Smallpox vaccine and vaccinia complement control protein

描述(由申请人提供)：补体(C1)系统由关键的宿主天然免疫介质组成，有助于控制入侵的生物体。C‘的激活也是先天免疫系统和获得性免疫系统之间的主要联系，并有助于增强体液和细胞免疫反应。正痘病毒编码分泌的蛋白质，抑制宿主C‘激活，阻断C’介导的病毒中和和炎症。因此，编码补体控制蛋白(CCP)的痘病毒基因是进一步减毒天花疫苗的理想候选基因。重要的是，目前尚不清楚操纵这些CCP是否也能增强C‘增强的对病毒的适应性免疫。我们假设痘苗补体控制蛋白(VCP)是一种毒力因子，既在保护病毒免受天然免疫方面发挥核心作用，又具有免疫调节作用，下调抗原特异性T和B细胞反应的大小、持续时间和质量。我们进一步假设，通过改变VCP基因，我们既可以进一步减弱病毒以制造更安全的疫苗，也可以增强适应性免疫反应，从而提供更好的保护。为了开发操作VCP功能的候选天花疫苗，我们将：1.确定痘苗病毒突变体的体外复制和体内致病性，在这些突变体中，我们选择性地修改VCP基因来操纵其功能。2.确定VCP功能修饰的天花疫苗的体液免疫和细胞免疫应答。3.在正痘病毒和异源挑战模型的背景下，确定用含有修饰的VCP的病毒接种疫苗所产生的保护作用。我们相信，vcp是新疫苗策略的一个有希望的靶点，它有可能提高下一代天花疫苗的安全性和免疫原性。

DESCRIPTION (provided by applicant): The complement (C1) system is comprised of critical host innate immune mediators that help control invading organisms. Activation of C' is also a major link between the innate and adaptive immune systems and serves to augment both humoral and cellular immune responses. Orthopoxviruses encode secreted proteins that inhibit host C'-activation and block C'-mediated virus neutralization and inflammation. Thus, the poxvirus genes that encode complement control proteins (CCP) are ideal candidates with which to further attenuate smallpox vaccines. Importantly, it is not known whether manipulating these CCPs could also augment C'-enhanced adaptive immunity to the virus. We hypothesize that the vaccinia complement control protein (VCP) is a virulence factor with both a central role in protecting the virus from innate immunity and an immunoregulatory role that down regulates the magnitude, duration, and quality of antigen-specific T and B cell responses. We further hypothesize that by altering the VCP gene we can both further attenuate the virus to make a safer vaccine as well as enhance adaptive immune responses that would confer superior protection. To develop candidate smallpox vaccines that manipulate the function of VCP, we will: 1. Define the in vitro replication and in vivo pathogenicity of vaccinia virus mutants in which we selectively modify the VCP gene to manipulate its function. 2. Define the humoral and cellular immune responses to smallpox vaccines with modified VCP functions. 3. Define the protection conferred by vaccinations with viruses containing modified VCP in the context of both orthopoxvirus and heterologous challenge models. We believe that VCP is a promising target for novel vaccine strategies that has the potential to enhance both the safety and immunogenicity of next generation smallpox vaccines