Building the foundations of commensal vaccines

建立共生疫苗的基础

基本信息

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
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/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

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.

项目摘要/摘要引起或抑制适应性免疫响应已成为肿瘤学，自身免疫性和传染病。检查点抑制剂已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护理标准。疫苗是生物医学研究的惊人成就； 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（一种先前无法治愈的疾病）的长期缓解。但是，当前调节适应性免疫学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，全球刺激或抑制免疫功能导致自身免疫性或机会性感染。尽管具有非凡的特性，但许多疫苗需要针和冷链，使其难以在低收入和中等收入国家中部署，并且没有诱导粘膜免疫，因此接种疫苗的人可以感染他人。设计的T细胞尚未成功迄今为止，针对实体瘤，并且离体T细胞工程的昂贵且难以扩展。在这里，我们建议通过利用主机的“殖民者互动计划”来解决这些挑战。肯定来自微生物组的细菌菌株引起了惊人的潜力，特异性和耐用的免疫反应。在新的在实验室中未发表的项目启发了我们在这里提出的工作，我们证明了反诉讼可以通过工程性细菌来反应免疫反应，以表达宿主表面上的抗原。共生细菌具有理想疫苗载体的所有关键属性：它们影响高潜力，抗原特异性T和B细胞反应；在年的时间范围内，殖民化是持久的数十年（实验证据表明它们引起的免疫反应也是如此）。和殖民者安全地调节免疫功能，以避免自身免疫攻击的宿主组织。我们的愿景是创建一个通用平台，以某种方式引起潜在耐用的适应性免疫响应这是安全且便宜的。我们想法的内核是开发一组疫苗脚手架共生是调整，定植是给药的方式。我们提出了一个四部分的过程建立共生疫苗的基础：目标1：确定一组免疫力的共生调节性能；目标2：优化抗肿瘤治疗的CD8+ T细胞诱导；目标3：增强B单元预防病毒感染的诱导；和目标4：重定向殖民主义特异性Tregs针对自身免疫性疾病。这些目标可以并行，其中任何一个目标都会产生很大的影响。我们请注意，尽管采用了这项工作，但它将创建有用的工具，用于通过微生物组，就像针对T细胞工程的生物制剂和方法对其他子学科所做的那样免疫学。