Live nasal recombinant B. pertussis vaccine against tuberculosis

鼻用重组百日咳杆菌结核活疫苗

基本信息

批准号：
10442002
负责人：
Peter Goldstein
金额：
$ 32.93万
依托单位：
ILIAD BIOTECHNOLOGIES, LLC
依托单位国家：
美国
项目类别：
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/10442002
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 Immune response Immunity Immunologics Immunology Infant Infection Infrastructure Interleukin-17 Interruption Intranasal Administration Laboratories Lead Lung Lung infections Macaca Macaca fascicularis Macaca mulatta Manufacturer Name Membrane Modeling Mucosal Immune Responses Mucous Membrane Mus Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Nose Outcome Papio Parasites Peptide Hydrolases Persons Pertussis Pertussis Vaccine Phase Phase II Clinical Trials Positioning Attribute Positron-Emission Tomography 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 memory cell 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 base clinical development clinical translation clinically relevant cost efficacy testing functional hypothalamic amenorrhea immunogenicity improved lead candidate lung colonization mouse model nonhuman primate novel vaccines prevent programs protective efficacy response success transmission process vaccine candidate vaccine distribution vaccine evaluation vaccine platform vaccine strategy vaccine trial vector

项目摘要

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：重组百日咳鼻腔结核活疫苗一种有效的结核病疫苗，可阻止感染并阻断受感染青少年的结核病传播尽管卡介苗在全球范围内用于婴儿，但成人和成人迫切需要卡介苗作为其补充。在预防播散性结核病方面效果中等，因此需要新的疫苗策略改善结核病的控制和预防，每年感染超过 1000 万人。保护性免疫尚未确定，但已发现局部肺驻留记忆 T 细胞。在许多先前的动物模型研究中，涉及预防肺部结核病。此外，最近的证据表明，分泌 IL-17 的 T 细胞在受感染人类的肺组织中富集可能涉及肺部感染的免疫控制，需要新的疫苗策略。可以诱导粘膜反应并更好地诱导肺部的保护性 T 细胞。将推进基于 B-Tech 的活疫苗平台，B-Tech 是一种百日咳博德特氏菌减毒株，已经完成了 2 期临床试验，并证明了诱导持久和特异性的能力我们建议开发平台细菌载体（称为）。 B-Tech-Mtb）用于鼻内疫苗接种，B-Tech 菌株短暂定植于鼻咽粘膜。动物模型和人类并诱导粘膜（包括分泌性 IgA 和常驻记忆 T 细胞）以及针对百日咳抗原的全身反应（包括血清抗体和循环 T 细胞）。此外，B-Tech 疫苗是冻干的，在 25°C 下具有 >2 年稳定性，并且可以由大多数生产商生产即使不是所有发展中国家都以低成本进行，在小鼠研究中，短暂的定殖会诱导居民。与抵抗百日咳博德特氏菌感染有关的记忆 T 细胞反应确实是短暂的。百日咳博德特氏菌在鼻咽粘膜上的定植导致粘膜树突状细胞的靶向， Th17 T 细胞反应的诱导，以及与我们建议对肺部强大的分泌性 IgA 和驻留 T 细胞记忆进行改造。我们实验室开发的转基因细菌系统，用于表达和分泌多种结核分枝杆菌我们将构建并测试 B-Tech- 已作为肠胃外疫苗进行临床测试的混合抗原。小鼠和非人灵长类动物模型鼻内给药后，MTB 候选疫苗分泌通过开发 B. 结核分枝杆菌抗原，在粘膜诱导位点附近连续选择。百日咳菌株分泌一种或多种 Mtb 抗原，我们预计 Th1/Th17 偏向 T 细胞反应将比之前其他粘膜或肠胃外疫苗研究中观察到的反应更强烈如果成功，该计划将能够生产增强型结核病疫苗。特异性粘膜免疫反应，包括常驻记忆 T 细胞反应，导致保护结核病挑战模型。