Building the foundations of commensal vaccines

建立共生疫苗的基础

• 批准号: 10709507
• 负责人: MICHAEL ANDREW FISCHBACH
• 金额: $ 77.09万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709507
• 关键词: Acute Lymphocytic Leukemia; Adaptive Immune System; Address; Adjuvant; Antigens; Area; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Bacteria; Basic Science; Biological Products; Biomedical Research; CD19 gene; CD8-Positive T-Lymphocytes; COVID-19 vaccine; Cancer Vaccines; Cell physiology; Cells; Characteristics; Cold Chains; Communicable Diseases; Data; Discipline; Disease; Disease remission; Ear; Endowment; Engineering; Epithelium; Failure; Foundations; Goals; Gossypium; Head; Human; Human Microbiome; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; Immunologic Adjuvants; Immunologics; Immunology; Immunosuppression; Infection; Intravenous; Malignant Neoplasms; Metastatic Neoplasm to the Lung; Methods; Modality; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mus; Nature; Needles; Oncology; Opportunistic Infections; Organism; Patients; Process; Property; RNA vaccine; Regulatory T-Lymphocyte; Respiratory Disease; Sampling; Side; Skin; Solid Neoplasm; Specificity; Staphylococcus epidermidis; Surface; Swab; T-Lymphocyte; TNF gene; Therapeutic; Therapeutic Uses; Tissues; Topical application; Toxic effect; Tumor Antigens; Upper respiratory tract; Vaccinee; Vaccines; Virus Diseases; Vision; Wild Type Mouse; Work; adaptive immune response; adaptive immunity; anti-PD-1; antigen-specific T cells; antiviral immunity; autoimmune pathogenesis; cancer cell; cancer therapy; cell type; chimeric antigen receptor T cells; commensal bacteria; cost; engineered T cells; immune checkpoint blockade; immune function; immunoregulation; inhibitor; innovation; insight; low and middle-income countries; melanoma; microbiome; neoplastic cell; non-Native; nonhuman primate; pandemic pathogen; patient subsets; prevent; programs; response; scaffold; side effect; standard of care; subcutaneous; success; tool; tumor; vector vaccine

PROJECT SUMMARY/ABSTRACT Eliciting or suppressing an adaptive immune response has become central to oncology, autoimmunity, and infectious disease. Checkpoint inhibitors have revolutionized the treatment of cancer, while TNF inhibitors and other immune-suppressive biologics have become the standard of care in autoimmune diseases. Vaccines are a stunning accomplishment of biomedical research; the mRNA vaccines for SARS-2 are only the latest example. CAR-T cells induce long-term remission in acute lymphoblastic leukemia, a previously incurable disease. However, current methods for modulating adaptive immunity have serious limitations. Checkpoint inhibitors and biologics only work in a subset of patients, and global stimulation or suppression of immune function frequently leads to autoimmunity or opportunistic infection. Despite their extraordinary properties, many vaccines require a needle and a cold chain, making them difficult to deploy in low- and middle-income countries, and they fail to induce mucosal immunity, so vaccinated people can infect others. Engineered T cells have not been successful against solid tumors to date, and ex vivo T cell engineering is costly and difficult to scale. Here, we propose to address these challenges by tapping into the host’s ‘colonist interaction program’. Certain bacterial strains from the microbiome elicit a strikingly potent, specific, and durable immune response. In a new unpublished project in the lab that inspired the work we propose here, we showed that the anti-commensal immune response can be redirected against the host by engineering commensal bacteria to express host antigens on their surface. Commensal bacteria have all the key attributes of an ideal vaccine vector: they induce highly potent, antigen-specific T and B cell responses; colonization is durable on the timescale of years to decades (experimental evidence suggests the same is true for the immune response they elicit); and colonists modulate immune function safely, in a way that spares host tissue from autoimmune attack. Our vision is to create a general platform for eliciting a potent and durable adaptive immune response in a way that is safe and inexpensive. The kernel of our idea is to develop a set of vaccine scaffolds in which a commensal is the adjuvant and colonization is the mode of administration. We propose a four-part process to build the foundations of commensal vaccines: Goal 1: identify a core set of commensals with immune modulatory properties; Goal 2: optimize CD8+ T cell induction for antitumor therapy; Goal 3: enhance B cell induction for preventing viral infection; and Goal 4: redirect colonist-specific Tregs against autoimmune disease. These goals can proceed in parallel, and success in any one of them would have a great deal of impact. We note that although this work is applied, it will create useful tools for basic research into immune modulation by the microbiome, just as biologics and methods for T cell engineering have done for other sub-disciplines of immunology.

项目总结/摘要 引发或抑制适应性免疫应答已经成为肿瘤学、自身免疫和免疫调节的核心。 传染病检查点抑制剂已经彻底改变了癌症的治疗，而TNF抑制剂和 其它免疫抑制生物制剂已经成为自身免疫疾病的标准治疗。疫苗是 这是生物医学研究的一个惊人成就; SARS-2的mRNA疫苗只是最新的例子。 CAR-T细胞诱导急性淋巴细胞白血病的长期缓解，这是一种以前无法治愈的疾病。 然而，目前用于调节适应性免疫的方法具有严重的局限性。检查点抑制剂和 生物制剂仅在一部分患者中起作用，并且免疫功能的全面刺激或抑制经常 导致自身免疫或机会性感染。尽管它们具有非凡的特性，但许多疫苗需要一个 针头和冷链，使它们难以在低收入和中等收入国家部署， 诱导粘膜免疫，因此接种疫苗的人可以感染其他人。工程化T细胞尚未成功 迄今为止，体外T细胞工程是针对实体瘤的，并且离体T细胞工程是昂贵的并且难以规模化。 在这里，我们建议利用主机的“殖民者互动程序”来解决这些挑战。某些 来自微生物组的细菌菌株引起惊人的有效、特异性和持久的免疫应答。在一个新 在实验室中未发表的项目，激发了我们在这里提出的工作，我们表明，反倾销 通过工程改造大肠杆菌以表达宿主 表面的抗原。共生细菌具有理想疫苗载体的所有关键属性：它们诱导 高度有效的抗原特异性T和B细胞应答;定植可持续数年， 几十年（实验证据表明，它们引起的免疫反应也是如此）; 安全地调节免疫功能，使宿主组织免受自身免疫攻击。 我们的愿景是创建一个通用平台，以某种方式引发有效和持久的适应性免疫反应。 既安全又便宜。我们想法的核心是开发一套疫苗支架， 佐剂为水杨酸，给药方式为定植。我们提出了一个由四部分组成的过程 目标1：确定一套具有免疫力的核心疫苗， 调节特性;目标2：优化用于抗肿瘤治疗的CD 8 + T细胞诱导;目标3：增强B细胞 诱导以预防病毒感染;和目标4：重定向针对自身免疫性疾病的集落特异性TCLs。 这些目标可以并行进行，其中任何一个目标的成功都会产生很大的影响。我们 请注意，尽管这项工作是应用，它将创造有用的工具，为基础研究免疫调节， 微生物组，就像T细胞工程的生物制剂和方法对微生物组的其他子学科所做的那样， 免疫学