Psoralen-Killed, Metabolically-Active Anthrax Vaccine

补骨脂素灭活、具有代谢活性的炭疽疫苗

• 批准号: 6818020
• 负责人: Thomas W. Dubensky
• 金额: $ 146.16万
• 依托单位: CERUS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6818020
• 关键词: Bacillus anthracis; DNA repair; anthrax toxin; anthrax vaccines; attenuated microorganism; bacterial antigens; bacterial genetics; bioterrorism /chemical warfare; cooperative study; genetic strain; guinea pigs; host organism interaction; immune response; immunization; laboratory mouse; mass spectrometry; microorganism immunology; mutant; nucleic acid sequence; photoactivation; plasmids; psoralens; sporogenesis; ultraviolet radiation; vaccine development; virulence

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.

描述(申请人提供)：唯一获得许可的人类炭疽疫苗，炭疽疫苗吸收(AVA)，开发于20世纪50年代末，免疫原性很差。长达18个月的疫苗接种方案和所需的年度加强剂对军事人员的免疫接种在安全性和实用性方面都特别成问题。有可能出现新的毒力毒株，这些毒株经过战略性改造，以破坏AVA疫苗引发的有限免疫反应，这构成了真正的威胁。Cerus利用其基于专利S-59补骨脂素的技术开发了一种临床安全和有效的抗微生物病原体疫苗的新方法。S-59补骨脂素(S-59)在欧洲被批准用于人类，作为商业上可用于血小板的截留病原体灭活系统的一部分。作为概念的证明，人类病原体单核细胞增多性李斯特菌的突变株是通过删除uvrAB基因而产生的。这一缺失使得DNA修复突变细菌对S-59/长波紫外线灭活非常敏感，但保留了李斯特菌的代谢活性和表达谱。结果表明，S-59/UVA灭活UvrAB李斯特菌在免疫动物中诱导保护性记忆T细胞反应和显著的抗体反应。在这一应用中，我们建议利用同时具有pXO1和pXO2毒力质粒的宿主菌株，构建一组基于无孢子型炭疽杆菌DNA修复突变体的S-59/UVA灭活炭疽疫苗候选菌株。这项提议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身上进行进一步测试。建议在小鼠和豚鼠身上进行一系列实验，以确定基于安全性、免疫原性和诱导对致命毒素或孢子攻击的保护作用的最佳炭疽疫苗候选。我们推测，与AVA疫苗相比，这种在整个炭疽菌有机体内结合无活性和代谢活性的独特方法将导致一种疫苗，其诱导保护性细菌特异性免疫的深度(即粘膜、体液和细胞免疫)、广度(针对包括囊膜在内的多种细菌抗原的免疫反应)和持久性(长期免疫记忆)与AVA疫苗相比有所增加。实现这项提案中提出的主要目标将为该计划的长期目标以及将该项目推向初步人类临床试验以测试该平台的免疫原性和安全性奠定基础。这项工作的最终目标是用S-59补骨脂素/长波紫外线灭活基因定义的炭疽弱毒株取代目前的AVA人炭疽疫苗。为了实现这一目标，开发一种结合灭活疫苗的安全性和减毒活疫苗的效力的新型疫苗，我们组建了一个经验丰富的财团，成员包括在细菌发病机制、革兰氏阳性遗传学、新型疫苗平台开发、传染病疫苗开发和生产性合作历史方面有证明的专业知识的科学家。