Building the foundations of commensal vaccines

建立共生疫苗的基础

基本信息

批准号：
10478380
负责人：
MICHAEL ANDREW FISCHBACH
金额：
$ 79.43万
依托单位：
STANFORD UNIVERSITY
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：
2022-09-23 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10478380
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 Engineering Epithelial 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 disease pathogen patient subsets prevent programs response scaffold side effect standard of care subcutaneous success tool tumor vector vaccine vector-induced

项目摘要

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.

项目概要/摘要引发或抑制适应性免疫反应已成为肿瘤学、自身免疫学和免疫学的核心检查点抑制剂彻底改变了癌症的治疗，而 TNF 抑制剂和其他免疫抑制生物制剂已成为自身免疫性疾病的标准治疗方法。生物医学研究的惊人成就；SARS-2 mRNA 疫苗只是最新的例子。 CAR-T 细胞可诱导急性淋巴细胞白血病（一种以前无法治愈的疾病）的长期缓解。然而，目前调节适应性免疫的方法有严重的局限性。生物制剂仅对一小部分患者有效，并且经常刺激或抑制整体免疫功能导致自身免疫或机会性感染，尽管许多疫苗具有非凡的特性，但仍需要一定的时间。针和冷链，使它们难以在低收入和中等收入国家部署，而且它们未能诱导粘膜免疫，因此接种疫苗的人可以感染其他人。迄今为止，针对实体瘤的研究还不够深入，而离体 T 细胞工程成本高昂且难以规模化。在这里，我们建议通过利用主持人的“殖民者互动计划”来应对这些挑战。来自微生物组的细菌菌株在一种新的免疫反应中引发了惊人的有效、特异性和持久的免疫反应。实验室中未发表的项目启发了我们在这里提出的工作，我们表明反共生通过改造共生细菌来表达宿主，可以将免疫反应重定向到针对宿主共生细菌具有理想疫苗载体的所有关键属性：它们诱导高效、抗原特异性 T 和 B 细胞反应可在数年时间内持续存在；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且持久的适应性免疫反应我们想法的核心是开发一套疫苗支架，其中共生是佐剂，定植是管理模式。我们提出了一个由四部分组成的过程。建立共生疫苗的基础：目标 1：确定一组具有免疫能力的核心共生体调节特性；目标 2：优化 CD8+ T 细胞诱导以进行抗肿瘤治疗；目标 3：增强 B 细胞诱导预防病毒感染；目标 4：重新定向殖民者特异性 Tregs 来对抗自身免疫性疾病。这些目标可以并行进行，其中任何一个目标的成功都会对我们产生巨大的影响。请注意，虽然这项工作已得到应用，但它将为免疫调节的基础研究创造有用的工具正如 T 细胞工程的生物制剂和方法对微生物组其他子学科所做的那样免疫学。