Psoralen-Killed, Metabolically-Active Anthrax Vaccine

描述（由申请方提供）：唯一获得许可的人用炭疽疫苗，即吸收炭疽疫苗（AVA），于20世纪50年代末开发，免疫原性较差。延长18个月的疫苗接种方案和每年需要加强剂，在安全性和实用性方面对军事人员的免疫接种特别成问题。新的强毒株可能被战略性地改造，以破坏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，利用其基于专利S-59 peptide的技术，针对微生物病原体生产临床安全和有效的疫苗。在欧洲，S-59血小板素（S-59）已获批用于人用，作为市售血小板用INTERCEPT病原体灭活系统的一部分。作为概念的证明，通过删除uvrAB基因来产生人类病原体单核细胞增生李斯特菌的突变株。这种缺失使得DNA修复突变体细菌对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uvrAB诱导了免疫动物的保护性记忆T细胞应答和显著的抗体应答。通过这种应用，我们建议构建一组基于非产孢B的S-59/UVA灭活炭疽疫苗候选物。炭疽菌DNA修复突变体，其利用具有pXO 1和pXO 2毒力质粒的宿主菌株。这项提案的主要目标是确定一种候选疫苗，以便在非人灵长类动物中进行进一步测试。建议在小鼠和豚鼠中进行一系列实验，以根据安全性、免疫原性和对致死毒素或孢子攻击的诱导保护来鉴定最佳炭疽疫苗候选物。我们假设，这种独特的方法结合非活力与代谢活性的背景下，整个B。与AVA疫苗相比，使用炭疽菌生物体的疫苗将产生诱导保护性细菌特异性免疫的疫苗，其具有增加的深度（即粘膜、体液和细胞免疫）、广度（针对多种细菌抗原包括荚膜的免疫应答）和持久性（长期免疫记忆），以及实用的免疫方案。实现本提案中提出的主要目标将为该项目的长期目标奠定基础，并将该项目推向初步人体临床试验，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一种S-59青霉素/UVA光灭活的B的遗传上确定的减毒非产孢菌株取代目前的AVA人炭疽疫苗。炭疽病为了实现这一目标，开发出一种新型疫苗，将灭活疫苗的安全性与减毒活疫苗的效力相结合，我们组建了一个经验丰富的联盟，由在细菌发病机制、革兰氏阳性遗传学、新型疫苗平台开发、传染病疫苗开发方面具有记录在案的专业知识的科学家组成，以及富有成效的合作历史。

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.