Smallpox vaccine and vaccinia complement control protein

描述（由申请人提供）：补体（C1）系统由关键的宿主先天免疫介质组成，有助于控制入侵的生物体。C'的激活也是先天免疫系统和适应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。正痘病毒编码抑制宿主C′活化和阻断C′介导的病毒中和和炎症的分泌蛋白。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者。重要的是，尚不清楚操纵这些ccp是否也可以增强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，在保护病毒免受先天免疫和降低抗原特异性T细胞和B细胞反应的强度、持续时间和质量的免疫调节中发挥核心作用。我们进一步假设，通过改变VCP基因，我们既可以进一步削弱病毒，制造出更安全的疫苗，也可以增强适应性免疫反应，从而提供更好的保护。为了开发能够操纵VCP功能的候选天花疫苗，我们将：1。确定牛痘病毒突变体的体外复制和体内致病性，我们选择性地修饰VCP基因以操纵其功能。2. 定义对具有改良VCP功能的天花疫苗的体液和细胞免疫反应。3. 定义在正痘病毒和异源攻击模型的背景下，用含有修饰VCP的病毒接种疫苗所赋予的保护。我们相信VCP是一个有希望的新疫苗策略靶点，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