Preclinical Development of a Tularemia Vaccine

兔热病疫苗的临床前开发

基本信息

批准号：
8610228
负责人：
Jason F Huntley
金额：
$ 35.25万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-15 至 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8610228
关键词：
Acellular Vaccines Aerosols Animal Model Animals Antibodies Attenuated Vaccines Bacteria Biological C3H/HeN Mouse CD4 Positive T Lymphocytes Categories Cells Cessation of life Complex Data Development Dose Drug Formulations Escherichia coli Exhibits Flow Cytometry Francisella tularensis Goals Histologic Human Immune response Immunity Immunization Immunocompromised Host Immunologics Inbred BALB C Mice Individual Infection Interferons Interleukin-2 Laboratories Lead Left Licensing Life Liposomes Lung Mammals Mass Spectrum Analysis Membrane Membrane Proteins Mission Morbidity - disease rate Mus Onset of illness Organism Outcome Passive Transfer of Immunity Pathologic Phase II Clinical Trials Play Protein Subunits Proteins Proteomics Rattus Recombinant Proteins Role Route Safety Serum Structure Study of serum Subunit Vaccines Systemic disease T-Cell Depletion TNF gene Techniques Testing Time Tularemia Vaccines Vesicle Virulence animal rule base cell type cytokine efficacy testing human mortality immunogenicity monophosphoryl lipid A mortality novel vaccines pathogen pre-clinical protective efficacy protein E public health relevance research study safety testing subcutaneous two-dimensional vaccine candidate vaccine development vaccine evaluation vaccinology weapons

项目摘要

DESCRIPTION (provided by applicant): Francisella tularensis is a Gram-negative intracellular bacterium capable of causing fatal systemic disease (tularemia) in a number of mammals, including humans. The bacterium is widely recognized as one of the most dangerous bacterial pathogens known because of its ease of aerosolization, low infectious dose (ID50 < 10 organisms), multiple routes of infection, rapid disease onset, severe morbidity and mortality (33% human mortality rate if left untreated), and requirement for BSL3 laboratory manipulation. Despite concerns over the deliberate use of F. tularensis as a biological weapon, a licensed tularemia vaccine is not currently available and little is known about the correlates of protective immunity. Although phase 2 clinical trials are currently being planned for the live vaccine strain (LVS) of F. tularensis, there are well-documented concerns about LVS reversion to wild-type virulence, safety in immunocompromised individuals, and efficacy against an aerosol exposure. Given the clear need for a safe and effective tularemia vaccine, the goals of this proposal are to test the efficacy and safety of new acellular (subunit) vaccine formulations, derived from bacterial outer membrane vesicles (OMVs), in multiple animal models. In preliminary studies, we have demonstrated that OMVs provide up to 100% protection against Type A F. tularensis pulmonary challenge in mice. As such, this proposal will extend those findings by: (1) Evaluating the ability of OMVs to protect mice and rats from Type A F. tularensis pulmonary infection; (2) Evaluating the safety of OMV immunization in mice and rats; (3) Comparing the protective capacity of OMVs and LVS against Type A F. tularensis pulmonary challenge; (4) Developing and testing new recombinant protein vaccine formulations to protect against Type A F. tularensis pulmonary challenge, based upon recent data defining the components of OMVs; (5) Characterizing the immune responses induced by OMV immunization; (6) Characterizing the immune responses required to protect against and eliminate Type A F. tularensis pulmonary challenge. Taken together, the proposed experiments have enormous potential to advance a lead tularemia vaccine formulation and to test the safety and efficacy of new vaccine formulations against Type A F. tularensis pulmonary challenge.

描述（由申请人提供）：土拉弗朗西斯菌是一种革兰氏阴性细胞内细菌，能够在包括人类在内的许多哺乳动物中引起致命的全身性疾病（兔热病）。该细菌因其易于雾化、感染剂量低（ID50 < 10个生物体）、感染途径多、发病快、发病率和死亡率严重（人类死亡率为33%）而被广泛认为是已知最危险的细菌病原体之一。如果不治疗），以及 BSL3 实验室操作的要求。尽管人们对故意使用土拉菌作为生物武器感到担忧，但目前还没有获得许可的土拉菌疫苗，而且人们对保护性免疫的相关性知之甚少。尽管目前正在计划对土拉弗拉菌活疫苗株 (LVS) 进行 2 期临床试验，但人们对 LVS 恢复野生型毒力、免疫功能低下个体的安全性以及对抗气溶胶暴露的功效表示担忧。鉴于对安全有效的兔热病疫苗的明确需求，该提案的目标是在多种动物模型中测试源自细菌外膜囊泡 (OMV) 的新型无细胞（亚单位）疫苗制剂的功效和安全性。在初步研究中，我们已经证明 OMV 对小鼠 A 型土拉毛霉肺部攻击提供高达 100% 的保护。因此，该提案将通过以下方式扩展这些发现：（1）评估 OMV 保护小鼠和大鼠免受 A 型土拉弗朗西斯肺部感染的能力；（2）评价OMV免疫小鼠和大鼠的安全性； (3) 比较OMVs和LVS对A型土拉菌肺部攻击的保护能力； (4) 根据定义 OMV 成分的最新数据，开发和测试新的重组蛋白疫苗制剂，以防止 A 型土拉弗氏菌肺部攻击； (5)表征OMV免疫诱导的免疫反应； (6) 表征防御和消除 A 型土拉弗氏菌肺部攻击所需的免疫反应。总而言之，所提出的实验具有巨大的潜力，可以推进土拉菌病疫苗的主要配方，并测试新疫苗配方针对 A 型土拉热病肺部攻击的安全性和有效性。