Development of a DNA-based multi-vaccine for the treatment of allergy caused by plant pollen related food allergens

Research project P 13827 DNA-based immunotherypy for the treatment of allergy Josef THALHAMER 28.06.1999 Allergic symptoms caused by type I allergies like rhinitis, bronchial asthma and conjunctivitis are widespread among the human population of industrialized countries. A sustained production of IgE molecules against common environmental antigens is one of the characteristic events in allergic disease and cytokines like IL-4 and its inhibitory counterpart IFN-y are assumed to determine the course and severity of the allergic phenomenon. With DNA-based immunization a new and powerful method for vaccine research and development arose in the last years. Recent publications also have demonstrated a potential role of this immunization technique for allergy treatment. A special feature of this method, and the major difference between conventional immunization with protein antigens (or allergens) and plasmid DNA, is the induction of an INF-y mediated anti-allergic Th- I type response. Therefore, the aim of the present project is to establish a DNA-based desensitization protocol in mice. Genes of various clinically relevant allergens are cloned into an expression vector which is then used for immunization. Two major questions will be addressed: 1) can an established atopic response be converted into a non-allergic one? 2) does a Th1 response induced by plasmid DNA prevent an allergic response? The first approach represents the concept of an immunotherapy against ongoing allergic responses, whereas the second approach can be seen as a vaccination against the development of new allergic responses. Many allergens can be divided into certain groups (or symptoms) according to their cross-reactivity (like the 17 kDa tree pollen allergens, tree pollen related food allergens, plant panallergens; etc.). This has led to the assumption that a limited number of allergens may offer a successful treatment against a wide range of symptoms. In a three- step approach we intend to characterize potent Th1 response inducing allergens, select the dominant cross- protecting allergens within a certain group and again pick out the most effective candidates for a combinded DNA multi-vaccine against different groups and syndroms.

Type I allergy represents a hypersensitivity disease based on the production of certain antibody types (IgE) against otherwise harmless molecules (i.e., allergens). Regulatory molecules (cytokines) are assumed to determine the course of severity of the allergic phenomenons. With DNA-based immuniziation a new and powerful method for vaccine research and development arose in the last years. A special feature of this approach, and the major difference to immunization with protein, is the induction of anti-allergic immune responses. Gene vaccines consist of pure genetic information (plasmid DNA). After injection, the gene vaccine is translated into the respective gene products which are presented to the immune system and thus trigger specific immune responses. The high purity of gene vaccines minimizes the risk of inflammatory or anaphylactic side effects as can be induced by impurities caused during the production of conventional vaccines. In addition, gene vaccines are cheap, easy to handle and stable without cooling. In the present project we used an animal model to develop and characterize gene vaccines against allergens from tree pollen, grass pollen, weeds and food. The results demonstrated that genetic immunization, both, protects from an allergic response as well as balances an established allergic reaction thus indicating the protective and therapeutic potential of this method. This approach was successful not only with vaccines against single allergens but also with multi vaccines covering whole groups of allergens. Furthermore, we found out that single gene vaccines can protect against a variety of related allergens. This indicates, that gene vaccines consisting of few defined and highly pure components may enable to treat complex allergic diseases. State of the art Genetic immunization was first published in 1992 and led to an intensive and systematic research in this field in the last 5 years. Gene vaccines give great hope for fighting the most far reaching infectious diseases of the world, such as malaria, HIV and tuberculosis, and they enable novel approaches for tumor treatment. Beyond, as could be demonstrated with the present project, genetic immunization represents an excellent method for the development of prophylactic and therapeutic vaccine strategies for allergy treatment. With respect to economic aspects, our research is pushing innovative advances in the field of vaccine research and development.