Safe and universal live-attenuated plague vaccine

 描述（由申请人提供）：鼠疫耶尔森氏菌是鼠疫的病原体，在世界范围内杀死的人比任何其他传染病病原体都多。鼠疫是通过跳蚤叮咬、接触、胃肠道吸收或气溶胶传播。Y.鼠疫几乎遍布全球， 不同的动物和跳蚤宿主目前的流行病学研究记录了全世界每年约4，000例人间鼠疫病例，但发病率在新的大流行病开始时波动并缓慢增加。亚洲鼠疫大流行（1855-1959年）是通过减毒活鼠疫疫苗EV 76停止的。然而，EV 76免疫引起严重的副作用，包括鼠疫，这使得FDA无法获得EV 76的许可。Y的衰减。鼠疫菌EV 76是基于其色素沉着表型（Δpgm），即耶尔森氏杆菌素铁载体产生的损失。减毒仅限于皮肤感染，而不是血流或气溶胶接种。患有血色病的个体，其组织铁含量增加，易感染EV 76并发展为鼠疫。我们在这里报告说，Y。在铁（Δpgm）和锰（ΔyfeAB）清除方面有缺陷的鼠疫EV 76变体即使在患有血色病的动物中也显示出降低的毒力，同时保留引发免疫应答的能力。来自EV 76疫苗的保护性免疫应答集中于Y的F1荚膜抗原。鼠疫和克服caf 1A：IS 1541逃逸变体。我们还表明，LcrV，另一种鼠疫保护性抗原，作为帽蛋白的Y。鼠疫III型机器，在Cys 273处谷胱甘肽化;这种修饰防止在鼠疫感染或EV 76免疫期间针对LcrV的保护性抗体应答的发展。通过产生具有lcrVC 273 A（非谷胱甘肽化LcrV的等位基因）的EV 76 Δpgm、ΔyfeAB变体，我们提出开发对F1和LcrV都具有安全性、免疫原性并且不能被逃逸突变体击败的减毒活鼠疫疫苗。这一假设将在不同动物的腺鼠疫和肺鼠疫模型中进行检验。

 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.