Safe and universal live-attenuated plague vaccine

安全通用的鼠疫减毒活疫苗

• 批准号: 8952411
• 负责人: Olaf Schneewind
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8952411
• 关键词: Address; Adverse effects; Aerosols; Alleles; Animals; Antibody Response; Antigens; Asians; Attenuated; Bite; Blood Circulation; Bubonic Plague; Cavia; Clinical Trials; Communicable Diseases; Complex; Cutaneous; Defect; Development; Disease; Disease Outbreaks; Disease model; Engineering; Epidemic; Epidemiologic Studies; Escape Mutant; FDA approved; Fleas; Genes; Hemochromatosis; Human; Immune response; Immunity; Immunization; Individual; Infection; Inherited; Ions; Iron; Knockout Mice; Lesion; Licensing; Licensure; Life; Manganese; Metals; Modeling; Modification; Morbidity - disease rate; Mus; Needles; Pathogenicity Island; Phenotype; Pigmentation physiologic function; Plague; Plague Vaccine; Pneumonic Plague; Production; Proteins; Rattus; Reporting; Rodent; Safety; Siderophores; Testing; Tissues; United States; Vaccines; Variant; Virulence; Virulent; Yersinia pestis; attenuation; base; gastrointestinal; immunogenic; immunogenicity; improved; killings; mortality; mouse model; pandemic disease; prevent; public health relevance; subcutaneous; uptake; yersiniabactin

 DESCRIPTION (provided by applicant): Yersinia pestis, the causative agent of plague, killed more people worldwide than any other infectious disease agent. Plague is transmitted by flea bite, contact, gastrointestinal-uptake or aerosol. Y. pestis has a near global distribution in many different animal and flea hosts. Current epidemiological studies record approximately 4,000 human plague cases annually world-wide, however morbidity rates oscillate and increase slowly towards the onset of a new pandemic. The Asian Plague Pandemic (1855-1959) was halted through the live-attenuated plague vaccine EV76. Nevertheless, EV76 immunization causes serious side effects including plague disease, which preclude FDA licensure of EV76. Attenuation of Y. pestis EV76 is based on its pigmentation phenotype (Δpgm), i.e. loss of yersiniabactin siderophore production. Attenuation is confined to cutaneous infection, not to bloodstream or aerosol inoculation. Individuals with hemochromatosis, whose tissue iron content is increased, are susceptible to infection with EV76 and develop plague disease. We report here that Y. pestis EV76 variants defective in both iron- (Δpgm) and manganese (ΔyfeAB) scavenging display reduced virulence even in animals with hemochromatosis, while retaining the ability to elicit immune responses. Protective immune responses from the EV76 vaccine are focused on the F1 capsular antigen of Y. pestis and are overcome by caf1A:IS1541 escape variants. We show also that LcrV, another plague protective antigen that functions as the cap protein of Y. pestis type III machines, is glutathionylated at Cys273; this modification prevents development of protective antibody responses against LcrV during plague infection or EV76 immunization. By generating EV76 Δpgm, ΔyfeAB variants with lcrVC273A, an allele for non-glutathionylated LcrV, we propose to develop live-attenuated plague vaccines that are safe, immunogenic for both F1 and LcrV and that cannot be defeated by escape mutants. This hypothesis will be tested in bubonic and pneumonic plague disease models with different animals.

 描述（由适用提供）：瘟疫的病因耶尔森尼亚佩斯蒂斯（Yersinia Pestis）杀死了全世界在全球范围内的人数比任何其他传染病药物都多。瘟疫是通过跳蚤叮咬，接触，胃肠道摄取或气溶胶传播的。 Y. Pestis在许多人中几乎全球分布 不同的动物和跳蚤宿主。当前的流行病学研究记录了每年在全球范围内大约4,000例人鼠疫病例，但是发病率振荡并在新大流行病开始时缓慢增加。亚洲瘟疫大流行（1855-1959）通过实时损伤的瘟疫疫苗EV76停止。然而，EV76免疫抑制会引起严重的副作用，包括瘟疫疾病，这阻止了EV76的FDA许可。 Y. Pestis EV76的衰减基于其色素沉着表型（ΔPGM），即Yersiniaaabactin didophore产生的损失。衰减仅限于皮肤感染，而不是血液或气溶胶接种。血色素肿瘤的患者（其组织铁含量增加）容易感染EV76并患上鼠疫疾病。我们在这里报告说，Y. pestis EV76变体在铁（ΔPGM）和锰（ΔyfeAB）中都有缺陷，即使在患有血糖症的动物中也显示出降低的病毒，同时保留了引起免疫调查的能力。来自EV76疫苗的保护性免疫备件集中在Y. Pestis的F1帽抗原上，并通过CAF1A的克服：IS1541逃生变体。我们还表明，在Cys273时，LCRV是另一种瘟疫保护的抗原，该抗原充当鼠疫型III型机器的帽蛋白。这种修饰可阻止在鼠疫感染或EV76免疫抑制期间对LCRV的受保护抗体反应的发展。通过生成EV76ΔPGM，使用LCRVC273A（一种非谷胱甘肽二离子化的LCRV）的ΔYFEAB变体，我们建议开发安全的，即F1和LCRV的疫苗生成疫苗的实时衰减疫苗，并且不能被逃生突变型逃脱。该假设将在具有不同动物的Bubonic和Pneumonic Plague疾病模型中进行检验。