Development of a simple and effective therapy against post-exposure anthrax

开发一种简单有效的针对暴露后炭疽病的疗法

• 批准号: 8393130
• 负责人: JIANFENG ZHANG
• 金额: $ 11.07万
• 依托单位: VAXIN INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8393130
• 关键词: A/J Mouse; Address; Adenoviruses; Adverse effects; Affect; Aftercare; Animal Model; Animals; Anthrax Vaccines; Anthrax disease; Anthrax exposure; Antibiotic Therapy; Antibiotics; Antigens; Bacillus anthracis; Bacillus anthracis spore; Biological Warfare; Bioterrorism; Biothrax; Bypass; Categories; Centers for Disease Control and Prevention (U.S.); Ciprofloxacin; Collaborations; Contracts; Development; Dominant-Negative Mutation; Dose; Effectiveness; Foundations; Funding; Genes; Goals; Health Professional; Immunity; Individual; Infection; Injection of therapeutic agent; Institutes; Intranasal Administration; Licensing; Macaca; Modeling; Mus; Mutation; Needles; New Zealand; Nose; Oryctolagus cuniculus; Patients; Perception; Phase; Population; Prophylactic treatment; Proteins; Public Health; Safety; Scientist; Serotyping; Small Business Innovation Research Grant; Testing; Therapeutic Agents; Time; United States Dept. of Health and Human Services; Vaccination; Vaccines; anthrax lethal factor; anthrax protective factor; authority; base; disorder prevention; effective therapy; immunogenic; immunogenicity; immunoprophylaxis; improved; mutant; nonhuman primate; novel strategies; preclinical study; research and development; respiratory; vaccine candidate; vector

DESCRIPTION (provided by applicant): The use of both vaccination and antibiotic therapy is the most effective approach against inhalational anthrax. Unfortunately, there are two significant problems associated with current post-exposure prophylaxis (PEP): 1) the limitations of the anthrax vaccine adsorbed (AVA) which requires multiple needle injections by health professionals to achieve a protective immunity and 2) the concern over adverse effects of the long-term antibiotic treatment. It is essential to develop a simple and effective approach against post-exposure anthrax. Vaxin is developing a replication competent adenovirus-free, non-replicating adenovirus 5 (Ad5)-vectored nasal anthrax vaccine encoding a humanized wild type (wt) B. anthraxcis protective antigen (PA) gene (AdwtPA) and has demonstrated that: 1) protection with single dose; 2) excellent safety profile in animals; 3) easy, patient- friendly, needle-free administration; 4) rapid and long-lasting immunity; and 5) its protection potency is not impaired by pre-existing anti-Ad5 immunity. However, AdwtPA expressing wt PA protein may not safe for individual who has been freshly exposed to anthrax spores. Fortunately, numerous studies have demonstrated that dominant negative inhibitory (DNI) PA mutants are not only more immunogenic but also more effective than wt PA as a therapeutic agent. Therefore, it would be reasonable to expect that an Ad5 vector encoding a humanized DNI PA mutant gene (AdDNIPA) could be a better and safer PEP vaccine against anthrax infection. More importantly, use of AdDNIPA as a component of PEP should be able to minimize the time and dose required for post-exposure antibiotic therapy. In this proposal, we will generate a RCA-free AdDNIPA vector expressing secretory PA83 protein with K397D and D425K double mutations as a new nasal anthrax vaccine candidate and evaluate its immunogenicity and the protection efficacy as a PEP vaccine in conjunction with a short-course ciprofloxacin prophylaxis against respiratory anthrax in A/J mice. PUBLIC HEALTH RELEVANCE: Novel approaches for the prophylaxis and treatment of post-exposure anthrax are still required for counteracting the threat posed by bioterrorist attacks. Evidence is emerging that nasal spray of a non-replicating adenovirus serotype 5-derived vectors encoding Bacillus anthracis protective antigen can bypass pre-existing anti-Ad5 immunity and confer immediate protection like a therapeutic agent and elicit rapid and sustained protective immunity as a vaccine. Use of this adenovirus vectored anthrax nasal vaccine as a component of post-exposure prophylaxis will significantly reduce the time and dose required for antibiotic therapy.

描述（由申请人提供）：疫苗接种和抗生素治疗是针对吸入炭疽的最有效方法。不幸的是，当前暴露后预防（PEP）存在两个重大问题：1）吸附的炭疽疫苗的局限性（AVA）需要卫生专业人员进行多次注射以实现保护性免疫，而2）对长期抗生素治疗的长期不良影响的关注。针对暴露后炭疽病，开发一种简单有效的方法至关重要。 Vaxin正在开发一种胜任无腺病毒的复制，无复制的腺病毒5（AD5）向量的鼻炭疽疫苗，编码人性化野生型（WT）B。炭疽病b。 2）动物的出色安全性； 3）容易，友好，无针的管理； 4）快速和持久的免疫力； 5）预先存在的抗AD5免疫力不会损害其保护效力。但是，对于新鲜暴露于炭疽孢子的人来说，表达WT PA蛋白的ADWTPA可能不安全。幸运的是，许多研究表明，主要的负面抑制（DNI）PA突变体不仅具有免疫原性，而且比WT PA作为治疗剂更有效。因此，可以合理地期望编码人源化DNI PA突变基因（ADDNIPA）的AD5载体可能是针对炭疽感染的更好，更安全的PEP疫苗。更重要的是，将ADDNIPA用作PEP的组成部分，应能够最大程度地减少暴露后抗生素治疗所需的时间和剂量。 In this proposal, we will generate a RCA-free AdDNIPA vector expressing secretory PA83 protein with K397D and D425K double mutations as a new nasal anthrax vaccine candidate and evaluate its immunogenicity and the protection efficacy as a PEP vaccine in conjunction with a short-course ciprofloxacin prophylaxis against respiratory anthrax in A/J mice. 公共卫生相关性：仍需要进行预防和治疗暴露后炭疽病的新方法来抵消生物恐怖袭击所带来的威胁。有证据表明，非复制腺病毒血清型的鼻腔喷雾5衍生的矢量源编码炭疽芽孢杆菌保护性抗原可以绕开现有的抗AD5免疫力，并允许立即保护治疗剂，例如治疗剂，并在疫苗作为疫苗作为疫苗的快速保护和持续的保护性免疫。使用该腺病毒载体鼻疫苗作为暴露后预防的组成部分将大大减少抗生素治疗所需的时间和剂量。