Increasing the protective efficacy of vaccines against poxviruses through the tar

摘要 该项目的目标是，第一，提高针对天花和其他强毒的痘病毒活疫苗的效力和安全性，第二，提高活牛痘病毒疫苗作为疫苗平台的效力，以保护在生物防御和新出现的感染领域中重要的多种病原体。 该项目的具体目标如下： 1.确定病毒诱导免疫反应的关键机制，特别是那些有助于痘苗病毒MVA疫苗效力的机制： 目标是学习如何通过操纵这些过程的病毒控制来最大限度地诱导保护性反应。 2.确定不同的正痘病毒，特别是痘苗病毒MVA、痘苗病毒(WR)和牛痘病毒是否影响树突状细胞(DC)对病毒感染的反应。目标是确定对DC功能产生物种特异性影响的机制。我们将利用这些信息来操纵DC对感染反应的病毒控制，以最大限度地提高疫苗病毒诱导的保护性反应。 3.确定是否可以通过修饰疫苗病毒编码的辅助蛋白来提高MVA疫苗的效力。 目的是确定是否可以通过表达两个牛痘/牛痘病毒辅助基因来改善牛痘病毒MVA疫苗的稳定性、递送方案和效力，这两个辅助基因编码的蛋白质使MVA病毒疫苗能够将其细胞内成熟病毒(IMV)嵌入A型包涵体颗粒中。 目前的MVA病毒疫苗为目前获得许可的天花疫苗提供了一种安全的替代方案，这些疫苗与严重的不良反应有关。然而，由于MVA病毒在人类细胞中的复制是有缺陷的，需要大剂量的MVA，并且可能需要多次剂量才能有效地预防特定的病原体。因此，提高这种稳定性和传递性的方法 疫苗以及增强疫苗病毒免疫原性的方法，最好是将疫苗接种减少到单剂，将大大提高这种疫苗载体的效力。

Abstract The objectives of this project are first, to increase the efficacy and safety of live poxvirus vaccines against smallpox and other virulent poxviruses, and second, to increase the efficacy of live vaccinia virus vaccines as a vaccine platform for protection against multiple agents important in the fields of biodefense and emerging infections. The specific aims of this project are as follows: 1. To identify key mechanisms of viral induction of immune responses, particularly those contributing to the efficacy of vaccinia virus MVA vaccines: The goal is to learn how to maximize the induction of protective responses through the manipulation of viral control of these processes. 2. To determine if different orthopoxviruses, specifically vaccinia virus MVA, vaccinia virus (WR), and cowpox virus differentially affect dendritic cell (DC) responses to viral infection. The goal is to determine the mechanisms contributing to species-specific effects upon DC functions. We will use this information to manipulate viral control of DC responses to infection in order to maximize protective responses induced by vaccine viruses. 3. To determine if the efficacies of MVA vaccines can be improved by modification of accessory proteins encoded by the vaccine virus. The goal is to determine if the stability, delivery regimen, and the efficacy of vaccinia virus MVA vaccines can be improved by the expression of two cowpox/vaccinia virus accessory genes that encode proteins enabling the MVA virus vaccine to embed its intracellular mature virus (IMV) within A-type inclusion particles. The current MVA virus vaccine provides a safe alternative to the currently licensed smallpox vaccines that are associated with a significant degree of adverse effects. However, because of the MVA virus is defective for replication in human cells, large doses of MVA are needed, and multiple doses may be needed for effective protection against specific agents. Therefore, methods to enhance the stability and delivery of this vaccine, as well as methods to enhance the immunogenicity of this vaccine virus, preferably to the point of reducing the vaccination to a single dose, would significantly enhance the efficacy of this vaccine vector.