Parasite Vaccinology - CNRS URA 1961  


  HEADDr. LONGACRE Shirley / longacre@pasteur.fr
  MEMBERSDr. FALANGA Pierre / Dr. DELRIEU Isabelle / ROSARIO Sandrine (MAGNAN Mélanie, remplaçante)


  Annual Report

Introduction

LVP activities concern two major components of subunit vaccines: recombinant protein antigens and immuno-stimulating adjuvants. Initial efforts focused on candidates of interest for blood stage malaria vaccine(s), and more recently other infectious diseases, since the approaches developed may be applicable to vaccines targeting other pathogens.

Recombinant subunit vaccine antigens

Target antigens are produced in the baculovirus/insect cell expression system, which reliably reproduces proteins with complex native conformations, as well as some post-translational modifications. Past work focused on C-terminal merozoite surface protein 1 (MSP1p19), a leading vaccine candidate for both P. falciparum and P. vivaxhuman malaria. Positive results from several primate vaccination trials, led to industrial production of two PfMSP1p19 GLP preclinical lots. A GMP clinical lot is scheduled for production in 2009, to be followed by a phase-1 clinical trial. The LVP has been heavily involved in the technical issues associated with GLP-GMP production. The figure shows superimposed X-ray crystallographic structures of PfMSP1p19 and PcMSP1p19 (closely related to P. vivax), both determined with baculovirus recombinant proteins (collaboration G. Bentley, IP). Other recombinant MSP antigens (PfMSP4 and PfMSP5) are promising vaccine candidates, and human antibodies to PfMSP1p19 and PfMSP4 in particular are major mediators of neutrophil respiratory burst activity, highly correlated with acquired long-term clinical protection from malaria (article submitted to Blood). Patent applications have been filed by the IP for all of the malaria antigens.

Immuno-potentiation

Good immuno-stimulators are needed to boost immune responses to vaccine candidates, usually poorly antigenic when administered alone. The LVP has been investigating novel approaches to augment the immunogenicity of recombinant proteins, based on post-translational modifications. One of the laboratory’s main objectives is to confirm initial proof-of-principle observations using other antigens targeting malaria and other infectious diseases of current interest. We plan also to verify that modified antigens are not toxic in primates. Concurrently we are actively exploring other expression systems and purification protocols to optimize yields of modified antigens, under conditions appropriate for subsequent industrial scale-up.

Keywords: Subunit vaccines, baculovirus-insect cells, malaria, adjuvants



  Publications

Polson H, Conway D, Fandeur T, Mercereau-Puijalon O, Longacre S (2005) Gene polymorphism of Plasmodium falciparummerozoite surface proteins 4 and 5, Mol. Biol. Parasit. 142, 110-115.

Bonnet S, Pêtres S, Holm I, Fontaine T, Rosario S, Roth C, and Longacre S (2006) Soluble and glyco-lipid modified baculovirus Plasmodium falciparumC-terminal Merozoite Surface Protein 1, two forms of a leading malaria vaccine candidate. Vaccine 24, 5997-6008.

Perraut R, Marrama L, Diouf B, Sokna C, Tall A, Nabeth P, Trape J-F, Longacre S, & Mercereau-Puijalon O (2005) Antibodies to the conserved C-terminal domain of the Plasmodium falciparummerozoite surface protein-1 and to the merozoite extract and their relationship with in vitro inhibitory antibodies and protection against clinical malaria in a Senegalese village. J. Infect. Dis. 191, 264-271.

Arnot, D., Cavanagh, D., Remarque, E., Creasey, A., Sowa, M., Morgan, W., Holder, A. Longacre, S., and A. Thomas (2008) Comparative testing of six antigen-based malaria vaccine candidates directed toward merozoite-stage Plasmodium falciparum. Clin. Vaccine Immunol. 15, 1345-1355.





Activity Reports 2009 - Institut Pasteur
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