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.
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.
To obtain at least one malaria vaccine candidate stably expressed in MeV that
induces humoral and cellular immune responses.
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.
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.
Etna Biotech SpA
Piazza Stesicoro 59
Tel/Fax: +39 095 250 0276
|2||Hermann Bujard||Zentrum Molekulare Biologie|
University of Heidelberg
Im Neuenheimer Feld 282
|Tel: +49 6221 54 6800|
Fax: +49 6221 54 6809
|3||David Arnot||Edinburgh University|
The King’s Buildings
UK-EH9 3JR Edinburgh
|Tel: +44 131 650 5525|
Fax: +44 131 650 6556
1 rue Pierre Fontaine
FR-91058 Evry Cedex
|Tel: +33 1 60 91 33 10|
Fax: +33 1 60 91 33 29
|5||Alan Thomas||Biomedical Primate Research Center|
Lange Kleiweg 151
PO Box 3306
NL-2280 GH Rijswijk
|Tel: +31 15 284 2688|
Fax: +31 15 284 3987