Smallpox vaccine and vaccinia complement control protein

天花疫苗和牛痘补体控制蛋白

• 批准号: 7901695
• 负责人: Stuart N. Isaacs
• 金额: $ 2.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901695
• 关键词: Address; African; Animals; Antibody Formation; Antigens; Attenuated; B-Lymphocytes; Biological Assay; Biological Response Modifiers; Centers for Disease Control and Prevention (U.S.); Chickens; Collaborations; Complement; Complement component C1s; Development; Gene Proteins; Genes; Genome; Immune response; Immune system; Immunity; Immunodeficient Mouse; In Vitro; Inflammation; Invaded; Knock-out; Lead; Link; Listeria; Measures; Mediating; Modeling; Monkeypox; Monkeypox virus; Mouse Pox Virus; Mus; Natural Immunity; Organism; Orthopoxvirus; Ovalbumin; Pathogenesis; Pathogenicity; Play; Poxviridae; Proteins; Reagent; Recombinants; Role; Safety; Serum; Smallpox Vaccine; System; Testing; Vaccinated; Vaccination; Vaccines; Vaccinia; Vaccinia virus; Viral Proteins; Virulence Factors; Virulent; Virus; Virus Inactivation; immunogenicity; in vivo; mutant; next generation; novel vaccines; protein function; response

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

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，这些介体有助于控制入侵的生物。 C'的激活也是先天性和适应性免疫系统之间的主要联系，并且可以增强体液和细胞免疫反应。正托病毒编码抑制宿主C'-激活和阻断C'-介导的病毒中和和炎症的分泌蛋白质。因此，编码补体控制蛋白（CCP）的痘病毒基因是理想的候选者，可以进一步减弱天花疫苗。重要的是，尚不清楚操纵这些CCP是否也可以增强对病毒的适应性免疫。我们假设疫苗补体控制蛋白（VCP）是一种毒力因子，在保护病毒免受先天免疫力和免疫调节作用方面既具有核心作用，又降低了调节抗原特异性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轻病毒，以制造更安全的疫苗，并增强适应性免疫反应，从而提供优质的保护。为了开发操纵VCP功能的候选天花疫苗，我们将：1。定义疫苗病毒突变体的体外复制和体内致病性，其中我们选择性地修改VCP基因以操纵其功能。 2。定义具有修饰VCP功能的天花疫苗的体液和细胞免疫反应。 3。定义在正托病毒和异源挑战模型的背景下，用含有修饰VCP的病毒疫苗接种的保护。我们认为，VCP是新型疫苗策略的有希望的目标，具有提高下一代天花疫苗的安全性和免疫原性的潜力

项目成果

Elucidating the role of the complement control protein in monkeypox pathogenicity.

• DOI: 10.1371/journal.pone.0035086
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Hudson PN;Self J;Weiss S;Braden Z;Xiao Y;Girgis NM;Emerson G;Hughes C;Sammons SA;Isaacs SN;Damon IK;Olson VA
• 通讯作者: Olson VA