Delivery of Particle Vaccines to Control Trafficking Patterns of T Cells

描述（由申请人提供）：本提案的总体目标是开发用生物材料递送抗原和佐剂的新方法，并研究宿主对这些新疫苗的反应，最终目标是开发针对传染病的成功疫苗和治疗干预措施。K22奖将通过提供必要的初始支持来帮助我获得额外的培训和指导，并建立我作为独立研究者的研究生涯。疫苗接种仍然是预防传染病最有效的医疗干预措施之一。然而，目前临床使用的疫苗佐剂是细胞毒性细胞免疫反应的不良激活剂。为了解决这个问题，我们最近开发了一种新型的基于脂质的纳米颗粒系统，它可以共同捕获抗原和佐剂，并有效地将它们递送到抗原提呈细胞。据我们所知，这些合成囊泡增强了蛋白质抗原的交叉呈递，诱导了大量扩增的CD8+ T细胞反应，其强度大大超过了之前报道的任何其他蛋白质疫苗。此外，与目前许可的佐剂免疫相比，装载候选疟疾抗原的icmv也能以更大的亲和力引发更高的抗体滴度。这些结果表明，这些携带抗原/佐剂的icmv形成了一种非常有效的全蛋白疫苗。然而，在作者的研究和文献中还不完全了解的是抗原特异性T细胞在全动物水平上对颗粒疫苗接种的反应的扩增和运输模式。初步研究表明，有效引流到淋巴结的颗粒促进了引流淋巴结中抗原特异性CD8+ T细胞的扩张和维持，而保留在注射部位的颗粒以降低引流效率促进了抗原经历的CD8+ T细胞在颗粒注射部位的长时间积累。本研究旨在研究疫苗颗粒的组织分布与T细胞运输模式之间的关系，并开发一种疫苗平台，可以利用这种颗粒介导的宿主细胞应答来实现组织特异性免疫。具体目标是：(1)我们能否控制体内抗原特异性T细胞的运输模式，并利用沉积在组织中的病原体模拟颗粒建立组织特异性记忆T细胞？我们能否利用这种方法诱导对流感病毒的免疫？(2)我们能否利用可注射凝胶中装载的icmv开发模拟感染的材料，并将这种新的疫苗递送方法应用于粘膜组织的长期记忆反应？这些研究的结果将有助于确定颗粒免疫后控制T细胞运输模式的因素，并可能导致可应用于许多其他传染病的疫苗平台。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop novel approaches in delivery of antigens and adjuvants with biomaterials and to investigate host responses in response to these new vaccines, with the ultimate goal to develop successful vaccines and therapeutic interventions against infectious diseases. The K22 award will help me by providing the initial support necessary to gain additional training and mentoring and establish my research career as an independent investigator. Vaccination remains one of the most effective medical interventions against infectious diseases. However, vaccine adjuvants currently used in clinics are poor activators of cytotoxic cellular immune responses. To address this, we have recently developed a novel class of lipid-based nanoparticulate system that can co-entrap antigen and adjuvant and efficiently deliver them to antigen presenting cells. These synthetic vesicles enhanced cross-presentation of protein antigens, inducing massively expanded CD8+ T cell responses, substantially stronger than any other previously reported protein vaccines, to the best of our knowledge. In addition, ICMVs loaded with candidate malaria antigen also elicited significantly higher antibody titers with greater avidity, compared with immunization with currently licensed adjuvants. These results indicate that these antigen/adjuvant-carrying ICMVs form an extremely potent whole-protein vaccine. However, what is not fully known in the author's studies and also in the literature is the expansion and trafficking patterns of antigen-specific T cells at whole-animal level in response to particle vaccination. Preliminary studies have shown that particles that efficiently drain to lymph nodes promoted expansion and maintenance of antigen-specific CD8+ T cells at draining lymph nodes, whereas particles that remain deposited at injection site with reduced draining efficiency promoted accumulation of antigen- experienced CD8+ T cells at the particle injection site for an extended period. This proposal aims to investigate the relationship between tissue distribution of vaccine particles and trafficking patterns of T cells and to develop a vaccine platform that can exploit this particle-mediated host cellular response toward tissue-specific immunity. The specific aims are (1) Can we control the trafficking patterns of antigen-specific T cells in vivo and establish tissue-specific memory T cells using pathogen-mimicking particles deposited in tissues? And can we utilize this approach to induce immunity against influenza virus? (2) Can we develop infection- mimicking materials using ICMVs loaded in injectable gels and apply this new vaccine delivery approach to confer long-term memory response in mucosal tissues? The results from these studies will help to identify factors governing trafficking patterns of T cells following particle immunization, and may lead to a vaccine platform that could be applied to numerous other infectious diseases. Public Health Relevance: The results obtained from these proposed studies may lead to development of a vaccine platform that can elicit potent cellular immune responses and control the distribution of antigen-specific T cells. Such vaccine platform could be applied as novel vaccination strategies against infectious diseases and would have a major impact on public health.