Protection Against Inhalation Anthrax with Inactivated Spores

使用灭活孢子预防吸入性炭疽

• 批准号: 7454509
• 负责人: Donald G. Guiney
• 金额: $ 97.31万
• 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/7454509
• 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; Condition; 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; Numbers; 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; TLR7 gene; Testing; Tissues; Universities; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Virulent; Vulnerable Populations; anthrax toxin; base; cytokine; design; dosage; experience; immunogenicity; innovation; interest; killings; multidisciplinary; nonhuman primate; novel; novel strategies; 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）：该合作研究伙伴关系的总体目标是开发一种高效的炭疽孢子肺部感染免疫对策。这一应用的基本策略包括开发一种孢子疫苗，该疫苗将灭活的、经辐照的无毒炭疽孢子与强有力的佐剂结合，以引起对吸入性炭疽的免疫。该合作申请代表了来自两个学术机构、一个非营利研究机构和两家生物技术公司的微生物学家、免疫学家和化学家的多学科合作伙伴关系。该应用程序专门响应RFA请求，以制定针对肺部和纵隔淋巴结感染孢子期的对策。初步数据显示，灭活的、辐照过的来自无毒炭疽菌株的孢子，与佐剂一起给予，通过一种需要效应CD 4 + T细胞的新机制诱导保护性免疫。对吸入性炭疽孢子的免疫发展迅速，不依赖于保护性抗原。这种针对孢子的对策代表了对专注于诱导对PA的抗体应答的努力的有力补充。该伙伴关系提供了创新和实用的方法，以综合努力的重点是最大限度地提高孢子疫苗的效力。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：为辐照孢子疫苗开发有效佐剂;里程碑2：分析辐照孢子疫苗多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免疫保护的机制;里程碑4：确定免疫小鼠中保护的相关性;里程碑5：确定最具活性的疫苗/佐剂组合在保护豚鼠免受完全毒性炭疽感染中的效力;里程碑6：确定最佳疫苗/佐剂组合在保护兔免受完全毒性炭疽感染中的效力;里程碑7：确定安全性、免疫原性，使用非人灵长类动物的最佳孢子/佐剂疫苗组合的有效性该伙伴关系将采用创新的化学方法来开发新型佐剂和佐剂/佐剂制剂。孢子组合以最大化CD 4 + T细胞应答。微生物学家和免疫学家之间的合作将有助于了解肺组织中预防炭疽孢子的免疫学基础，并将指导最有效疫苗的生产和测试。在适当的吸入性炭疽动物模型方面具有专业知识的合作研究人员将证明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加强公众健康。