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，有助于控制入侵生物。C'的激活也是先天性和适应性免疫系统之间的主要联系，并用于增强体液和细胞免疫应答。正痘病毒编码分泌蛋白，其抑制宿主C '-活化并阻断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是否也可以增强对病毒的C '-增强的适应性免疫。我们假设牛痘补体控制蛋白（VCP）是一种毒力因子，在保护病毒免受先天性免疫中起核心作用，并具有下调抗原特异性T和B细胞应答的幅度、持续时间和质量的免疫调节作用。我们进一步假设，通过改变VCP基因，我们可以进一步减毒病毒，使疫苗更安全，以及增强适应性免疫反应，将赋予上级保护。为了开发操纵VCP功能的候选天花疫苗，我们将：1。定义在体外复制和在体内的痘苗病毒突变体的致病性，其中我们选择性地修改VCP基因，以操纵其功能。2.定义对具有修饰的VCP功能的天花疫苗的体液和细胞免疫应答。3.定义在正痘病毒和异源攻毒模型的背景下，接种含有修饰VCP的病毒所赋予的保护作用。我们相信VCP是一个很有前途的新疫苗策略的靶点，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