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，退伍军人中结核病（TB）的发病率有所增加 随着多重耐药和极端耐药分枝杆菌的出现， 结核（Mtb）菌株。此外，目前的疫苗不能引起针对结核病的持久保护性免疫， 尤其是在成年人中。因此，该应用解决了对有效的结核病疫苗的关键未满足的需求 从而显著提高退伍军人的生活质量。在此，我们建议进行临床前研究， 将确定保护性CD 8 + T细胞表位，并开发鼻内疫苗递送平台，用于设计 下一代结核病疫苗由结核分枝杆菌（Mtb）感染引起的结核病的全球负担是 巨大的。目前世界上三分之一的人口感染了结核分枝杆菌，这是一种空气传播的病原体， 每年死亡百万人。多重耐药和极端耐药结核病的不断出现 治疗选择昂贵且有限的菌株进一步加剧了全球负担。这个问题 结核病持续存在，因为目前的疫苗不能产生针对结核病的持久保护性免疫，特别是在成人中。 挑战是多方面的，因为Mtb通过呼吸道进入宿主，因此， 保护将需要在前线安装肺部驻留的CD 4+和CD 8+记忆T细胞， 立即对感染作出反应。传统的疫苗和批准的佐剂通常引起弱，短- 活的T细胞反应，而肠胃外疫苗接种在体内安装保护性免疫是无效的。 粘膜。此外，大多数病毒载体和亚单位TB疫苗使用Mtb抗原的一个小子集， 导致表位多样性不足以提供最佳保护，部分原因是 在Mtb感染和赋予保护性免疫力的过程中没有完全确定。因此，我们的整体目标是 发现免疫原性的保护性Mtb表位，并将其纳入创新的纳米颗粒（NP）中， 基于鼻内疫苗，旨在促进肺中平衡的CD 4+和CD 8 + T细胞应答， 预防肺结核作为实现这一目标的一种手段，我们发现了超过10，000种与HLA结合的肽， A*02：01、B*07：02、B*35：01和B*35：03。 现在的挑战是确定Mtb反应性CD 8 + T细胞识别的表位，这些表位可以保护免受 在临床前人源化HLA-Itg小鼠模型中的感染。此外，使用不同的感染模型，我们 开发了多种纳米颗粒平台，用于同时递送抗原和佐剂， 产生保护性的组织驻留CD 8 + T细胞（Trm）。在这些令人兴奋的出版和初步的指导下 结果，我们将测试这一中心假设：鼻内免疫与亚单位疫苗组成的新的 Mtb抗原和佐剂将在肺中产生CD 8 + Trm应答。Mtb反应性CD 8 + Trm的安装 在病原体进入的端口处，将保护三种新型人源化小鼠免受致命的气溶胶攻击。 用临床分离的Mtb强毒株HN 878建立模型。我们检验这一假设的策略是， (a)定义HLA-B*07：02呈现的免疫显性CD 8 + T细胞表位，保护B7.2tg小鼠免受Mtb感染 感染;和（B）定义由多个B*07：02相关抗原呈递的共同免疫显性CD 8 + T细胞表位 等位基因[称为B7超型]，保护HLA-I转基因小鼠模型免受结核分枝杆菌感染。我们 由生物化学家、免疫学家、微生物学家和生物工程师组成的多学科团队， 以实现既定的具体目标。我们预计，成功完成拟议的研究 将为针对结核分枝杆菌感染和结核病的下一代疫苗设计提供信息。我们创新的“发现和 “交付”的疫苗设计方法将影响针对结核病和其他肺部疾病的临床实践范式 传染病，如SARS-COVID 19和流感。因此，从我们的研究中出现的疫苗范例 它承诺大大提高我们退伍军人的生活质量。