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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.

项目总结/文摘