The applicant is a female, assimilated Polish scientist, who has worked in the fields of transgenic plants and edible vaccines. She wants to complete her training at the Pasteur Institute in Paris, in the fields of protein and antibody engineering. The combination of both competences will have an enormous potential in health.
Dengue is a re-emerging disease, which is viral, vector-borne, poverty-linked and affects 100 million persons each year. No vaccine or specific treatment is available. The dengue virus has 4 serotypes, DEN1 to DEN4. Monoclonal antibody mAb4E11 is directed against the DEN1 virus. It binds to domain 3 of the viral envelope protein E, neutralizes the viruses of the 4 serotypes, and protects the mouse.
The project consist in:
- understanding the molecular mechanisms by which mAb4E11 interacts with the dengue virus and neutralizes its 4 serotypes; and
- using this knowledge to develop derivatives of mAb4E11 that could be used in passive immunotherapy.
The project could also lead to improved vaccines or diagnostics. Put briefly, Domain 3 (rE3) of protein E will be expressed in a recombinant form. Assays will be set up to quantify the interactions between rE3 and:
- the proteinous receptors of the virus on target cells; and
- the heparan sulfate co-receptors.
Known mutations that affect virulence, will be introduced into rE3 by mutagenesis and their effects on these interactions measured. The binding site for mAb4E11 and for the viral (co-)receptors will be identified at the surface of rE3 by mutagenesis and compared. The relations between the molecular structure of mAb4E11 and the neutralization (or enhancement) of the viral infection will be analyzed by constructing recombinant derivatives of this antibody.
The structures of rE3 and mAb4E11 will be determined in collaboration. These studies will result in the development of potent derivatives of mAb4E11, for use in passive immunotherapy against the 4 serotypes of the dengue virus.
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