Protection Against Inhalation Anthrax with Inactivated Spores

使用灭活孢子预防吸入性炭疽

• 批准号: 7901437
• 负责人: Donald G. Guiney
• 金额: $ 102.61万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901437
• 关键词: Adjuvant; Adoptive Transfer; Adverse effects; Aerosols; Affect; Aluminum Hydroxide; Animal Model; Anthrax Attack; Anthrax Vaccines; Anthrax disease; Antibodies; Antibody Formation; Antibody-mediated protection; Antigens; Attenuated; Bacillus anthracis; Bacillus anthracis spore; Bacteria; Bacterial Vaccines; Biochemistry; Biological Assay; Biotechnology; Breathing; CD4 Positive T Lymphocytes; Cavia; Cells; Cellular Immunity; Chemicals; Cold Chains; Collaborations; Combined Vaccines; Complement; Data; Development; Drug Formulations; Effectiveness; Germination; Goals; Human; Immune; Immune response; Immunity; Immunization; Immunologics; Immunologist; Individual; Infection; Infectious Disease Immunology; Inflammatory; Injection of therapeutic agent; Institutes; Institution; Licensing; Ligands; Literature; Lung; Mediastinal lymph node group; Mediating; Methods; Microbiology; Modeling; Mus; Oryctolagus cuniculus; Pharmaceutical Chemistry; Phase; Population; Populations at Risk; Preparation; Primates; Process; Production; Proteins; Public Health; Recombinants; Reproduction spores; Request for Applications; Research; Research Institute; Research Personnel; Research Proposals; Route; Safety; Schedule; T cell response; TLR7 gene; Testing; Tissues; Universities; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Virulent; Vulnerable Populations; anthrax toxin; base; cytokine; design; dosage; efficacy testing; experience; immunogenicity; innovation; interest; killings; multidisciplinary; nonhuman primate; novel; novel strategies; product development; programs; research study; response; subcutaneous; vaccine development

DESCRIPTION (provided by applicant): The overall goal of this Cooperative Research Partnership is to develop a highly effective immunologic countermeasure to pulmonary infection with anthrax spores. The basic strategy of this application involves the development of a spore-based vaccine that combines killed, irradiated avirulent anthrax spores with powerful adjuvants to elicit immunity to inhalation anthrax. This Cooperative application represents a multi-disciplinary partnership combining microbiologists, immunologists, and chemists from two academic institutions, a non- profit research institution, and two biotechnology companies. The application responds specifically to the RFA request to develop countermeasures that target the spore phase of infection in the lung and mediastinal lymph nodes. Preliminary data shows that killed, irradiated spores from an avirulent anthrax strain, given with adjuvants, induce protective immunity by a novel mechanism requiring effector CD4+ T cells. Immunity to inhalation anthrax induced by spores develops rapidly and is independent of protective antigen (PA). This countermeasure targeted to spores represents a powerful complement to efforts focused on the induction of antibody responses to PA. The partnership provides innovative and practical approaches in an integrated effort focused on maximizing the effectiveness of the spore-based vaccine. The partnership has established the following milestones in the development process: Milestone 1: Develop effective adjuvants for the irradiated spore vaccine; Milestone 2: Analyze the efficacy and safety in mice of a variety of adjuvants for the irradiated spore vaccine, and compare intranasal and subcutaneous routes of administration; Milestone 3: Determine the mechanism of immune protection induced by the irradiated spore vaccine; Milestone 4: Identify correlates of protection in immunized mice; Milestone 5: Determine the efficacy of the most active vaccine/adjuvant combinations in protecting guinea pigs against fully virulent anthrax infection; Milestone 6: Determine the efficacy of the optimal vaccine/adjuvant combinations in protecting rabbits against fully virulent anthrax infection; Milestone 7: Determine safety, immunogenicity, and efficacy of the optimal spore/adjuvant vaccine combination using non-human primates The partnership will employ innovative chemical methods to develop novel adjuvants and preparations of adjuvant/spore combinations to maximize the CD4+ T cell response. Collaboration between microbiologists and immunologists will facilitate an understanding of the immunologic basis for protection against anthrax spores in the pulmonary tissues and will guide production and testing of the most effective vaccine. Collaborating investigators with expertise in the appropriate animal models of inhalation anthrax will demonstrate the effectiveness of the products ultimately selected by the iterative testing process. This project will enhance public health through protection against anthrax.

描述（由申请人提供）：这种合作研究合作伙伴关系的总体目标是为炭疽孢子的肺部感染开发高效的免疫学对策。该应用的基本策略涉及开发基于孢子的疫苗，该疫苗结合了杀死的，辐照的无毒炭疽孢子和强大的佐剂，以引起免疫吸入炭疽。该合作应用代表了由两家学术机构，一个非利润研究机构和两家生物技术公司组合的微生物学家，免疫学家和化学家的多学科合作伙伴关系。该应用程序特别响应RFA请求，以开发针对肺部和纵隔淋巴结中感染孢子阶段的对策。初步数据表明，用佐剂给出的无毒性炭疽菌株杀死的辐照孢子，通过需要效应子CD4+ T细胞的新机制诱导保护性免疫。孢子诱导的吸入炭疽的免疫力迅速发展，与保护性抗原（PA）无关。针对孢子的这种对策代表了专注于诱导PA的抗体反应的努力的有力补充。该合作伙伴关系提供了创新和实用的方法，该方法旨在最大程度地提高基于孢子的疫苗的有效性。该合作伙伴关系在开发过程中建立了以下里程碑：里程碑1：为辐照的孢子疫苗开发有效的佐剂；里程碑2：分析各种佐剂的孢子疫苗的疗效和安全性，并比较鼻内和皮下给药途径；里程碑3：确定辐照孢子疫苗引起的免疫保护机制；里程碑4：确定免疫小鼠保护的相关性；里程碑5：确定最活跃的疫苗/佐剂组合在保护豚鼠免受完全毒性炭疽感染的功效；里程碑6：确定最佳疫苗/辅助组合在保护兔子免受完全毒性炭疽感染的功效；里程碑7：确定最佳孢子/辅助疫苗组合使用非人类灵长类动物的安全性，免疫原性和功效。合作伙伴关系将采用创新的化学方法来开发新颖的佐剂和辅助/孢子组合的制剂，以最大程度地介绍CD4+ T细胞响应。微生物学家与免疫学家之间的合作将有助于了解肺组织中炭疽孢子的免疫学基础，并将指导最有效的疫苗的生产和测试。在适当的吸入炭疽动物模型中具有专业知识的研究人员的合作将证明产品最终通过迭代测试过程选择的有效性。该项目将通过保护炭疽来增强公共卫生。