Novel vaccines for broad protection against avian influenza

描述（由申请人提供）：高致病性禽流感（HPAI）病毒可能在未来某个时候引起流感大流行。传统的流感疫苗生产方法可能太慢，无法有效应对这种大流行。因此，开发能够快速部署的疫苗平台以预防这种大流行非常重要。基于重组活的、减毒的或有复制缺陷的水疱性口炎病毒（VSV）的疫苗载体是迄今为止测试过的最有效的疫苗载体之一。它们还有一个主要优势，即人群中没有预先存在的对病媒的免疫力。VSV载体表达来自高致病性禽流感病毒的H5N1血凝素（HA）蛋白，可在小鼠和非人灵长类动物中诱导高滴度宽中和（交叉进化）抗体。它们还可以防止致命的AIV感染。当前项目的目标是进一步开发和测试新的、优化的、基于vsv的AIV疫苗载体，这些载体产生更高水平的AIV HA。这些载体还应诱导更高的中和抗体滴度，并有望产生最大的跨枝中和抗体滴度。待开发的优化的、高度减毒的或有复制缺陷的单循环VSV载体可作为广泛保护性的AIV疫苗的基础，这种疫苗可用于快速生产和部署，以应对流感病毒大流行。公共卫生相关性：据估计，20世纪的流感大流行已造成全世界4000多万人死亡。未来的大流行肯定会发生，而且极有可能是由禽流感病毒的突变和交叉进入人群引起的。这个项目的目标是研制一种新型疫苗，这种疫苗能产生非常广泛的中和抗体，对禽流感病毒株具有广泛的保护作用。此外，与传统流感疫苗不同，这种疫苗可以迅速生产和部署，以阻止大流行。

DESCRIPTION (provided by applicant): Highly pathogenic avian influenza (HPAI) viruses are likely to cause an influenza pandemic at some point in the future. Traditional methods of influenza vaccine production will probably be too slow to allow an effective response to such a pandemic. Development of rapidly deployable vaccine platforms capable of protecting against such a pandemic is therefore of major importance. Vaccine vectors based on recombinant live, attenuated or replication- defective vesicular stomatitis virus (VSV) are among the most potent vaccine vectors tested to date. They also have a major advantage in that there is no pre-existing immunity to the vector in the human population. VSV vectors expressing an H5N1 hemmaglutinin (HA) protein from an HPAI virus induce high-titer broadly neutralizing (cross-clade) antibodies in both mice and non-human primates. They also protect against lethal AIV infection. The goal of the current project is to further develop and test novel, optimized, VSV-based AIV vaccine vectors that produce much higher levels of the AIV HA. These vectors should also induce much higher neutralizing antibody titers and are expected to generate maximal cross-clade neutralizing antibody titers to AIVs. The optimized, highly attenuated or replication-defective, single-cycle VSV vectors to be developed could form the basis for a broadly protective AIV vaccine that could be produced and deployed rapidly in response to an influenza virus pandemic. PUBLIC HEALTH RELEVANCE: Influenza pandemics in the 20th century are estimated to have killed more than 40 million people worldwide. Future pandemics will surely occur and are highly likely to result from mutation of avian influenza virus and crossover into the human population. The goal of this project is to develop a novel type of vaccine that elicits very broad neutralizing antibody and broad protection against avian influenza virus strains. In addition, unlike traditional influenza vaccines, this vaccine could be produced and deployed rapidly to halt a pandemic.