Development of a lyophilized intradermal/intranasal ricin vaccine

冻干皮内/鼻内蓖麻毒素疫苗的开发

• 批准号: 7255730
• 负责人: ELLEN S VITETTA
• 金额: $ 58.83万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 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/7255730
• 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; Class; Clinical Trials; Code; Contracts; Country; Development; Disease; Disruption; 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; Numbers; Oral; Oryctolagus cuniculus; Patients; Plant Oils; Population; Positioning Attribute; Powder dose form; Preparation; Procedures; Production; Protocols documentation; Public Health; Publishing; Purpose; 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; day; experience; graft vs host disease; immunogenic; immunogenicity; improved; interest; killings; maternal compound W; mutant; novel; pilot trial; programs; user-friendly; vaccine evaluation; volunteer; wasting

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（由适用提供）：Ricin是蓖麻豆产生的高度致命的核毒素。每年通过蓖麻油生产的产物生成50,000吨Ricin。 Ricin在间谍和战争中的使用历史悠久，由CDC归类为B类Biothreat。没有批准的疫苗。 Ricin A链（RTA）在人类中有两种毒性：核糖体失活和血管泄漏综合征。我们以前在两个地点都产生了具有单个氨基酸变化的重组RTA突变体，并根据高产量和稳定性选择最佳候选疫苗。该疫苗（Rivax）被发展为冷冻的肌内配方。 Rivax非常有效地保护小鼠免受10 ld50 ricin的侵害。在兔子和人类中，它都是安全和免疫原性的。我们为Ricin开发了一种挑战模型，并为气溶胶挑战建立了BSL3实验室。在我们的挑战挑战研究过程中，我们发现，在用饲料传递时，利辛蛋白的毒性比较旧的文献所建议的要高1000-10,000。由于这一发现，赖辛代表着对我们平民的食物和供水的威胁，比我们以前意识到。该疫苗可能比以前所欣赏的要大。因此，我们现在提出开发：1）在环境温度或4？c上稳定的依瓦克斯的冻干形成； 2）一种不需要针的有效皮内疫苗接种方案，应在较低剂量下具有免疫原性； 3）一种鼻内配方，可保护粘膜免受粘液（和雾化）ricin的影响。 4）正常的毒理学研究将在我们最好的候选公式和方案上进行。这项研究与公共卫生（LAV语言）的相关性：至关重要的是，我们的军事和平民人口都可以使用经批准的Ricin疫苗，以保护他们免受摄入和雾化的Ricin的侵蚀。该提案代表了完成这一目标的关键步骤。