Evaluation of genetic vaccines for the treatment

The prevalence of allergic diseases has increased substantially over the past few decades in the industrialized world despite the introduction of new and effective drugs for their treatment. At present, allergic diseases affect more than one quarter of the population and several theories have been established to explain the constant rise of allergies. In recent years the so-called "hygiene hypothesis" has emerged as an elegant explanation, suggesting that bacterial infections very early in life give an important impetus to develop anti-allergic capacities of the immune system. Lack of childhood infections due to vaccination, the use of antibiotics and modern hygiene increases the risk of allergic reactions against potential allergens. Allergy can be defined as a disorder of the immune system, leading to inappropriate responses against commonly encountered substances that are otherwise harmless. Clinically, the most common allergic diseases are asthma, rhinitis/conjunctivitis (hayfever) and eczema. Allergic immune responses are characterized by the synthesis of allergen-specific IgE antibodies and the production of immunomodulatory molecules such as interleukin (IL)-4, IL-5 and IL-13. Today, most anti-allergic treatments only control the symptoms of allergy via immunosuppressive and anti- inflammatory agents such as antihistamines, corticosteroids and beta-agonists. The only curative approach targeting the disease is allergen-specific immunotherapy (SIT). Although SIT has already been introduced by Noon and Freeman in 1911, the immunological mechanisms underlying this treatment are still unclear. Although SIT has proven its suitability and clinical efficacy especially for mono-or oligosensitized patients and for treatment of hypersensitivities against stinging insects, only 30-50% of allergic rhinitis patients respond and SIT is even less effective for asthmatics. Another major disadvantage of classical SIT is the risk of anaphylactic side effects caused by systemic application of large amounts of allergen via subcutaneous injections. In summary, there is an urgent need for improvement and/or alternatives to conventional SIT. Over the last decade, the genetic vaccine revolution has provided researchers with exciting possibilities to design new advanced vaccines. Genetic vaccination employs the allergen in its purest form - the genetic information. Following transfection with the genetic material, cells of the vaccinated individual will translate the information into the respective allergen. This type of vaccine specifically induces a type of immune response dominated by the immunomodulator interferon gamma, which suppresses IL-4/IL-5 dependent allergic immune responses. Meanwhile, a panel of genetic vaccines has been successfully administered in animal models, including plasmid DNA, purified RNA, and "self-replicating" DNA/RNA. Also several different delivery methods such as intramuscular or intradermal injections, application via "gene gun", in vivo electroporation, intra-nodal injection and immunization via mucosal routes have been investigated in animal models. However, results from early clinical studies (for infectious diseases and cancer) have often been disappointing due to suboptimal utilization of the latest feasibilities of modern genetic vaccines. Although animal studies with anti-allergic genetic vaccines have been promising, a systematic evaluation of different vaccines, doses, immunization methods and schedules will be of crucial importance for the success of future clinical trials. For the proposed study, we will establish novel anti-allergic RNA vaccines and bacterial ghost-delivered genetic and recombinant vaccines and evaluate them together with the present state-of-the-art genetic vaccines, application methods, adjuvants and immunization protocols as a basis for preparing clinical application. Simultaneously with providing the urgently necessary comparative information about different vaccination approaches, an objective evaluation will also exert gentle pressure on planning of phase I trials, thus helping to speed up the process of developing rational anti-allergic genetic vaccines for human use.