Objective
This shared-cost RTD project is highly innovative and builds on novel principles for immunomodulation using targeted actions directed at distinct cellular subsets of the immune system. The aim of the project is to acquire basic information about mechanisms in immunomodulation and to apply this information in the development of new vaccine adjuvants, which will allow the broader use of mucosal vaccines and in particular oral vaccines. Such vaccines are at present much warranted and with appropriate immunomodulation may be made highly cost-effective and safe vaccines. Although several probe antigens will be used for the evaluation of adjuvant efficacy in the present proposal a special focus will be given the prevention of H. pylori infection as evaluated in the murine vaccine model.
Our approach to the construction of powerful mucosal vaccine adjuvants is unique. It is based on our accumulated knowledge of immune regulation and tolerance-induction at mucosal surfaces, our ambition to acquire detailed information on the mechanisms responsible for the mucosal adjuvant effects of cholera toxin (CT) and ISCOMS and, lastly, the ability to use this information in the construction of new non-toxic vaccine adjuvants. To achieve these goals we propose to:
A) Compare the mucosal adjuvant effects of CT and iscoms for induction of local mucosal and systemic responses using conventional protein antigens. We will use various gene knockout mice to establish which are the regulatory requirements for the adjuvant effects of the two systems and based on these findings formulate strategies for the construction of novel mucosal adjuvants. Preliminary results have clearly indicated that CT and ISCOMS use separate pathways (and perhaps target cells) for the induction of immune responses following oral administration.
Bl) We have separated adjuvanticity and toxicity in the cholera toxin system by constructing gene fusion proteins that target the ADP-ribosyl transferase activity of the CTAl subunit to antigen-presenting cells, primarily B cells. This represents a major break-through in toxin-adjuvant research. Exploring this novel non-toxic adjuvant system; CTAl-DD, should provide a strong basis for the design of future mucosal vaccine adjuvants.
B2) Develop new iscom formulations for optimal induction of mucosal and/or systemic immunity with special emphasis on induction of antigen-specific CTL-activity.
B3) Combining the CTAl-DD and iscom adjuvant systems to obtain synergistic or additive effects. We will also explore the possibility of
PLG-micro-encapsulation to protect the adjuvants/immunomodulators from degradation in the gut and to allow better up-take following oral administration.
C) Evaluation of adjuvant efficacy by analysis of immune protection in the murine H. pylori mode following mucosal immunization with the most promising candidates, including the CTAl-DD adjuvan system.
Our group, consisting of highly qualified and internationally well recognized scientists and two vaccine companies, will be linked together so that long-standing excellence of European research in the field of mucosal adjuvants will be further developed. The different laboratories undertaking the proposed work are already representing successful collaborations and have been selected on the basis of merits. The group has access to the latest technologies in immunology, ISCOM-design and molecular engineering and has produced pioneering work in many of the basic areas of research that will be required for this project.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences basic medicine immunology immunisation
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences basic medicine pharmacology and pharmacy pharmaceutical drugs vaccines
- engineering and technology other engineering and technologies microtechnology molecular engineering
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Coordinator
413 46 Gfteborg
Sweden
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