Vaccinating at Mucosal Surfaces with Nanoparticle-conjugated Antigen and Adjuvant

使用纳米颗粒结合的抗原和佐剂在粘膜表面进行疫苗接种

• 批准号: 10587388
• 负责人: SEBASTIAN JOYCE
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587388
• 关键词: Academic Medical Centers; Address; Adjuvant; Adult; Aerosols; Alleles; Antigen Presentation Pathway; Antigens; Bacteria; Binding; Biological Assay; Biomedical Engineering; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19; Cells; Cellular biology; Cessation of life; Chronic; Clinical; Common Epitope; Communicable Diseases; Disease; Drug resistant Mycobacteria Tuberculosis; Effector Cell; Epitopes; Generations; Goals; HLA-A gene; HLA-B Antigens; Human; Immune; Immunity; Immunization; Immunodominant Epitopes; Immunologist; Incidence; Infection; Lung; Modeling; Morbidity - disease rate; Mucous Membrane; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Peptides; Population; Positioning Attribute; Pre-Clinical Model; Predisposition; Publishing; Quality of life; Research; Respiratory System; Route; Severe Acute Respiratory Syndrome; Site; Subunit Vaccines; Surface; T cell response; T memory cell; T-Lymphocyte Epitopes; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Tuberculosis; Tuberculosis Vaccines; Vaccinated; Vaccination; Vaccine Design; Vaccines; Veterans; Virulent; Virus; Work; clinical practice; cost; density; design; flu; high throughput screening; humanized mouse; immunogenic; improved; in vivo; innovation; mortality; mouse model; multidisciplinary; nanoparticle; next generation; novel; novel vaccines; pathogen; pre-clinical; preclinical study; response; transmission process; vaccine delivery; vector

The incidence of tuberculosis (TB) has increased among Veterans in recent years because global TB burden has escalated with the emergence of multidrug-resistant and extremely drug resistant Mycobacterium tuberculosis (Mtb) strains. Further, current vaccines do not elicit long-lasting protective immunity against TB, especially in adults. Hence, this application addresses a critical unmet need for an effective vaccine against TB and thereby, significantly improve the quality of life of our Veterans. Herein, we propose pre-clinical studies that will identify protective CD8+ T cell epitopes and develop intranasal vaccine delivery platforms for the design of next generation TB vaccines. The global burden of TB caused by Mycobacterium tuberculosis (Mtb) infection is enormous. A third of the world’s population is currently infected with Mtb, an airborne pathogen that causes ~1.5 million deaths annually. The escalating emergence of multidrug-resistant and extremely drug resistant Mtb strains for which treatment options are costly and limited, further exacerbates global burden. This problem persists because current vaccines do not elicit long-lasting protective immunity against TB, especially in adults. The challenge is multifaceted because Mtb enters the host through the respiratory tract and, therefore, optimal protection will require installation of lung-resident CD4+ and CD8+ memory T cells positioned at the frontline to respond immediately to an infection. Traditional vaccines and approved adjuvants typically elicit weak, short- lived T cell responses, and parenteral vaccination is ineffective at installing protective immunity within the mucosae. Moreover, most virus-vectored and subunit TB vaccines employ a small subset of Mtb antigens, resulting in insufficient epitope diversity for optimal protection, partly because the epitopes that are presented during Mtb infection and confer protective immunity are not fully defined. Hence, our overall objective is to discover immunogenic, protective Mtb epitopes and to incorporate them in an innovative nanoparticle (NP)- based intranasal vaccine designed to promote a balanced CD4+ and CD8+ T cell responses in the lungs that are protective against TB. As a means to accomplish this goal, we discovered >10,000 peptides that bind to HLA- A*02:01, B*07:02, B*35:01, & B*35:03 in a high-throughput binding assay using ultrahigh-density peptide arrays. Now the challenge is to identify epitopes recognised by Mtb-reactive CD8+ T cells that can protect against infection in a preclinical, humanised HLA-Itg mouse models. Moreover, using different infection models, we have developed multiple nanoparticle platforms for simultaneous delivery of antigens and adjuvants that efficiently generate protective, tissue resident CD8+ T cells (Trm). Guided by these exciting published and preliminary results, we will test this central hypothesis: Intranasal immunization with subunit vaccines consisting of novel Mtb antigens and adjuvant will generate CD8+ Trm responses in the lungs. Installation of Mtb-reactive CD8+ Trm at the port of pathogen entry will protect against a lethal, aerosol challenge of three novel humanised mouse models with [there] clinical isolate of virulent Mtb, [including] HN878. Our strategy to test this hypothesis is to, (a) define immunodominant CD8+ T cell epitopes presented by HLA-B*07:02 that protect B7.2tg mice from Mtb infections; and (b) define common immunodominant CD8+ T cell epitopes presented by multiple B*07:02-related alleles [called B7 supertype] that protect HLA-I transgenic mouse models from Mtb infections. Our multidisciplinary team —consisting of biochemists, immunologists, microbiologists, and bioengineer, is ideally situated to pursue the stated Specific Aims. We anticipate that successful completion of the proposed research will inform next generation vaccine design against Mtb infections and TB disease. Our innovative “discover and deliver” approach to vaccine design will impact clinical practice paradigms against TB and other pulmonary infectious diseases such as SARS-COVID19 and Flu. Thereby, vaccine paradigms emerging from our research bears with it the promise to significantly improve the quality of life of our Veterans.

