Summary:

This SME-coordinated and dominated STREP will investigate new malaria vaccine candidates with the objective of taking at least one through to GLP pilot scale up. The most promising candidates will undergo in vitro and in vivo testing, lead optimisation, safety and toxicology testing according to GLP standards. The combination of efforts presented in this project will generate several recombinant measles viruses expressing a variety of malaria antigens based primarily upon MSP-1 and secondarily on AMA-1.

Background:

The two selected antigens, MSP-1 and AMA-1, are leading vaccine candidates associated with the surface of the merozoite, the parasite form that invades uninfected erythrocytes. Both were originally identified as targets of antibody-based immunity directed against asexual blood stage parasite multiplication. It has subsequently become clear that both antigens are also expressed during the development of liver stage schizonts (the prelude to blood stage development). As such they also represent potential targets for cellular immunity-based mechanisms of immunity and protection.

The attenuated MeV vaccine on which the project’s vectors are based is used worldwide, with excellent safety and efficacy records. Both the standard ‘empty’ vaccine strain and the derived vectors containing transgenes are, surprisingly for an RNA virus, genetically highly stable over many viral generations, and can infect essentially all human cell types, in particular antigen-presenting cells, thus inducing strong humoral and CD4⁺ and CD8⁺ T-cell responses. The vaccine is easy to produce economically; thus the vector is of a great interest for the development of multivalent vaccines for economically underprivileged countries such as sub-Saharan Africa.

The genetics of MeV and the technology for rescue of recombinant MeVs is well established and the long-lasting immunogenicity induced both in transgenic mice susceptible to MeV infection and in macaques using several vectored transgenes up to 5 kb in length has been documented.

Double transgenic mice, devoid of the IFN type I receptor and carrying a yeast artificial chromosome (YAC) which contains a 400 kb human insert mediating tissue expression of the MeV receptor, CD46, in a human-like fashion, have been generated in our Swiss laboratory. These will be crossed with HHD2 mice transgenic for the HLA-A0201 complex available at ZMBH (Heidelberg). Mice homozygous for all transgenic traits will be used to assay humoral immune responses (AB titers and their inhibition of parasite growth in vitro, AB isotype determination indicative for Th1/Th2 responses) and induction of MSP-1-specific CD8⁺ T cells via tetramer staining and flow cytometry. With these assays, which are in place at ZMBH, it will be feasible to compare many candidate antigens (not only malaria specific, but also others, such as HIV specific antigens), delivered as adjuvanted proteins or vectored by MeV.

The most promising P. falciparum antigen-vector combinations will be used in monkey immunisation studies (these animals can be efficiently infected with MeV), to determine various aspects of potential safety, as well as humoral and cellular immunity.

Large preparations of the most promising MeV recombinants will be produced under GLP conditions and validated by Texcell, a company specialised in carrying out safety tests for viruses destined for use in humans.

Aim:

To obtain at least one malaria vaccine candidate stably expressed in MeV that induces humoral and cellular immune responses.

Expected results:

It is expected that at least one of the candidate antigens will prove efficacious and safe following preclinical studies and it would then be produced under GLP conditions.

Potential applications:

A realistic application of the measles virus vector expressing malaria antigens would be in the immunisation of infants against both measles and malaria in malaria endemic regions.

Coordinator:

Partners:

Nº	Principal Scientific Participants	Official Address	Other Information
2	Hermann Bujard	Zentrum Molekulare Biologie University of Heidelberg Im Neuenheimer Feld 282 DE-69120 Heidelberg Germany	Tel: +49 6221 54 6800 Fax: +49 6221 54 6809 E-mail: h.bujard@zmbh.uni-heidelberg.de
3	David Arnot	Edinburgh University The King’s Buildings Mayfield Road UK-EH9 3JR Edinburgh United Kingdom	Tel: +44 131 650 5525 Fax: +44 131 650 6556 E-mail: d.e.arnot@ed.ac.uk
4	Yves Barbier	Texcell Genavenir 5 1 rue Pierre Fontaine FR-91058 Evry Cedex France	Tel: +33 1 60 91 33 10 Fax: +33 1 60 91 33 29 E-mail: ybarbier@texcell.fr
5	Alan Thomas	Biomedical Primate Research Center Lange Kleiweg 151 PO Box 3306 NL-2280 GH Rijswijk Netherlands	Tel: +31 15 284 2688 Fax: +31 15 284 3987 E-mail: thomas@bprc.nl