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Pre-clinical study of the immunogenicity of msp3 and glurp two p. falciparum antigens targeted by protective antibodies

Objective

To optimize the immunogenicity of MSP3 and GLURP by using several antigen-presentation systems in a) mice, b) Saimiri, c) Aotus, and d) Chimpanzee. To characterize the antibodies (fine epitope specificity, isotype) induced by the various protocols, and analyze their biological effect in defence mechanisms, a) in vitro, invasion and ADCI, b) in vivo by passive transfer in the humanized SCID mouse and in c) primate. Compare the results with P. falciparum challenge experiments in the primates immunized with MSP3 and GLURP. Complete the characterization of the B and T cell epitopes from MSP3 and GLURP by epidemiological field studies.
Expected Outcome

The optimal conditions for inducing antibodies against MSP3 and GLURP will be determined and functional protection assays established. Improved understand of the critical epitopes involved in the production of protective antibodies and cross-reactivity to MSP3 and GLURP.
* Immunizing mice with one lipopeptide, and one recombinant from MSP3 and one peptide and one recombinant derived from GLURP with the different adjuvants. The titer, and isotype as well as the ADCI effect of the antibodies obtained will be determined.

* Aotus will be BCG primed, immunized with PPD-coupled GLURP and MSP3 and subsequently challenged with P. falciparum.

* ADCI experiments will be conducted in SCID mice harbouring live P. falciparum and human monocytes by passively transferring total IgG from hyperimmune individuals to confirm the model. Anti-R0, anti-R2, and anti-MSP3 and other antibodies will subsequently be analyzed in the SCID model.

* Epidemiological studies with MSP3b and R0, and R2 in Dielmo.

* Mice will be immunized with new peptides and recombinant proteins derived from MSP3 and GLURP with the best performing adjuvant. The titer, and isotype and ADCI effect of the antibodies induced by new constructs will be determined.

* Immunizing Aotus and Saimiri with the GLURP and MSP3 vaccine formulation that induced antibodies which prove to be efficient in ADCI. The humoral and cellular immune responses of the monkeys will be analyzed.

* The antibody reactivity to epitopes identified in MSP3 clone 256 and 256B and peptides derived from GLURP will be analyzed in the population of Dielmo.

* Immunizing Aotus and Saimiri with antigens provided that they are superior to the initial constructs. The immunogenicity of the best performing MSP3 and GLURP antigen formulation will be determined in Chimpanzees.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Statens Serum Institut
Address
5,Artillerivej 5
2300 København S
Denmark

Participants (4)

INSTITUT PASTEUR
France
Address
Rue Du Docteur Roux 28
75724 Paris
Institut Pasteur de Lille
France
Address
1 Rue Du Professeur Albert Calmette
59019 Lille
Oswaldo Cruz Institute
Brazil
Address
4365,Av Brasil 4365
21045 Rio De Janeiro
UNIVERSIDAD DEL VALLE
Colombia
Address

0344406 Cali