近年来，由于全球结核病负担，结核病的事件（TB）增加了 随着多药耐药性和极度耐药性分枝杆菌的出现而升级 结核病（MTB）菌株。此外，当前的疫苗不会引起对结核病的持久保护性免疫 特别是在成年人中。因此，该应用程序解决了对TB有效疫苗的至关重要的需求 因此，大大改善了我们退伍军人的生活质量。在此，我们提出了临床前研究 将识别受保护的CD8+ T细胞表位，并开发用于设计的鼻内疫苗输送平台 下一代结核病疫苗。结核分枝杆菌（MTB）感染引起的结核病全球负担是 巨大的。目前，世界三分之一的人口感染了MTB，MTB是一种造成约1.5的空气传播病原体。 每年有百万人死亡。抗多药和极度耐药的MTB的出现不断升级 治疗方案的菌株成本高昂且有限，进一步加剧了全球负担。这个问题 持续存在，因为目前的疫苗不会引起对结核病的持久保护性免疫，尤其是在成年人中。 挑战是多方面的，因为MTB通过呼吸道进入宿主，因此是最佳的 保护将需要安装肺居民CD4+和CD8+记忆T单元，位于前线 立即回应感染。传统的疫苗和批准的调节器通常会引起弱，短暂的 活细胞的反应，父母的疫苗接种无效，无法在内部安装保护性免疫力 粘膜。此外，大多数病毒载体和亚基TB疫苗采用了一小部分MTB抗原， 导致情节多样性不足以进行最佳保护，部分是因为呈现的表位 在MTB感染和会议保护性免疫学期间，未完全定义。因此，我们的总体目标是 发现免疫原性，受保护的MTB表位，并将其纳入创新的纳米颗粒（NP） - 基于鼻内疫苗，旨在促进肺中均衡的CD4+和CD8+ T细胞反应 防止结核病。作为实现这一目标的一种手段，我们发现了与HLA-结合的10,000肽 A*02：01，B*07：02，B*35：01，＆B*35：03在使用超高密度肽阵列的高通量结合测定中。 现在，挑战是确定MTB反应性CD8+ T细胞所识别的表位，可以预防 在临床前，人性化的HLA-ITG小鼠模型中感染。此外，使用不同的感染模型，我们有 开发了多个纳米颗粒平台，可简单地递送抗原和调节剂 产生受保护的组织居民CD8+ T细胞（TRM）。在这些令人兴奋的发表和初步的指导下 结果，我们将检验以下中心假设：鼻内免疫和由新型疫苗组成的亚基疫苗 MTB抗原和调节将在肺部产生CD8+ TRM反应。 MTB反应性CD8+ TRM的安装 在病原体的港口，进入将防止三种新型人类小鼠的致命性气溶胶挑战 具有毒性MTB的临床分离的模型，[包括] HN878。我们检验该假设的策略是 （a）定义由HLA-B*07：02提出的免疫主导CD8+ T细胞表位保护B7.2TG小鼠免受MTB 感染； （b）定义由多个B*07：02相关的常见的免疫主导CD8+ T细胞表位 等位基因[称为B7超构型]，可保护HLA-I转基因小鼠模型免受MTB感染。我们的 多学科团队 - 生物化学家，免疫学家，微生物学家和生物工程师的一致是理想情况下 旨在追求具体的目标。我们预计拟议的研究成功完成 将针对MTB感染和结核病疾病的下一代疫苗设计告知下一代疫苗。我们创新的“发现和 传递“疫苗设计方法将影响针对结核病和其他肺部的临床实践范式 SARS-COVID19和流感等传染病。因此，我们的研究中出现的疫苗范例 熊有望显着改善退伍军人的生活质量。