Building the foundations of commensal vaccines

项目摘要/摘要 激发或抑制获得性免疫反应已成为肿瘤学、自身免疫和 传染病。检查点抑制剂使癌症的治疗发生了革命性变化，而肿瘤坏死因子抑制剂和 其他免疫抑制生物制品已经成为治疗自身免疫性疾病的标准药物。疫苗是 生物医学研究的惊人成就；针对SARS-2的基因疫苗只是最新的例子。 CAR-T细胞可诱导急性淋巴细胞性白血病的长期缓解，这是一种以前无法治愈的疾病。 然而，目前调节获得性免疫的方法有严重的局限性。检查点抑制剂和 生物制剂只对一小部分患者有效，而且经常对免疫功能进行全局刺激或抑制 导致自身免疫或机会性感染。尽管许多疫苗具有非同寻常的特性，但它们需要 针头和冷链，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传染给其他人。基因工程T细胞尚未成功 到目前为止，针对实体瘤，体外T细胞工程成本高昂，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。一定的 来自微生物组的细菌菌株能激发出惊人的强大、特异和持久的免疫反应。在一个新的 实验室中未发表的项目启发了我们在这里提出的工作，我们展示了反共生 通过设计共生菌来表达宿主，可以将免疫反应重新定向到宿主身上 它们表面上的抗原。共生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细胞反应；在几年的时间尺度上持续定植到 几十年(实验证据表明它们引发的免疫反应也是如此)；以及殖民者 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，以在某种程度上激发有效和持久的适应性免疫反应 这是安全和廉价的。我们想法的核心是开发一套疫苗支架，在其中 共生是辅助，殖民是管理模式。我们提出了一个由四个部分组成的过程 建立共生疫苗的基础：目标1：确定一组核心的与免疫共生的疫苗 调节特性；目标2：优化CD8 T细胞诱导用于抗肿瘤治疗；目标3：增强B细胞 用于预防病毒感染的诱导；以及目标4：重定向殖民者特有的Tregs以对抗自身免疫性疾病。 这些目标可以并行进行，任何一个目标的成功都将产生巨大的影响。我们 请注意，尽管这项工作得到了应用，但它将通过以下方式为免疫调节的基础研究创建有用的工具 微生物组，就像T细胞工程的生物制品和方法在其他学科中所做的那样 免疫学。

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 In a new unpublished project in the lab that inspired the work we propose here, we showed that the anti-commensal immune response can be redirected against the host by engineering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.