Innate Immunomodulating Genes of Smallpox Vaccines

天花疫苗的先天免疫调节基因

基本信息

批准号：
7425412
负责人：
Tilahun D Yilma
金额：
$ 34.22万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7425412
关键词：
Acquired Immunodeficiency Syndrome Affect Animal Model Anthrax disease Attenuated Awareness Binding Bioterrorism Caspase-1 Cells Cellular Immunity Cessation of life Code Communicable Diseases Competence Complication Cowpox Defect Development DryVax vaccine Ectromelia Fright Funding Gene Deletion Gene Targeting Genes Genome Goals HIV Homologous Gene Immune Immune response In Vitro Inactivated Vaccinia Virus Individual Infectious Agent Interferon Gamma Receptor Complex Interferon Type II Interleukin-1 Interleukin-18 Link Lymphokines Measures Mediating Modeling Modification Mus Numbers Poxviridae Proteins Rate Recombinants Research Personnel Risk SCID Mice Safety Serine Proteinase Inhibitors Smallpox Smallpox Vaccine Smallpox Viruses Testing Vaccinated Vaccines Vaccinia virus Virulence Virulent Virus Diseases Work attenuation base cytokine experience immunogenicity immunosuppressed in vivo interleukin-1beta-converting enzyme inhibitor mouse model nonhuman primate pandemic disease programs receptor vaccine efficacy vector

项目摘要

DESCRIPTION (provided by applicant): In the aftermath of the attacks of September 11 and the anthrax scare, we have a heightened awareness of US vulnerability to bioterrorism. One of the most feared infectious agents is variola virus, the causative agent of smallpox. The vaccine for smallpox, vaccinia virus (VV), is highly effective, but has an unacceptable rate of complications. Severe illness or death is rare in people with normal immune responses, but considerably more common in individuals with cell-mediated immune defects. The number of individuals that are at risk from this normally innocuous vaccine has greatly increased with the spread of the human immunodeficiency virus (HIV), requiring further improvement in the safety and efficacy of the vaccine. Poxviruses have multiple immune evasion genes that code for proteins that suppress the innate and adaptive immune responses and increase virulence. We have worked extensively to investigate the effects of inactivating VV immunomodulating genes including the interferon-gamma (IFN-gamma) receptor homolog (B8R) and serine protease inhibitors (B13R, and B22R). We have also demonstrated that rVVs expressing IFN-gamma have enhanced safety and efficacy. Based on our past experience, we propose developing a safer and more efficacious rVV based on the Wyeth strain for use as a smallpox vaccine as well as a vector for other infectious disease vaccines. IFN-gamma is a lymphokine that affects both innate and adaptive immune responses. We propose to enhance the safety and efficacy of smallpox vaccine by deleting VV innate immune suppressing genes and co-expressing the IFN-gamma gene. Preliminary safety and efficacy testing of our vaccines will be first determined in a murine model before testing the most promising recombinants in the more expensive nonhuman primate model.

描述（由申请人提供）：在 9 月 11 日的袭击和炭疽恐慌之后，我们更加意识到美国对生物恐怖主义的脆弱性。最可怕的传染源之一是天花病毒，它是天花的病原体。天花疫苗痘苗病毒（VV）非常有效，但并发症发生率高得令人无法接受。在免疫反应正常的人中，严重疾病或死亡很少见，但在有细胞介导的免疫缺陷的人中更为常见。随着人类免疫缺陷病毒（HIV）的传播，这种通常无害的疫苗面临风险的人数大大增加，需要进一步提高疫苗的安全性和有效性。痘病毒具有多个免疫逃避基因，这些基因编码的蛋白质可抑制先天性和适应性免疫反应并增加毒力。我们广泛研究了灭活 VV 免疫调节基因的影响，包括干扰素γ (IFN-γ) 受体同源物 (B8R) 和丝氨酸蛋白酶抑制剂（B13R 和 B22R）。我们还证明表达 IFN-γ 的 rVV 具有增强的安全性和有效性。根据我们过去的经验，我们建议基于惠氏毒株开发一种更安全、更有效的rVV，用作天花疫苗以及其他传染病疫苗的载体。 IFN-γ 是一种淋巴因子，影响先天性和适应性免疫反应。我们建议通过删除VV先天免疫抑制基因并共表达IFN-γ基因来增强天花疫苗的安全性和有效性。我们的疫苗的初步安全性和有效性测试将首先在小鼠模型中确定，然后在更昂贵的非人类灵长类动物模型中测试最有希望的重组体。