850/3.79, Radboud University, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: 31-24-3610524; Fax: 31-24-3610520; E-mail: h.stunnenberg{at}ncmls.ru.nl.

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				N. S. Outchkourov, W. Roeffen, A. Kaan, J. Jansen, A. Luty, D. Schuiffel, G. J. van Gemert, M. van de Vegte-Bolmer, R. W. Sauerwein, and H. G. Stunnenberg Correctly folded Pfs48/45 protein of Plasmodium falciparum elicits malaria transmission-blocking immunity in mice PNAS, March 18, 2008; 105(11): 4301 - 4305. [Abstract] [Full Text] [PDF]