Oral Delivery of RNA Encoded Antigen

说明（由申请人提供）：迫切需要一种安全有效的艾滋病毒疫苗，以防治全世界的艾滋病祸害。尽管对于保护性或治疗性疫苗，免疫保护的相关因素尚未明确定义，但人们普遍认为，全身和粘膜CD4+和CD8+ T细胞和体液免疫是重要的。如何引起足够广泛、有效和持续的反应，特别是对粘膜的反应，还有待确定，这代表了我们理解上的一个关键差距。树突状细胞（DC）代表先天免疫和适应性免疫之间的接口，是产生适应性免疫反应中最有效和最重要的成分之一。疫苗的主要作用是在DC上装载抗原并提供激活刺激。我们的实验室已经证明mRNA负载的DC可以诱导CD4+， CD8+和抗体反应。我们确定了RNA激活先天免疫受体的机制，并开发了避免其激活并产生优越翻译效率的RNA。我们的假设是，将HIV抗原编码修饰的mRNA递送到口腔黏膜DC提供了一种独特的灵活而有效的免疫方法，RNA递送后DC的激活可以被控制以产生所需的免疫反应（例如，辅助免疫、细胞毒性免疫、抑制免疫、体液免疫和粘膜免疫），并且这种方法可以用于开发口服HIV疫苗。本研究的目的是优化口腔黏膜DC对RNA的摄取，增强DC对mrna编码抗原的抗原呈递，开发调节诱导的免疫反应类型的方法，并建立对HIV有效性的概念证明证据。在这些研究中，我们将结合目前在疫苗设计中使用的两种强有力的方法，开发一种口服递送的疫苗，DC靶向疫苗和mRNA编码抗原，开发一种口服递送的HIV疫苗，诱导全身粘膜免疫，可能对预防传播更重要。这一建议的相关性在于，它导致了一种容易交付的抗艾滋病毒疫苗的发展，这种疫苗将产生粘膜免疫。粘膜免疫是在粘膜传播过程中遇到HIV的第一个免疫反应，因此有更好的机会阻止感染。

DESCRIPTION (provided by applicant): A safe and effective vaccine for HIV is critically needed to combat the worldwide scourge of AIDS. While the correlates of immune protection have yet to be clearly defined, either for protective or therapeutic vaccines, it is widely believed that systemic and mucosal CD4+ and CD8+ T cell and humoral immunity are important. How sufficiently broad, potent, and sustained responses, particularly for mucosal, can be elicited has yet to be determined, and this represents a critical gap in our understanding. Dendritic cells (DC) represent the interface between innate and adaptive immunity and are among the most potent and important components in generating adaptive immune responses. The main action of a vaccine is to load a DC with antigen and deliver an activating stimulus. Our laboratory has demonstrated that mRNA loaded DC could induce CD4+, CD8+, and antibody responses. We identified the mechanisms whereby RNA activates innate immune receptors and developed RNA that avoids their activation and yields superior translational efficiency. Our hypotheses is that delivery of HIV antigen-encoding modified mRNA to DC in oral mucosa offers a uniquely flexible and potent approach to immunization, that DC activation after RNA delivery can be controlled to generate the desired immune responses (e.g. helper, cytotoxic, suppressor, humoral, and mucosal), and that this approach can be exploited for the development of orally delivered HIV vaccines. The aim of this proposal is to optimize RNA uptake by oral mucosal DC, enhance antigen presentation by DC of mRNA-encoded antigen, develop approaches to modulate the type of immune response induced, and establish proof-of-concept evidence for efficacy in HIV. In these studies, we will combine two powerful approaches currently in use in vaccine design to develop an orally deliverable vaccine, DC targeted vaccines and mRNA encoded antigen, to develop an orally deliverable HIV vaccine that induces systemic, and likely more important for prevention of transmission, mucosal immunity. The relevance of this proposal is that it leads to the development of an easily deliverable vaccine against HIV that will develop mucosal immunity. Mucosal immunity is the first immune response to encounter HIV during mucosal transmission and, thus, has a better chance of stopping infection.