Psoralen-Killed, Metabolically-Active Anthrax Vaccine

描述（由申请人提供）：唯一获得许可的人类炭疽疫苗是吸收炭疽疫苗（AVA），于20世纪50年代末开发，免疫原性很差。从安全性和实用性的角度来看，18个月的长期疫苗接种方案和每年需要的加强剂对军事人员的免疫尤其成问题。有可能出现新的毒性毒株，这些毒株已被战略性地改造，以破坏由AVA疫苗引起的有限免疫反应，这构成了真正的威胁。Cerus开发了一种新的方法，用于临床安全有效的针对微生物病原体的疫苗，利用其基于专有的S-59补骨脂素技术。S-59补骨脂素（S-59）在欧洲被批准用于人用，作为市售的血小板阻断病原体失活系统的一部分。作为概念的证明，通过删除uvrAB基因创建了人类病原体单核增生李斯特菌的突变株。这种缺失使得DNA修复突变菌对S-59/UVA光介导的失活非常敏感，但保留了李斯特菌遗传库的代谢活性和表达。结果，S-59/ uva灭活的李斯特菌uvrabb在接种动物中诱导保护性记忆T细胞反应和显著的抗体反应。利用具有px1和pXO2毒力质粒的宿主菌株，基于非孢子源性炭疽芽胞杆菌DNA修复突变体构建S-59/UVA灭活炭疽候选疫苗。本提案的主要目标是确定一种候选疫苗，以便在非人类灵长类动物中进行进一步试验。在小鼠和豚鼠中进行一系列实验，以确定一种基于安全性、免疫原性和对致命毒素或孢子攻击的诱导保护的最佳候选炭疽疫苗。我们假设，与AVA疫苗相比，这种将整个炭疽芽胞杆菌有机体的无活力与代谢活性相结合的独特方法将产生一种疫苗，该疫苗可诱导保护性细菌特异性免疫，其深度（即粘膜、体液和细胞免疫）、广度（针对多种细菌抗原的免疫反应，包括胶囊）和持久性（长期免疫记忆）与实际免疫方案相结合。实现本提案中提出的主要目标将为项目的长期目标奠定基础，并将项目推向初步的人体临床试验，以测试该平台的免疫原性和安全性。这项工作的最终目标是用S-59补骨脂素/UVA光灭活基因定义的减毒非孢子源性炭疽杆菌菌株取代目前的AVA人炭疽疫苗。为了实现这一目标，开发一种新型疫苗，将灭活疫苗的安全性与减毒活疫苗的效力结合起来，我们组建了一个经验丰富的联盟，由具有细菌发病机制、革兰氏阳性遗传学、新型疫苗平台开发、传染病疫苗开发和富有成效合作历史的专家组成。

DESCRIPTION (provided by applicant): The only licensed human anthrax vaccine, anthrax vaccine absorbed (AVA), was developed in the late 1950s and is poorly immunogenic. The prolonged 18-month vaccination regimen and required annual boosters are especially problematic for immunization of military personnel both in terms of safety and in terms of practicality. The possibility of new virulent strains that have been strategically engineered to subvert the limited immune response elicited by the AVA vaccine constitutes a genuine threat. Cerus has developed a novel approach for clinically safe and potent vaccines against microbial pathogens utilizing its technology based on the proprietary S-59 psoralen. The S-59 psoralen (S-59) is approved for human use in Europe as part of the commercially available INTERCEPT pathogen inactivation system for platelets. As a proof of concept, mutant strains of the human pathogen Listeria monocytogenes were created by deleting the uvrAB genes. This deletion rendered the DNA repair mutant bacteria exquisitely sensitive to S-59/UVA light-mediated inactivation, but preserved metabolic activity and expression of the Listeria genetic repertoire. As a result, S-59/UVA-inactivated Listeria uvrAB-induced protective memory T cell responses and significant antibody responses in vaccinated animals. With this application, we propose to construct a panel of S-59/UVA inactivated anthrax vaccine candidates based on nonsporogenic B. anthracis DNA repair mutants utilizing host strains having both pXO1 and pXO2 virulence plasmids. The primary goal of this proposal is to identify a vaccine candidate for further testing in nonhuman primates. A series of experiments to be performed in both mice and guinea pigs are proposed to identify an optimal anthrax vaccine candidate based on safety, combined with immunogenicity and induction of protection against lethal toxin or spore challenge. We hypothesize that this unique approach of combining non-viability with metabolic activity within the context of the whole B. anthracis organism will result in a vaccine that induces protective bacterial-specific immunity with increased depth (i.e. mucosal, humoral, and cellular immunity), breadth (immune response targeted at multiple bacterial antigens including capsule), and durability (long-term immunological memory) with a practical immunization regimen, as compared to the AVA vaccine. Achieving the primary goal set forth in this proposal will set the stage for longer-term objectives of the program, and for moving the project toward an initial human clinical trial to test the immunogenicity and safety of this platform. The ultimate goal of this work is to replace the current AVA human anthrax vaccine with an S-59 psoralen/UVA light inactivated genetically defined attenuated nonsporogenic strain of B. anthracis. To accomplish this goal to develop what is a new class of vaccines that combine the safety of a killed vaccine with the potency of a live-attenuated vaccine, we have assembled an experienced consortium comprised of scientists with documented expertise in bacterial pathogenesis, Gram-positive genetics, novel vaccine platform development, infectious disease vaccine development, and a history of productive collaboration.