The Development Of A Novel Vaccine For Alzheimer’s Disease And Establishment Of Clinical Immunological Evaluation System For HBV Therapeutic Vaccines

Vaccine could treat diseases via stimulating body’s own immune responses, and regulating specific immune aims to elicit appropriate responses against pathogens. Currently, there is no effective drug treatment against various chronic infections and related diseases, but the therapeutic vaccine technology, which has good specficity and low cost, presents a great opportunity to solve the problems.Alzheimer’s disease (AD) is a one of nervous system chronic illness. The most important pathological hallmark is formation of extracellular senile plaques (SP) containing the peptide β amyloid (Aβ). It is reported that vaccinations using Aβ protein could well clear the Aβ deposits in murine models. However, at the same time, this vaccination induced some patients appearing meningoencephalitis because of CD4+T cells activations. To reduce T cell activation, but yet remain the high level of anti-Aβ42antibody is a great challenge in the field of immunology. In this study, we demonstrated that a co-immunization of AP42could not only induce high level of antibodies against the Aβ42, but also inhibit its T cell-mediated inflammation. This protocol could improves cognitive deficits significantly in an AD model and the induced immunity does not lead the CD4+T cell-mediated infiltrations in CNS. Therefore, co-immunization strategy elicited a protective response against the AD without pathogenesis may lead to the development of a safety immunotherapeutic means against AD in humans. Besides the immunization protocol, we also improved the adjuvant for AD vaccine. We tried both of the immunosuppressive and enhanced adjuvant as the co-immunization adjuvant. We found that immunosuppressive adjuvant could not improve the co-immunization function, but the enhanced adjuvant had this function. So we screen the adjuvant in influenza vaccine, found Nizatidine, a small molecular compound, could stimulate immune response. The results also showed that Nizatidine was able to confirm the co-immunization affection and be used in the AD co-immunization vaccine.Back to investigation of the reason for Aβ42protein vaccine failure in the clinical trial due to the inflammatory responses, one of the main reasons was that no systematic immune analysis particularly in cell mediated responses in the most of therapeutic vaccine research. Now cell based clinical immunological evaluations become a major hurdle against development of therapeutic vaccines. Therefore, the establishment of a comprehensive clinical evaluation system for therapeutic vaccines is an urgent need. In the second part of this paper, we participated in a small clinical trial of ongoing therapeutic HBV vaccine-YIC, to establish a clinical evaluation system analysis of detecting the T cell specific immune responses. One of which, is the T cell multi-function analysis and realized by the secretion of cytokines of a single T cell. In this study, we examined that totally21kinds of cytokine expressions within the population of CD4+T and CD8+T, and further correlating between the level of cytokine expressions and clinical outcomes over the course of vaccinations. We observed that the levels of ALT and HBV DNA were significant difference between the group of YIC and placebo in immune responses, particularly in the activations of CD4and CD8. CD4+T cells in the YIC group were exhibited a significant activation after four immunizations, whereas the CD8+T cells were activated after six immunizations. These results provided the first evident to show that a therapeutic vaccination could modulate host cell mediated responses. The evaluation system could be further explored to become a clinical analysis means to assist evaluations for the development of therapeutic vaccines during clinical trials.In summary, we developed a novel therapeutic vaccine based on the co-immunization technology against AD. This vaccine provides effective treatment against AD but yet not adverse effects, and used Nizatidine as adjuvant to improve the co-immunization vaccine. To fill the gap between immunology and clinical evaluation for therapeutic vaccine, we developed a clinical evaluation system based on analysis of multi-functional T cells during vaccinations.