Avian Influenza Virus Vaccines Bearing Immunomodulators

描述(申请人提供)：禽流感病毒对发展中国家和发达国家的人和鸡的健康构成重大威胁。鸡和水生禽类还提供了流感病毒的宿主，在过去几年中，这种病毒越来越多地越过了禽类与人类之间的屏障，在几个大陆上造成了人类的致命疾病。作为大流行性流感病毒株的潜在来源，这一蓄水池令人严重关切。目前有灭活疫苗可用于预防一些流行毒株，对于这些毒株来说，疫苗在预防疾病方面是有效的。然而，这些疫苗并不能完全防止病毒脱落。现有灭活疫苗的另一个重大问题是，它们对不同的流感毒株提供的交叉保护最小。灭活疫苗的保护作用是由病毒血凝素和神经氨酸酶抗体介导的。这些蛋白质抗原表位的微小变化，称为“抗原漂移”，可能会严重降低疫苗效力。在哺乳动物中，已经做出了令人鼓舞的努力，使用添加细胞因子的灭活疫苗诱导T细胞毒性和Th1型反应，因为这些反应对同型和异型流感毒株更有效。然而，这些努力并不容易转化为商业上可行的禽类疫苗的生产。为了解决这个问题，我们提出了一种分子方法，将鸡免疫调节细胞因子和趋化因子锚定在流感病毒的包膜糖蛋白上。病毒将被完全灭活，方案是保持附着分子的生物活性不变。我们的假设是，细胞因子或趋化因子修饰的病毒颗粒除了保护性体液反应外，还会诱导有效的Th1和/或T细胞毒反应，从而对同型和异型流感病毒株提供更好的保护。

DESCRIPTION (provided by applicant): Avian influenza viruses pose a significant health threat for both humans and chickens in developing and developed countries. Chickens and aquatic avian species also provide a reservoir of influenza viruses that have increasingly in the last several years crossed the avian-human barrier and caused fatal disease in humans across several continents. This reservoir is of major concern as a potential source of pandemic influenza virus strains. Inactivated vaccines are currently available for protection against some of the circulating strains, and for these strains the vaccines are effective in preventing disease. However, these vaccines do not completely prevent viral shedding. Another significant problem with existing killed vaccines is that they confer minimal cross-protection to divergent influenza strains. Protection induced by inactivated vaccines is mediated by antibody to the viral hemagglutinin and neuraminidase. Minor changes in antigenic epitopes of these proteins, termed "antigenic drift" can severely reduce vaccine efficacy. Encouraging efforts have been made in mammals to induce T cytotoxic and Th 1 type responses using killed vaccines supplemented with cytokines, since these responses are more efficacious against homotypic and heterotypic strains of influenza. However, these efforts are not easily translated to the production of commercially feasible avian vaccines. To address this problem, we are proposing a molecular approach that will anchor chicken immunomodulatory cytokines and chemokines to the envelope glycoproteins of influenza virus. The viruses will be completely inactivated with a protocol that leaves the bioactivity of the attached molecule intact. Our hypothesis is that cytokine- or chemokine-modified virus particles will induce an efficacious Th1 and/or T cytotoxic responses in addition to a protective humoral response and thus, provide better protection against homotypic and heterotypic influenza strains.