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Are Extensive T Cell Epitope Polymorphisms in the Plasmodium falciparum Circumsporozoite Antigen, a Leading Sporozoite Vaccine Candidate, Selected by Immune Pressure?¹

Chutima Kumkhaek^2,*, Kooruethai Phra-ek^2,||, Laurent Rénia^#, Pratap Singhasivanon, Sornchai Looareesuwan, Chakrit Hirunpetcharat^¶, Nicholas J. White^,, Alan Brockman^||,, Anne Charlotte Grüner^#, Nicolas Lebrun^**, Ali Alloueche^*, François Nosten^||,,, Srisin Khusmith^* and Georges Snounou^3,*,*

^* Department of Microbiology and Immunology, Department of Tropical Hygiene, Department of Tropical Medicine, Wellcome Unit Faculty of Tropical Medicine, and ^¶ Department of Microbiology, Faculty of Public Health, Mahidol University, Bangkok, Thailand; ^|| Shoklo Malaria Research Unit, Mae Sot, Thailand; ^# Département d’Immunologie and ^** Service Commun de Séquençage, Institut Cochin, Institut National de la Santé et de la Recherche Médicale Unite 567, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 8104, Université René Descartes, Paris, France; Centre for Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, United Kingdom; ^* Chiron Vaccines, Siena, Italy; ^* Unité de Parasitologie Bio-Medicale, CNRS Unité de Recherche Associée 2581, Institut Pasteur, Paris, France; and ^* Equipe Parasitologie Comparée et Modèles Expérimentaux USM0307, CNRS IFR101, Muséum National d’Histoire Naturelle, Paris, France

Protective cellular immune responses depend on MHC presentation of pathogen-derived Ag fragments. MHC diversity renders this process sensitive to point mutations coding for altered amino acid sequence of the short target Ag-derived peptides epitopes. Thus, in a given host, a pathogen with an altered epitope sequence will be more likely to escape detection and elimination by the immune system. At a population level, selection by immune pressure will increase the likelihood of polymorphism in important pathogen antigenic epitopes. This mechanism of immune evasion is found in viruses and other pathogens. The detection of polymorphic hot spots in an Ag is often taken as a strong indication of its role in protective immunity. We provide evidence that polymorphisms in the T cell epitopes of a malaria vaccine candidate are unlikely to have been selected by immune pressure in the human host.

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