Replication-deficient rabies vectors against rabies infection

复制缺陷型狂犬病载体对抗狂犬病感染

• 批准号: 8289515
• 负责人: JAMES P MCGETTIGAN
• 金额: $ 37.86万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289515
• 关键词: A Mouse; Active Immunization; Address; Animal Model; Animals; Applications Grants; Cessation of life; Child; Clinical Trials; Communicable Diseases; Data; Developed Countries; Developing Countries; Development; Disease; Dose; Effectiveness; Exposure to; Financial cost; Future; Generations; Genes; Goals; HIV-1; Healthcare; Human; Immune; Immune response; Immunity; Immunization; Immunization Schedule; Immunoglobulins; Inactivated Vaccines; Incidence; Infection; Kinetics; Laboratories; Life; Lyssavirus; Mesocricetus auratus; Modeling; Molecular; Mus; Neuraxis; Passive Immunization; Patients; Peripheral; Phosphoproteins; Populations at Risk; Prevention; Prophylactic treatment; Protocols documentation; Rabies; Rabies Vaccines; Rabies virus; Reporting; Research Infrastructure; Signal Transduction; Site; Speed; Suggestion; System; Testing; Time; United States; Vaccination; Vaccines; Veterinarians; Virus; Virus Diseases; animal rule; base; combat; cost; design; global health; immunogenic; immunogenicity; killings; lot production; meetings; novel; prevent; public health relevance; research study; response; therapy development; vector; vector vaccine

DESCRIPTION (provided by applicant): Rabies is a major global health issue that kills approximately 40,000 to 70,000 people per year and over 10 million people receive post-exposure prophylaxis (PEP) after exposure to potentially infected animals. Cost and compliance issues have greatly hampered the effectiveness of current vaccines. To confound this issue, current vaccines are not effective at preventing disease from several newly identified rabies related viruses. In addition, live rabies virus (RV) was recently discovered in a lot of vaccine that was supposed to contain inactivated RV. Taken together, the development of novel pre- and post-exposure vaccines is necessary to combat this global health issue. Since pre-exposure vaccination is reserved only for those at-risk populations, such as laboratory workers and veterinarians, PEP is the world-wide standard for human rabies prevention. Current PEPs are comprised of one dose of passive immunization (rabies immune globulin) along with five active immunizations with rabies vaccines. The experiments in this proposal are designed to test the hypothesis that replication-deficient RVs would make excellent rabies PEPs and will require only one to two doses. A hallmark of RV infection that makes PEP feasible is the relatively long period between the time of exposure at the peripheral site and the time when RV infects the central nervous system. As such, a rapid humoral response is absolutely required for a successful PEP. Therefore, the goal of this grant application to identify the most promising vector in small animal models [mice (Aim I) and Syrian hamsters, (Aim II)]. The responses and protection will be compared with animals inoculated with a commercially available inactivated RV vaccine. In summary, the development of a treatment that relies on only one to two doses of vaccine instead of six inoculations will greatly enhance the effectiveness of human RV prevention and has the potential to save many lives and reduce costs in both developing and developed countries. In addition, this data will be useful for the development of replication-deficient RV vectors for vaccines against other infectious diseases, such as HIV-1. PUBLIC HEALTH RELEVANCE: The goal of this application is to develop safe and effective alternatives to the current human rabies post- exposure prophylaxis. The development of treatment that relies on only one to two doses of vaccine instead of six inoculations will greatly enhance the effectiveness of rabies virus prevention, save lives and reduce costs in developing and developed countries.

描述(申请人提供)：狂犬病是一个主要的全球健康问题，每年导致约40,000至70,000人死亡，1000多万人在接触潜在感染的动物后接受暴露后预防(PEP)。成本和合规问题极大地阻碍了当前疫苗的有效性。为了解决这个问题，目前的疫苗在预防几种新发现的狂犬病相关病毒方面并不有效。此外，最近在许多本应含有灭活RV的疫苗中发现了活狂犬病病毒(RV)。综上所述，开发新的暴露前和暴露后疫苗对于应对这一全球健康问题是必要的。由于暴露前疫苗接种仅限于实验室工作人员和兽医等高危人群，因此PEP是预防人类狂犬病的世界标准。目前的PEP包括一剂被动免疫(狂犬病免疫球蛋白)和五种狂犬病疫苗主动免疫。这项建议中的实验旨在测试这样一个假设，即复制缺陷的RV将产生优秀的狂犬病PEP，并且只需要一到两剂。轮状病毒感染使PEP可行的一个标志是，在外周部位暴露的时间和轮状病毒感染中枢神经系统的时间之间的时间相对较长。因此，快速的体液反应绝对是成功的PEP所必需的。因此，这项赠款申请的目标是在小动物模型[小鼠(Aim I)和叙利亚仓鼠(Aim II)]中确定最有希望的媒介。这些反应和保护将与接种商业上可获得的灭活轮状病毒疫苗的动物进行比较。总而言之，开发一种只需一到两剂疫苗而不是六剂疫苗的治疗方法将极大地提高人类轮状病毒预防的有效性，并有可能在发展中国家和发达国家挽救许多人的生命并降低成本。此外，这些数据将有助于开发复制缺陷的轮状病毒载体，用于针对其他传染病的疫苗，如HIV-1。公共卫生相关性：该应用程序的目标是开发安全有效的替代方案，以替代目前的人类暴露后狂犬病预防措施。在发展中国家和发达国家，开发只需一到两剂疫苗而不是六剂疫苗的治疗方法，将极大地提高狂犬病病毒预防的有效性，拯救生命并降低成本。

项目成果

Investigating the role for IL-21 in rabies virus vaccine-induced immunity.

• DOI: 10.1371/journal.pntd.0002129
• 发表时间: 2013
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Dorfmeier CL;Tzvetkov EP;Gatt A;McGettigan JP
• 通讯作者: McGettigan JP

Experimental rabies vaccines for humans.

• DOI: 10.1586/erv.10.105
• 发表时间: 2010-10
• 期刊: Expert review of vaccines
• 影响因子: 6.2
• 作者: McGettigan JP

Safety and serological response to a matrix gene-deleted rabies virus-based vaccine vector in dogs.

• DOI: 10.1016/j.vaccine.2014.01.043
• 发表时间: 2014-03-26
• 期刊: VACCINE
• 影响因子: 5.5
• 作者: McGettigan, James P.;David, Frederic;Figueiredo, Monica Dias;Minke, Jules;Mebatsion, Teshome;Schnell, Matthias J.
• 通讯作者: Schnell, Matthias J.

Lymph node but not intradermal injection site macrophages are critical for germinal center formation and antibody responses to rabies vaccination.

淋巴结而非皮内注射部位的巨噬细胞对于生发中心的形成和狂犬病疫苗接种的抗体反应至关重要。

• DOI: 10.1128/jvi.03409-14
• 发表时间: 2015
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Lytle,AndrewG;Shen,Shixue;McGettigan,JamesP
• 通讯作者: McGettigan,JamesP