Lipid/DNA/Antigen Complexes for Influenza A Viral Vaccination

用于甲型流感病毒疫苗接种的脂质/DNA/抗原复合物

• 批准号: 7050653
• 负责人: Jeff C Fairman
• 金额: $ 44.76万
• 依托单位: JUVARIS BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050653
• 关键词: DNA; active immunization; antigens; infection; influenza; lipids; proteins

DESCRIPTION (provided by applicant): Influenza A (fluA) infection causes annual substantial morbidity and mortality worldwide, particularly for infants, the elderly, and the immuncompromised. FluA mainly replicates in the respiratory tract, with virulent strains also disseminating to other tissues, such as the central nervous system. A growing concern is the recent spread of virulent avian influenza viruses, such as H5N1, in Asia, which could substantially increase the risk of a human pandemic. Sporadic cases of avian-to-human transmission, with a high mortaility rate have recently occurred. Because of its ability to readily undergo genetic reassortment and be generated by recombinant DNA, and to be rapidly spread by exposure to respiratory secretions, FluA is also a potential biothreat agent. Current vaccines, such as the parenterally administered trivalent inactivated vaccine (TIV) or live attenuated vaccine (LIV) given intranasally, induce minimal or modest levels of cytolytic T-lymphocyte (CTL) activity, and provide protection mainly by the production of CD4 T-cell dependent neutralizing antibodies. The efficacy of these vaccines is highly dependent on close matching of the hemagglutinin (HA) and neuraminidase (NA) surface proteins of the vaccine with currently circulating virus. Should neutralizing antibody fail to prevent infection of the respiratory tract, subsequent clearance of viral infection is mainly dependent on T cells, particularly CTL. Juvaris BioTherapeutics is developing and characterizing a unique adjuvant that is particularly promising for vaccines that induce both high levels of antibody and T-cell immunity, including CTL. The adjuvant is based on a complex of lipid carrier and non-coding DNA (CLDC), and is effective via multiple routes, including parenteral, respiratory, and oral. Inclusion of protein antigens with CLDC results in an extremely robust humoral and CD4 and CDS T-cell response to model antigens, such as ovalbumin or moth cytochrome c, as well as antigens from pathogens that target the respiratory tract, such as Yersinia pestis and Mycobacterium tuberculosis. Certain vaccination routes, such as intraperitoneal and oral administration results in particularly striking levels of CTL in the lung. The specific goals of this proposal are to optimize the CLDC- vaccine system for influenza A-specific T-cell responses in vivo, particularly in the lung. This optimal formulation will be used to evaluate protection against intranasal challenges with mouse attenuated influenza A strains (HKx31 and PR/8/34) as well as highly virulent recent isolate strains of avian H5N1 virus. A major focus will be in comparing vaccine efficacy based solely on T-cell immunity to internal virion proteins with that afforded by these responses in combination with antibody to external proteins. If successful, Phase II will examine potential manufacturing methods for the vaccine and large animal efficacy studies.

描述（由申请人提供）：流感（FLUA）感染会导致全球年度大量发病率和死亡率，尤其是对于婴儿，老年人和免疫进来的。 Flua主要在呼吸道中复制，具有强大的菌株也将其传播到其他组织，例如中枢神经系统。一个日益增长的关注是亚洲有毒的禽流感病毒（例如H5N1）的传播，这可能会大大增加人类大流行的风险。最近发生了零星到人类传播的零星病例，最近发生了高降低率。由于它能够轻易地经历遗传重组并通过重组DNA产生，并通过暴露于呼吸道分泌物来迅速传播，因此Flua也是一种潜在的生物疗法。当前的疫苗，例如肠胃造成的三价灭活疫苗（TIV）或实时衰减疫苗（LIV），在内部内诱导最小或适中的细胞溶解T-淋巴细胞（CTL）活性，并主要通过CD4 T-CELL T-CELL依赖性抗体的产生来提供保护，并主要通过提供保护。这些疫苗的功效高度依赖于疫苗的疫苗与目前循环病毒的疫苗的表面蛋白的紧密匹配。如果中和抗体无法防止感染呼吸道，随后的病毒感染清除率主要取决于T细胞，尤其是CTL。 Juvaris Biotherapeics正在开发和表征独特的佐剂，对于诱导高水平的抗体和T细胞免疫（包括CTL）的疫苗特别有希望。佐剂基于脂质载体和非编码DNA（CLDC）的复合物，并且通过多种途径，包括肠胃外，呼吸和口服。将蛋白质抗原与CLDC纳入蛋白质抗原会导致对模型抗原（例如卵毛蛋白或类型细胞色素c）以及针对呼吸道的病原体的抗原的CD4和CDS T细胞反应，例如pestis pestis和mycobacterium and Coptium yersinia and Mycobacterium。某些疫苗接种途径，例如腹膜内和口服给药，导致肺中特别明显的CTL水平。该提案的具体目标是优化用于体内流感A特异性T细胞反应的CLDC疫苗系统，尤其是在肺中。该最佳配方将用于评估小鼠衰减菌株（HKX31和PR/8/34）以及高度毒性的近来分离株的禽类H5N1病毒的菌株（HKX31和PR/8/34）的鼻内挑战的保护。主要重点是将仅基于T细胞免疫对内部病毒素蛋白的免疫与这些反应与外部蛋白抗体结合使用的疫苗疗效与这些反应提供的疫苗功效。如果成功，第二阶段将检查疫苗和大型动物疗效研究的潜在制造方法。