Preclinical Development of a Tularemia Vaccine

兔热病疫苗的临床前开发

基本信息

批准号：
8075918
负责人：
Jason F Huntley
金额：
$ 45.45万
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/8075918
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 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 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. PUBLIC HEALTH RELEVANCE STATEMENT: Francisella tularensis (tularemia) has been classified as a Category A Select Agent, indicating that it could be used as a biological weapon with substantial loss of human life. Because no vaccine is currently licensed for human use, the development of new vaccine formulations should remain a national priority. The projects outlined in this proposal seek to advance a lead tularemia vaccine candidate and test new vaccine formulations for efficacy and safety.

描述（由申请人提供）：Francisella tuarlarensis是一种革兰氏阴性的细胞内细菌，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（Tuarlaremia）。该细菌被广泛认为是最危险的细菌病原体之一，因为其易于雾化，低传染剂量（ID50 <10个生物），多种感染途径，快速疾病发作，严重的发病率和死亡率（如果遗留未经培养的（如果不培养的，则为33％））以及BSL3实验室的要求。尽管担心故意将tularensis用作生物武器，但目前尚无持有的Tularemia疫苗，对保护性免疫的相关性知之甚少。尽管目前正在计划针对F. tularensis的实时疫苗菌株（LV）进行临床试验，但人们对LVS恢复对野生型毒力，免疫功能低下的个体的安全性以及对气溶胶暴露的有效性有充分记录的担忧。鉴于明确需要安全有效的Tuarlaremia疫苗，该提案的目标是测试多种动物模型中细菌外膜囊泡（OMV）的新细胞（亚基）疫苗配方的功效和安全性。在初步研究中，我们已经证明OMV可为小鼠的A型F. tularensis肺挑战提供多达100％的保护。因此，该建议将通过以下发现来扩展这些发现：（1）评估OMV保护小鼠和大鼠免受A型F型肺部感染的能力；（2）评估小鼠和大鼠OMV免疫的安全性；（3）比较OMV和LV的保护能力与A型F. tularensis肺挑战；（4）根据定义OMV的成分的最新数据，开发和测试新的重组蛋白疫苗制剂，以防止A型F. tularensis肺挑战；（5）表征OMV免疫引起的免疫反应；（6）表征防御和消除A型F. tularensis肺挑战所需的免疫反应。综上所述，提出的实验具有巨大的潜力，可以推进铅虫疫苗配方，并测试针对A型F. tularensis肺挑战的新疫苗配方的安全性和功效。公共卫生相关性声明：弗朗西斯氏菌（Francisella tularensis）（Tularemia）已被归类为ASSECTON ASSECTANT，表明它可以用作具有大量人类生命的生物武器。由于目前尚无疫苗用于人类使用的许可，因此新疫苗配方的开发应仍然是国家优先事项。该提案中概述的项目旨在推进促虫疫苗候选铅，并测试新的疫苗配方以实现疗效和安全性。