Servicio de Información Comunitario sobre Investigación y Desarrollo - CORDIS

FP6

AIM Informe resumido

Project ID: 509670
Financiado con arreglo a: FP6-MOBILITY
País: United Kingdom

Final Activity Report Summary - AIM (Antibody Immunotherapy for Malaria)

The project had the goal of developing novel fully human antibodies as potential therapeutic agents both for the treatment and understanding of malaria immunity. Malaria remains one of the most deadly infectious diseases and there is a clear need to develop novel control strategies to limit the parasite in people. Two potential immunological strategies are to develop vaccines and / or therapeutic antibodies. Development of these for the most deadly human malaria parasite, Plasmodium falciparum at the preclinical stage has been hampered by a lack of a good in vivo challenge model. We recently provided a solution by generating a novel mouse model combining both rodent malaria parasites (Plasmodium berghei) transgenic for key P. falciparum antigens and mice transgenic for human Fc-receptors [PLoS Pathogens. 18;3(5):e72 ].

We used this model to show that recombinant Abs directed against the malaria parasite, could protect mice from a lethal malaria infection, but only in the presence of the appropriate human Fc-receptors. The work showed that transgenic models can be used to assess immunity to the human parasite P. falciparum mediated by human antibodies and human antibody receptors. This model has a number of advantages over both primate models and in vitro studies. For example, the most commonly used in vitro assay would not have predicted that the antibody used was protective because the in vitro assay did not replicate the important in vivo interaction between the antibody and the cell-surface receptor. The study also validated the target of the antibody (merozoite surface protein 1; MSP119) as a major vaccine candidate. Vaccine development is laborious, costly and time consuming. We recently demonstrated that sera from a well characterised cohort of immune Gambians could also protect in our Fc?RI transgenic mouse. Therefore, antibodies from volunteer vaccinees could be assessed for protection using this mouse model, allowing vaccination regimens to be optimized rapidly prior to clinical trials in humans.

Our work also highlighted the potential inadequacies of in vitro assays, placing greater emphasis on the need for effective in vivo studies. The model can now be used to develop vaccination strategies, which produce effective antibodies that protect in vivo, and to identify particularly effective types of antibody, for example by using different human FcRs. For sound scientific reasons already alluded to we shall focus on MSP1-19, although aware that this approach may potentially be used to present a cocktail of promising antigens to the immune system, as recently demonstrated successfully with MSP119-AMA1 fusion proteins using conventional adjuvants.

This humanised mouse model provides a very important tool in malaria vaccine development to validate target antigens, to assess the effect of specific antibodies, and to optimise vaccine delivery methods prior to clinical trials in humans. Our work, funded largely by the European Commission, was published in PLoS Pathogens was highlighted by Nature, Lancet Infectious Diseases, JAMA, and New Scientist as having the potential to make a significant impact on malaria vaccine research. This work was also published on the CORDIS website at: http://cordis.europa.eu/fetch?CALLER=MSS_NEWS_NL_EN&ACTION=D&DOC=36&CAT=NEWS&QUERY=011a03d6ac75:947d:21b32e79&RCN=27729

Reported by

THE UNIVERSITY OF NOTTINGHAM
NOTTINGHAM
United Kingdom
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