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MALTRANS
MALARIA
Framework programme: 5
Project number:
QLK2-CT-1999-00753
EC contribution: € 2 499 962
Duration: 36 months
Type: RS
Starting date: 1 March 2000
Graphic element Project Interruption of Malaria Transmission Vaccine Strategies
Keywords: Transmission; blockade; vaccines; malaria

Summary:

Malaria is one of the major infectious diseases in the world with tremendous impact on quality of life. Malaria control is difficult and the available tools are limited. Vaccines designed for different stages of the parasite life cycle will be the only long-term and cost-effective tool to control this ever growing problem. Malaria vaccines aim at interruption of the life cycle of Plasmodium falciparum by vaccine-induced immune responses. The sexual stages of the cycle occur in the human host and in the mosquito vector, and are responsible for transmission and spread of the parasite in the population. Sexual stage vaccines aim at an arrest of the transmission and therefore spread or (re-)introduce the disease in a risk area. The objectives are: 1) the production of a transmission-blocking (TB)-Pfs48/45 peptide vaccine up to the phase of clinical testing 2) the identification and characterisation of novel parasite-and/or mosquito-derived targets for TB-immunity 3) the improvement of the bio-assay for the measurement of TB-immunity; identification of correlates of protection. 4) the development of a model for malaria transmission in non-human primates as a tool for functional analysis of vaccine candidates and a pre-screen for vaccine trials in humans.

Description:

TB-vaccine production: Pfs48/45 is currently the most advanced transmission-blocking (TB) vaccine candidate in Europe. By application of phage-display technology, peptides (mimotopes) have been identified which mimic epitopes of Pfs48/45 that are targets for TB-antibodies. Constrained mimotopes will be structurally characterised (nuclear magnetic resonance) and optimised. mimotopes will be validated before testing in animals by confirming their recognition by (natural) human anti-Pfs48/45 antibodies. Rodents and non-human primates will be immunised with constrained mimotopes for the induction of TB-immunity.

New targets: Novel antigens on gametocyte-infected red blood cells will be identified and (monoclonal)-antibodies (mAbs) will be raised and tested for their capacity to interfere with gametocyte maturation and infectivity. Novel antigens on sporogonic stages of the murine malaria parasite P. berghei will be identified from an available panel of mAbs generated against Pbs21/25 double gene knockout ookinetes and tested for their capacity to induce TB abs. Gene function will be studied by the construction of transgenic/knockout parasites.

Assays: The standard membrane-feeding assay (which is the gold standard for the measurement of TB antibodies) will be simplified and the sensitivity will be increased by application of quantitative molecular techniques. Alternative correlates of protective immunity will be developed using immuno-assays.

Animal models: Next to available murine models, a non-human primate infected with (genetically modified) P. knowlesi will be developed to be a model for TB vaccine research. Homologues of P falciparum vaccine candidates (Pfs48/45) will be isolated. The biological function of the 48/45 kD protein will be studied in transgenic/knockout and gene replacement parasites.

Coordinator:

R.W. Sauerwein
UMC St Radboud
440 Medical Microbiology
P.O. Box 9101
6500 HB Nijmegen
The Netherlands
Tel: +31 24 361 4356
Fax: +31 24 354 0216
E-mail: r.sauerwein@mmb.azn.nl

Partners:

Principal
Scientific
Participants
Official Address Other Information
2H. G. StunnenbergUniversity of Nijmegen
NL-Nijmegen
The Netherlands
3M. Dyer & K. DayUniversity of Oxford
UK-Oxford
United Kingdom
4R.E. SindenImperial College of Science, Technology and Medicine
UK-London
United Kingdom
5P. BillingsleyUniversity of Aberdeen
UK-Aberdeen
United Kingdom
6P. AlmeidaUniversidade Nova de Lisboa
PT-Lisbon
Portugal
7A. Thomas and C.H.M. KockenBiomedical Primate Research Center
NL-Rijswijk
The Netherlands
8L. Ranford-CartwrightUniversity of Edinburgh
UK-Edinburgh
United Kingdom
9G. Target and C. SutherlandLondon School of Hygiene and Tropical Medicine
UK-London
United Kingdom
10A.P. WatersLeiden University Medical Center
NL-Leiden
The Netherlands
11J.M. Garcia AntonLIPOTEC S.A.
ES-Barcelona
Spain

 
 
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