A SAFER AND MORE EFFICACIOUS SMALLPOX VACCINE

更安全、更有效的天花疫苗

• 批准号: 7715613
• 负责人: Tilahun D Yilma
• 金额: $ 8.45万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715613
• 关键词: Anthrax disease; Attenuated; Awareness; Bioterrorism; Cells; Cessation of life; Computer Retrieval of Information on Scientific Projects Database; Defect; Disease; Fright; Funding; Genes; Grant; HIV; Health; Human; Immune; Immune response; Inactivated Vaccinia Virus; Individual; Infectious Agent; Institution; Interferon Type II; Journals; Macaca; Mediating; Modeling; Nature; New York City; Numbers; Rate; Recombinant Vaccines; Research; Research Personnel; Resources; Rinderpest; Risk; SIV; Safety; Smallpox; Smallpox Vaccine; Smallpox Viruses; Source; United States National Institutes of Health; Vaccines; Vaccinia virus; Virulence; Virulence Factors; Virus; Virus Diseases; Work; attenuation; base; cell mediated immune response; experience; improved; prevent; vaccine safety

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: 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. Various strains of vaccinia virus (VV) are highly effective in preventing this disease, but have definite rates 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), and it now becomes important to improve the efficacy and safety of this vaccine. We have worked extensively with VV as a recombinant vaccine for a number of diseases; our rinderpest vaccine was described as one of two outstanding rVVs in a leading journal (G. Ada, Nature 349:369, 1991). We have also developed strategies for attenuating VV while enhancing efficacy, with one of the most effective being the incorporation of the interferon-gamma (IFN-gamma) gene. We have shown that expression of IFN-gamma leads to a TH1 immune response essential against viral infection with no deleterious effects. We have also studied the effects of inactivating VV immunomodulating genes such as B8R, B13R, and B22R that are virulence factors in VV. Based on our past experience, we propose developing a safer and more efficacious vaccine for smallpox based on the New York City Board of Health (Wyeth) strain of VV that is currently used in the US. We will delete the B8R gene and insertionally inactivate the TK virulence gene with the human IFN-gamma gene to increase attenuation of the virus and the protective cell-mediated immune responses. This recombinant VV will be compared to the parental vaccine in both normal and simian immunodeficiency virus-infected macaques (used as a model for HIV-infected humans) to assess efficacy and safety for normal and immunodeficient individuals.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 目标：在 9 月 11 日的袭击和炭疽恐慌之后，我们更加意识到美国容易受到生物恐怖主义的影响。最可怕的传染源之一是天花病毒，它是天花的病原体。痘苗病毒（VV）的各种毒株对于预防这种疾病非常有效，但并发症的发生率也很高。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，现在提高这种疫苗的功效和安全性变得非常重要。我们与 VV 进行了广泛合作，将其作为针对多种疾病的重组疫苗；我们的牛瘟疫苗被一家领先期刊描述为两种杰出的 rVV 之一（G. Ada, Nature 349:369, 1991）。我们还开发了减弱 VV 同时增强疗效的策略，其中最有效的策略之一是掺入干扰素-γ (IFN-γ) 基因。我们已经证明，IFN-γ 的表达会导致针对病毒感染所必需的 TH1 免疫反应，且不会产生有害影响。我们还研究了灭活 VV 免疫调节基因（例如 B8R、B13R 和 B22R（VV 毒力因子））的影响。根据我们过去的经验，我们建议以目前在美国使用的纽约市卫生局 (Wyeth) VV 毒株为基础，开发一种更安全、更有效的天花疫苗。我们将删除 B8R 基因，并用人 IFN-gamma 基因插入灭活 TK 毒力基因，以增强病毒的减弱能力和保护性细胞介导的免疫反应。这种重组 VV 将与正常和猿类免疫缺陷病毒感染的猕猴（用作 HIV 感染人类的​​模型）中的亲本疫苗进行比较，以评估正常和免疫缺陷个体的有效性和安全性。