Introduction: The focus of our Unit is to analyze human-P.falciparum(P.f) immune interactions. Our goals are a) to provide knowledge about various factors that modulate this interaction towards either susceptibility or resistance, and b) to employ this knowledge in order to manipulate identified mechanisms to the benefit of human kind, while establishing continuity between research, antigen discovery, and product development.

Vaccine Development: In the recent years, we have successfully implemented 7 vaccine trials in humans in phase I and phase IIb with two of our patented vaccine candidates and, by the end of 2010 we have initiated 3 additional trials with 3 of our patented vaccine candidates.

Asexual Blood Stages: Results from a total of 17 immuno-clinical studies converge to support the vaccine potential of Merozoite Surface Protein 3 (MSP3). The presence of IgG3 anti-MSP3 as anti-SR11.1 was found to have a major predictive effect against malaria infection in children. Clinical trials have, for the first time, brought the proof that induction of a monocyte dependent antibody effect translates into clinical protection. We have produced a therapeutic human anti-MSP3 mAb and tested it in the chimpanzee. We have characterized a MSP3 multigene family, sharing three B-cell epitopes that are fully conserved in all isolates tested. We have designed 8 novel vaccine constructs derived from the MSP3 multigene family and have analysed their immunogenicity in 3 strains of mice as well as evaluated their immunogenicity on human lymphocytes grafted in the NSG immunodeficient mouse. The best formulation will be taken in phase I clinical trials.

We have developed a novel concept for vaccine discovery and have demonstrated its feasibility by the fast screening of 100 new P.fgenes, leading to the identification of 3 novel major vaccine candidates involved in defence in humans.

We performed a very detailed analysis of the phenotype of myeloid cells in individuals living in endemic areas as well as in cells from European volunteers undergoing an induced sporozoïte challenge. Results show extremely fast and profound modifications in blood monocyte-macrophages, characterize the inflammation induced by P.f, lead to characterize different cell populations with different functions, some effective in ADCI associated with control of parasite loads in vivo and vice versa. We have characterized the molecular events leading to MN-dependant Ab-mediated parasite killing, showing that it requires the co-activation of FcγRII and RIII, and only hormonal concentrations of Ab (700pM).

Drug resistance and drug development: Our longstanding efforts to develop a small laboratory model receptive to P.falciparumhave led to design a novel model of P.fin NSG mice which led to successful infection in 100 % of the inoculated mice, rapid rise of parasitemia to 30- 40 % parasitemia, (up to 67 %) and consistent results form mouse to mouse. Characteristics of the model are closer to human infection with evidence of synchronisation, sequestration and receptivity to various P.fstrains. This model has been employed to modelize resistance to Artemisin derivatives. The resistance of a sensitive strain of P.fcould be increased by 100-fold, reaching the LD 50 in mice and with a corresponding shift in effective concentration in vitro, which had not been observed yet in partially Artemisin-resistant parasites in the field. Given the paramount role of Artemisin derivates for both the control of malaria at collective level and the treatment of malaria cases at individual level, this result indicates an immediate and major threat on the projects of malaria’s so-called elimination.

Liver Stages (LS): We have identified major regulatory regions in both MSP3 and LSA3 vaccine candidates which led, for the latter, to tailor the molecule in order to remove those regulatory regions which inhibit the production of the major surrogate, Interferon-γ. A novel construct has been designed based on those results and compared with the full-length molecule in terms of immunogenicity upon human lymphocytes grafted in NSG mice. The novel construct has yielded satisfactory responses in 5 groups of mice grafted with lymphocytes from 3 different donors, whereas the former construct did not induce immune responses in the same model. This leads to initiate phase I and phase II trials with induced challenge using the new construct.

We have characterized a novel Ag, SR11.1 that combines the features of LSA3 and MSP3 and induces protection against mosquito’s challenges by P. yoeliiin mice and by P.fin primates.

We have identified a novel hepatoma cell line fully susceptible to P.fLiver Stage development, the least known phase of the Plasmodiumlife cycle.

Keywords: malaria – vaccine – drugs – pathology

JAFARSHAD, A., H. DZIEGIEL, M.A., Rasmus LUNDQUIST, R., NIELSEN, L.K., SINGH,S., DRUILHE, P.. (2007) A novel Antibody-Dependent Cellular Cytotoxicity mechanism involved in defence against malaria requires costimulation of monocytes FcγRII and FcγRIII. J Immunol. 1;178(5):3099-106 - PMID: 17312157

ROUSSILHON, C., OEUVRAY, C., MÜLLER-GRAF, C., TALL, A., ROGIER. C., TRAPE, J.F., THEISEN, M., BALDE, A., PERIGNON, J.L., DRUILHE, P.. (2007) Long term clinical protection from falciparummalaria is strongly associated with IgG3 antibodies to Merozoite Surface Protein 3. PLoS Medicine, 4, Issue 11, e320 - PMID: 18001147

CHIMMA, P., ROUSSILHON, C., SRATONGO, P., RUANGVEERAYUTH, R., PATTANAPANYASAT, K., PERIGNON, J.L.., ROBERTS, D.J., DRUILHE, P.. (2009) A Distinct Peripheral Blood Monocyte Phenotype is Associated with Parasite Inhibitory Activity in Acute Uncomplicated Plasmodium falciparumMalaria. PLoS Pathog. 5 (10)e1000631 - PMID: 19851453

Sirima, S.B., Tiono, A.B., OuEdraogo, A., Diarra, A., OuEdraogo, A.L., Yaro, J.B., OuEdraogo, E., Gansané, A., Bougouma, E., Konaté, A.T., Kaboré, Y., Traoré, A., Chilengi, R., Soulama, I., Luty, A.J., Druilhe, P., Cousens, S., Nébié, I..(2009) Safety and immunogenicity of the malaria vaccine candidate MSP3 long synthetic peptide in 12-24 months-old Burkinabe children.PLoS One. 2009 Oct 26;4(10):e7549. Erratum in: PLoS One. 2010;5(4).

ARNOLD, L. TYAGI, R.K., MEJIA, P., VAN ROOIJEN, N., PERIGNON, J.L.,DRUILHE, P..(2010)Analysis of innate defences against Plasmodium falciparum in immunodeficient mice.Malar. J.2010 Jul 9, 9:197