Summary:

This STREP, co-ordinated and lead by an SME, will focus on the development of new malaria vaccine candidates with the aim of taking at least one product to the stage of pilot scale. Products showing most promise, once expressed in the Tetrahymena system (or Ciliate system), will proceed to antigen testing in vitro and in vivo, to assess their structure and antigenic integrity. At least one product is expected to reach lead optimisation, safety and toxicology testing.

Combining the expertise of the two academic malaria research laboratories with the novel Ciliate-based expression system under development by the SME, will generate recombinant Tetrahymena thermophila strains expressing malaria antigens based primarily upon MSP-1 and the var2CSA genes of Plasmodium falciparum. To utilise the capabilities of the participants to greatest efficiency, this STREP will comprise, beside the Project Management, work packages dealing with the generation of antigen expressing Ciliate strains, pilot scale production and purification of the antigens and the testing and validation of candidate vaccines.

This STREP application, co-ordinated by Cilian AG, will provide an expression platform that can easily combine antigens to develop new combination vaccines that may be more promising than vaccines currently under development. Ciliate-based expression of Plasmodium falciparum proteins in secreted, membrane bound or cytosolic forms will complement the work done under the larger European malaria vaccine development project.

Background:

Malaria kills over one million children in Africa alone each year, with an addition of up to 500 million episodes of clinically significant illness due to malaria annually.Worldwide deaths are estimated at between 2 and 3 million per annum. Few other infectious diseases place such a burden on the social, economic and healthcare systems of developing countries. Therefore there is a pressing need for the development of a vaccine against malaria, to ease at least part of this overwhelming burden on the continent of Africa, which suffers the majority of the deaths and illness caused by the malaria parasite.

Aim:

The aim of this project is to use an innovative new expression platform based on the Ciliate Tetrahymena thermophila in conjunction with two novel malaria vaccine candidates, as a method of advancing these antigens to pre-clinical testing, prior to testing in humans. It will produce novel Tetrahymena organisms expressing Plasmodium falciparum antigens at pilot-scale production levels.

The two antigens selected are novel yet promising candidates based on the Nterminal region of MSP-1 and the Var2 CSA variant of the PfEMP-1 antigen family.

Expected results:

The main objective of this STREP is to produce within three years at least two candidate vaccine antigens against the blood stage of the malaria parasite Plasmodium falciparum, ready to use for pre-clinical evaluation. The candidate antigens (MSP-1 and VAR2CSA) will be expressed by the novel expression platform Tetrahymena thermophila, a free-living Ciliate, which expresses Plasmodium falciparum antigens efficiently. Partial results will be: vector constructs that are suitable for expression; appropriate reproducible lab scale purification protocols; optimised host strains; a first up- and downstream process up to pilot scale; and implementation of the first steps of a quality management for potential later GMP production.

Potential applications:

There are no effective vaccines for malaria currently available. Vaccination trials conducted in humans with existing candidates have been met with limited success. This stresses the need for continuing efforts towards testing novel candidates. This project offers a novel biotechnological approach to vaccine development and responds to the demands of developing countries, non-profit organisations and charity foundations, to technologically contribute to actions targeted at the major poverty-related diseases, including malaria. One goal of the approach is to apply the underlying technological concept of this project to the later industrial development and production of a new and highly effective vaccine candidates against malaria.

Coordinator:

Partners:

Nº	Principal Scientific Participants	Official Address	Other Information
2	David Cavanagh	Institute of Cell, Animal and Population Biology University of Edinburgh, Kings Buildings, West Mains Road Edinburgh EH9 3JT Scotland United Kingdom	Tel: +44 131 650 5459 Fax: +44 131 650 7322 E-mail: david.cavanagh@ed.ac.uk Web-site: homepages.ed.ac.uk/eang15
3	Thor Theander	Centre for Medical Parasitoolgy University of Copenhagen Panum Building 24.2 Blegdamsvej 3 DK-2200 Copenhagen N Denmark	Tel: +45 35 32 7677 Fax: +45 35 32 7851 E-mail: theander@biobase.dk Web-site: www.euromalvac.org/profiles/theander.htm