Novel Therapeutic Vaccines for Chronic HBV

描述（由申请人提供）：乙型肝炎病毒（HBV）是一种非细胞病变、嗜肝性DNA病毒，在大多数健康个体中可导致自限性急性感染，但也可引起慢性感染，特别是在通过垂直传播感染的新生儿中。慢性乙型肝炎感染是一个重大的全球卫生问题，直接影响到全世界3.5亿人，每年导致50万至120万人死亡。围产期获得慢性HBV感染的成年人患肝细胞癌的比率约为每十年5%，比未感染者的比率高出约100倍。抗病毒药物可以抑制病毒复制，有助于降低发病率和死亡率

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is a noncytopathic, hepatotropic DNA virus that results in a self-limited acute infection in a majority of otherwise healthy individuals but can also cause chronic infection, particularly in newborns infected by vertical transmission. Chronic hepatitis B infection is a significant global health issue directly affecting 350 million people worldwide and resulting in 0.5-1.2 million deaths per year. Adults with chronic HBV infection acquired in the perinatal period develop hepatocellular carcinoma at a rate of about 5% per decade, approximately 100-fold higher than the rate among uninfected individuals. Antiviral drugs can inhibit viral replication and contribute to reducing morbidity and mortality, but they do not represent a cure. Proof-of-concept studies with chimpanzees chronically infected with HBV have shown that a DNA vaccine encoding the HBV surface antigen (HBsAg) followed by a recombinant canarypox boost can produce a large decline in HBV DNA levels for several years. Despite this encouraging result in the only non-human model, clinical trials of therapeutic vaccines have not provided a strong enough response to suppress viral replication. We hypothesize that mixtures of variant HBsAg proteins containing xenogeneic hepadnavirus T epitopes will prime helper T cells and CTLs to recognize the viral protein in chronically infected individuals, which otherwise respond poorly to the viral protein. The use of mixtures of chimeric sequences is innovative; by combining several unique variants it is possible to cover most or all wild-type epitopes while maximizing the content of immunostimulatory sequences. This hypothesis is novel and indirectly supported by data obtained in our Preliminary Studies. However, it clearly requires more extensive experimental support, notably direct data on T-cell responses, and this will be provided by the feasibility stud of this Phase I SBIR. We propose to develop a therapeutic DNA vaccine product delivered by electroporation and expressing a mixture of HBsAg variants. A number of immunogenic HBsAg variants containing xenogeneic sequences with novel T epitopes have been identified using a directed molecular evolution approach. Mixing several variants will increase the immunotherapeutic potential of the combined vaccine by including many different xenogeneic epitopes. Beginning with seven individual variants, all possible 3-variant combinations will be screened using a tiered strategy to identify the most immunogenic mixtures in normal and HBsAg-transgenic mice. The main objective of this Proposal is to identify mixtures that can induce strong T-cell responses and that are safe and well tolerated. An important feature of this work is the existence of potential backup candidates at all stages of development. Advancing multiple candidates at the early stages of lead optimization increases the likelihood of a successful outcome. Success in developing this innovative DNA-based therapeutic vaccine for chronic HBV infection would fill a considerable unmet need in the treatment of this disease, which represents a major public health burden. PUBLIC HEALTH RELEVANCE: Hepatitis B virus infection can cause chronic disease in certain people, particularly newborns. This is a major health issue affecting over 350 million individuals worldwide resulting in 0.5-1.2 million deaths per year, often from liver cancer. We wil develop a vaccine to treat this chronic infection and potentially cure the disease.