Oral Delivery of RNA Encoded Antigen

RNA编码抗原的口服递送

• 批准号: 7484064
• 负责人: DREW WEISSMAN
• 金额: $ 21.97万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7484064
• 关键词: Acquired Immunodeficiency Syndrome; Adjuvant; Antibody Formation; Antigen Presentation; Antigens; CD8B1 gene; Cancer Vaccines; Cell Differentiation process; Cells; Clinical Trials; Complex; Dendritic Cell Vaccine; Dendritic Cells; Dendritic cell activation; Development; Disadvantaged; Feedback; Foundations; Genetic Translation; HIV; HIV Antigens; HIV vaccine; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Immunologic Receptors; Indium; Infection; Laboratories; Lipids; Longevity; Mediating; Messenger RNA; Mucosal Immune Responses; Mucosal Immunity; Mus; Oral; Oral mucous membrane structure; Peptides; Prevention; Production; Proteins; Purpose; RNA; Route; Scourge; Signal Transduction; Site; Standards of Weights and Measures; Stimulus; Surface; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Vaccine Adjuvant; Vaccine Design; Vaccines; Work; aziridine; base; concept; cytokine; cytotoxic; desire; immune function; neutralizing antibody; novel strategies; oral HIV vaccine; response; therapeutic vaccine; transmission process; uptake; vaccine development

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.

描述（由申请人提供）：迫切需要一种安全有效的艾滋病毒疫苗来打击全球的艾滋病祸害。尽管尚未明确定义免疫保护的相关性，但对于保护性或治疗性疫苗，人们普遍认为，系统性和粘膜CD4+和CD8+ T细胞以及体液免疫力很重要。还尚未确定足够广泛，有效和持续的反应，尤其是对于粘膜，尚未确定，这代表了我们理解的关键差距。树突状细胞（DC）代表了先天性和适应性免疫之间的界面，并且是产生适应性免疫反应的最有效和重要组成部分之一。疫苗的主要作用是用抗原加载DC并提供激活刺激。我们的实验室表明，加载的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，并产生了RNA，从而避免了它们的激活并产生了卓越的转化效率。我们的假设是，口服粘膜中DC的HIV抗原编码修饰的mRNA传递提供了一种独特的灵活且有效的免疫方法，可以控制RNA输送后的DC激活，可以控制所需的免疫反应（例如，抑制型，抑制型，hym and the hym and hym and hym and hym and hym and hym and Mucolal and Mucosal and Mucosal and Mucosal和Mucosal和Mucosal和Mucosal和Mucosal和Mucosal和Mucosal），或 疫苗。该提案的目的是通过口服粘膜DC优化RNA摄取，增强DC通过mRNA编码的抗原增强抗原表现，开发方法来调节引起的免疫反应的类型，并为HIV效率建立概念证明证据。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大方法，以开发一种口服可交付的疫苗，DC靶向疫苗和MRNA编码的抗原，以开发一种口服可兑换的HIV疫苗，可诱导系统性，并且可能更重要，可能更重要，以预防传播，粘膜免疫。该提案的相关性是，它导致开发一种针对HIV的易于可兑换的疫苗，该疫苗将产生粘膜免疫。粘膜免疫是粘膜传播期间对HIV的第一种免疫反应，因此有更好的机会阻止感染。