Development of a lyophilized intradermal/intranasal ricin vaccine

冻干皮内/鼻内蓖麻毒素疫苗的开发

基本信息

批准号：
7643996
负责人：
ELLEN S VITETTA
金额：
$ 54.03万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-15 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7643996
关键词：
Acquired Immunodeficiency Syndrome Active Immunization Adjuvant Aerosols Amino Acids Anatomy Antibodies Antibody Formation Award Bioterrorism Blood Blood Vessels Botulinum Toxins Castor Oil Centers for Disease Control and Prevention (U.S.)Chicago Clinical Trials Code Contracts Country Development Disease Dose Drug Formulations Escherichia coli Europe Food Freezing Fright Funding General Population Goals Government Grant Histopathology Hour Human Human Resources Immunization Immunoglobulin A Immunoglobulin G Immunotoxins Individual Injectable Injection of therapeutic agent Internet Intoxication Intramuscular Laboratories Language Learning Licensing Literature Malignant Neoplasms Methods Middle East Military Personnel Modeling Mucous Membrane Mus Names Needles Oral Oryctolagus cuniculus Patients Plant Oils Population Positioning Attribute Powder dose form Preparation Procedures Production Protocols documentation Public Health Publishing Recombinants Recording of previous events Reporting Research Research Personnel Ribosome Inactivation Ricin Ricin A Chain Ricin Vaccine Ricinus communis Route Safety Site Stress Structure Surface Survivors Symptoms Syndrome System Temperature Testing Time Tissues Toxic effect Toxicology Toxin Toxoids Training Treatment Protocols United States National Institutes of Health Upper Respiratory System Vaccinated Vaccination Vaccines Water Water Supply Work World War II aerosolized anthrax lethal factor base bean biothreat combat efficacy testing experience graft vs host disease immunogenic immunogenicity improved interest killings large scale production maternal compound W mutant novel pilot trial programs user-friendly vaccine candidate vaccine evaluation volunteer wasting weapons

项目摘要

DESCRIPTION (provided by applicant): Ricin is a highly lethal ribotoxin produced by castor beans. 50,000 tons of ricin are generated each year as a by product of castor oil production. Ricin has a long history of use in espionage and warfare and is classified by the CDC as a Class B biothreat. There is no approved vaccine. Ricin A chain (RTA) has two toxicities in humans: ribosome inactivation and vascular leak syndrome. We previously generated recombinant RTA mutants with single amino acid changes in both sites, and chose the best candidate vaccine based on high yield and stability. This vaccine (RiVax) was developed into a frozen, intramuscular formulation. Rivax is highly effective in protecting mice against ten LD50s of ricin. It was safe and immunogenic in both rabbits and humans. We developed a gavage challenge model for ricin and set up a BSL3 laboratory for aerosol challenges. During the course of our gavage challenge studies, we found that ricin was 1000-10,000 more toxic when delivered by gavage than the older literature had suggested. As a result of this finding, ricin represents a more serious threat to the food and water supply of our civilian population than we had realized previously. Thus there might be a greater need for this vaccine than previously appreciated. Hence, we now propose to develop: 1) a lyophilized formulation of RiVax that is stable at ambient temperatures or 4¿C; 2) an effective intradermal vaccination regimen that does not require needles and should be immunogenic at lower doses; 3) an intranasal formulation that will protect the mucosa against gavaged (and aerosolized) ricin. 4) Normal toxicology studies will be carried out on our best candidate formulations and regimens. Relevance of this research to public health (lav language): It is critical that both our military and civilian populations have access to an approved ricin vaccine that will protect them against both ingested and aerosolized ricin. This proposal represents a critical step in accomplishing this goal.

描述（由申请人提供）：蓖麻毒素是一种高度致命的核毒素，每年产生 50,000 吨蓖麻毒素，作为蓖麻油生产的副产品，蓖麻毒素在间谍活动和战争中的使用有着悠久的历史。 CDC 认定为 B 级生物威胁，目前尚无批准的疫苗，蓖麻毒素 A 链 (RTA) 对人体有两种毒性：核糖体失活和血管渗漏。我们之前生成了两个位点均具有单一氨基酸变化的重组 RTA 突变体，并基于高产率和稳定性选择了最佳候选疫苗，该疫苗 (RiVax) 被开发成冷冻肌肉注射制剂，可高度有效地保护。我们开发了一种针对蓖麻毒素的强饲攻击模型，并在我们的气溶胶攻击过程中建立了 BSL3 实验室。在灌胃挑战研究中，我们发现，通过灌胃给药时，蓖麻毒素的毒性比旧文献显示的要高 1000-10,000。这一发现的结果是，蓖麻毒素对我们平民的食物和水供应构成的威胁比我们更严重。因此，我们现在建议开发：1）在环境温度或 4°C 下稳定的 RiVax 冻干制剂。 C; 2) 不需要针头且应在较低剂量下具有免疫原性的有效皮内疫苗接种方案; 3) 可以保护粘膜免受灌胃（和雾化）蓖麻毒素的影响的鼻内制剂 4) 将进行正常毒理学研究。我们的最佳候选配方和方案这项研究与公共卫生的相关性（lav 语言）：至关重要的是，我们的军队和平民都可以获得经批准的蓖麻毒素疫苗，以保护他们免受这两种疾病的侵害。该提案代表了实现这一目标的关键一步。