Live nasal recombinant B. pertussis vaccine against tuberculosis

鼻用重组百日咳杆菌结核活疫苗

• 批准号: 10617757
• 负责人: Peter Goldstein
• 金额: $ 32.53万
• 依托单位: ILIAD BIOTECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-04 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617757
• 关键词: Adolescent; Adult; Animal Model; Antibodies; Antigens; Attenuated; Attenuated Vaccines; Bacteria; Bordetella pertussis; CD8-Positive T-Lymphocytes; Cell Separation; Cells; Chimeric Proteins; Clinical; Codon Nucleotides; Complement; DNA cassette; Data; Dendritic Cells; Developing Countries; Development; Discrimination; Dose; Effectiveness; Freeze Drying; Genetic Engineering; Goals; Hemagglutinin; Human; Hybrids; IL17 gene; Immune response; Immunity; Immunologics; Immunology; Infant; Infection; Infrastructure; Interruption; Intranasal Administration; Laboratories; Lead; Lung; Lung infections; Macaca; Macaca fascicularis; Macaca mulatta; Manufacturer; Membrane; Modeling; Mucosal Immune Responses; Mucous Membrane; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Nasopharynx; Nose; Outcome; PET/CT scan; Papio; Parasites; Peptide Hydrolases; Persons; Pertussis; Pertussis Vaccine; Phase; Phase II Clinical Trials; Positioning Attribute; Predisposition; Prevention; Production; Proteins; Publishing; Recombinants; Rhesus; Sampling; Secretory Immunoglobulin A; Serum; Site; Spleen; Structure of parenchyma of lung; Study models; System; T cell response; T-Lymphocyte; Techniques; Technology; Temperature; Testing; Tissues; Tuberculosis; Tuberculosis Vaccines; Type III Secretion System Pathway; Vaccination; Vaccine Production; Vaccines; Virulent; Virus; X-Ray Computed Tomography; bacterial vector; clinical development; clinical translation; clinically relevant; cost; efficacy testing; functional hypothalamic amenorrhea; immunogenicity; improved; lead candidate; lung colonization; mouse model; nonhuman primate; novel vaccines; parenteral administration; prevent; programs; protective efficacy; response; success; tissue resident memory T cell; transmission process; vaccine candidate; vaccine distribution; vaccine evaluation; vaccine platform; vaccine strategy; vaccine trial; vector

ABSTRACT: Live nasal recombinant B. pertussis vaccine against tuberculosis An effective TB vaccine that blocks infection and interrupts transmission of TB from infected adolescents and adults is urgently needed as a complement to the worldwide use of BCG in infants. Although BCG is moderately effective in preventing disseminated forms of TB, new vaccine strategies are necessary for improved control and prevention of TB which infects over 10 million people annually. True correlates of protective immunity have not been identified. However, local, lung-resident memory T cells have been implicated in protection against pulmonary forms of TB in many prior animal model studies. Furthermore, recent evidence shows that IL-17 secreting T cells that are enriched in the lung tissue of infected humans are likely involved with immunological control of pulmonary infections. New vaccine strategies are needed that can induce mucosal response and better induce protective T cells in the lungs. Our vaccine strategy will advance a live vaccine platform based on B-Tech, an attenuated strain of Bordetella pertussis, which has already completed Phase 2 clinical trials and has demonstrated ability to induce durable and specific mucosal and systemic immune responses. We propose to develop the platform bacterial vector (called B-Tech-Mtb) for intranasal vaccination. B-Tech strains transiently colonize the nasopharyngeal mucosa in animal models and humans and induce mucosal (including secretory IgA and resident memory T cells) and systemic (including serum antibodies and circulating T cells) responses against pertussis antigens. In addition, B-Tech vaccines are lyophilized, have >2-year stability at 25°C, and can be produced by most if not all developing countries at low cost. In murine studies, transient colonization induces a resident memory T cell response that is associated with protection against B. pertussis infection. Indeed, transient colonization of the nasopharyngeal mucosa by B. pertussis results in targeting of mucosal dendritic cells, the induction of Th17 T cell responses, and high expression of IL-17 that is associated with the development of robust secretory IgA and resident T cell memory in the lungs. We propose to engineer genetically modified bacterial systems developed in our labs for expression and secretion of several Mtb hybrid antigens that have been tested clinically as parenteral vaccines. We will construct and test B-Tech- Mtb vaccine candidates after intranasal administration in mice and non-human primate models, secreting selected M. tuberculosis antigens continuously in the vicinity of mucosal inductive sites. By developing B. pertussis strains secreting one or more Mtb antigens, we anticipate that Th1/Th17 skewed T cell responses will be more robust than observed in prior vaccine studies with other mucosally or parenterally administered TB vaccine candidates. With success, this program will enable production of enhanced Mtb- specific mucosal immune responses, including resident memory T cell responses, leading to protection in TB challenge models.

摘要：活鼻重组B.百日咳疫苗针对结核病 一种有效的结核病疫苗，可阻止感染并中断感染青少年的传播 迫切需要成人作为全球在婴儿中使用BCG的完整。虽然BCG是 适度有效地防止传播形式的结核病形式，新的疫苗策略是必要的 改善了TB的控制和预防，每年感染超过1000万人。真正的相关性 保护性免疫尚未确定。但是，局部肺居住记忆T细胞已经 在许多先前的动物模型研究中，在防御肺形式的TB中实施。此外， 最近的证据表明，IL-17分泌的T细胞富含感染人的肺组织 可能与肺部感染的免疫控制有关。需要新的疫苗策略 这可以诱导粘膜反应并更好地诱导肺部受保护的T细胞。我们的疫苗策略 将推进基于B-Tech的实时疫苗平台，B-Tech是一种衰减的Bordetella buttussis菌株，该菌株 已经完成了第二阶段临床试验，并且表现出诱导耐用和特定的能力 粘膜和全身免疫反应。我们建议开发平台细菌向量（称为） B-Tech-MTB）用于鼻内疫苗接种。 B-tech菌株瞬时在鼻咽粘膜中定居 动物模型和人类并诱导粘膜（包括秘密IGA和居民记忆T细胞） 和全身性（包括血清抗体和循环T细胞）对百日咳抗原的反应。 此外，B-Tech疫苗被冻干，在25°C下具有> 2年的稳定性，并且可以由大多数人产生 如果不是所有的发展中国家，以低成本。在鼠研究中，瞬态定植诱导了住所 记忆T细胞反应与对百日咳芽孢杆菌感染有关的保护。确实，瞬态 百日咳芽孢杆菌对鼻咽粘膜的定殖导致粘膜树突状细胞的靶向， Th17 T细胞反应的诱导和与IL-17的高表达 强大的IGA秘书和居民在肺部的T细胞记忆的发展。我们建议工程师 在我们的实验室中开发的转基因细菌系统以表达和分泌几种MTB 杂交抗原已在临床上作为父母疫苗进行了测试。我们将构建和测试B-Tech- MTB疫苗候选小鼠和非人类灵长类动物模型后的鼻内疫苗候选物，分泌 选定的粘膜电感部位附近的结核分枝杆菌抗原连续。通过开发B。 百日咳菌株分泌一种或多种MTB抗原，我们预计Th1/th17偏斜了T细胞 在先前的疫苗研究中，与其他粘膜外疫苗研究中观察到的反应更强大 候选结核病疫苗。随着成功，该计划将能够生产增强的MTB- 特定的粘膜免疫反应，包括居民记忆T细胞反应，从而在 结核病挑战模型。