Protection Against Inhalation Anthrax with Inactivated Spores

使用灭活孢子预防吸入性炭疽

• 批准号: 8058623
• 负责人: Donald G. Guiney
• 金额: $ 101.59万
• 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/8058623
• 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; 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(由申请者提供)：该合作研究伙伴关系的总体目标是开发一种针对炭疽孢子肺部感染的高效免疫学对策。这一应用的基本策略包括开发一种基于孢子的疫苗，该疫苗将被杀死的无毒炭疽孢子与强大的佐剂相结合，以诱导对吸入性炭疽的免疫力。这一合作申请代表了一个多学科的合作伙伴关系，包括来自两个学术机构、一个非营利性研究机构和两家生物技术公司的微生物学家、免疫学家和化学家。该应用程序专门响应RFA的请求，制定针对肺部和纵隔淋巴结孢子期感染的对策。初步数据显示，来自无毒炭疽菌株的被杀死的、辐射过的孢子，加上佐剂，通过一种需要效应器CD4+T细胞的新机制诱导保护性免疫。由孢子诱导的吸入性炭疽免疫反应迅速发展，且不依赖保护性抗原(PA)。这种针对孢子的对策是对专注于诱导对PA的抗体反应的努力的有力补充。该伙伴关系在一项综合努力中提供了创新和实用的方法，重点是最大限度地提高基于孢子的疫苗的效力。该伙伴关系在开发过程中确立了以下里程碑：里程碑1：为辐照孢子疫苗开发有效的佐剂；里程碑2：分析辐照孢子疫苗的各种佐剂在小鼠中的有效性和安全性，并比较鼻内和皮下给药途径；里程碑3：确定辐照孢子疫苗诱导的免疫保护机制；里程碑4：确定免疫小鼠中的保护相关性；里程碑5：确定最活跃的疫苗/佐剂组合在保护豚鼠免受全毒力炭疽感染方面的有效性；里程碑6：确定最佳疫苗/佐剂组合在保护兔子免受全毒力炭疽感染方面的有效性；里程碑7：确定使用非人类灵长类动物的最佳孢子/佐剂疫苗组合的安全性、免疫原性和有效性该伙伴关系将使用创新的化学方法来开发新的佐剂和佐剂/孢子组合的制剂，以最大限度地提高CD4+T细胞的反应。微生物学家和免疫学家之间的合作将有助于了解保护肺组织免受炭疽孢子侵袭的免疫学基础，并将指导最有效疫苗的生产和测试。具有适当吸入性炭疽动物模型专业知识的合作研究人员将展示迭代测试过程最终选择的产品的有效性。该项目将通过预防炭疽病来增进公众健康。