Mucosal RSV vaccine using CpG oligodeoxynucleotides

描述（由申请人提供）：含有某些未甲基化CpG序列（CpG ODN）的寡脱氧核苷酸与多种抗原共同使用时是强大的免疫刺激剂，使其成为预防性（如传染病）和治疗性（如癌症）疫苗的有吸引力的佐剂。除了在肠外给药时是有用的，它们在局部应用于粘膜组织时也是有效的。这使得它们在开发呼吸道合胞病毒（RSV）疫苗方面具有潜在的用途，这种疫苗将具有热稳定性，并且不需要无菌针头和注射器。除了在这个国家使用之外，这种疫苗在发展中国家也将具有巨大的效用，因为这些国家RSV的疾病负担最高，而且缺乏冷藏和无菌针头和注射器，因此无法使用其他方法。在初步研究中，我们已经表明，从RSV中纯化的融合糖蛋白(F)在没有佐剂的情况下经鼻给药时不具有免疫原性；然而，同时给药F和CpG ODN （F/CpG）在棉花大鼠肺中刺激了高度有效的免疫反应。虽然这一结果非常令人鼓舞，但受保护动物的肺部表现出非典型的组织病理学，使人想起早期福尔马林灭活（FI-RSV）疫苗所见。我们发表的关于FI-RSV的研究表明，与疫苗增强疾病相关的组织学表型可以通过添加单磷酰脂质A （MPL）来消除，因此我们相信F/CpG免疫伴随的非典型组织病理学也可以通过使用补充剂来消除。该I期申请的目的是表征细胞因子、趋化因子和细胞对F/CpG的反应，并将它们与原发性RSV感染和FI-RSV免疫进行比较。第二阶段活动将利用这些信息研制一种既有效又安全的疫苗。

DESCRIPTION (provided by applicant): Oligodeoxynucleotides containing certain unmethylated CpG sequences (CpG ODN) are powerful immunostimulants when co-administered with a variety of antigens, making them attractive adjuvants for prophylactic (e g infectious diseases) and therapeutic (e.g. cancer) vaccines. In addition to being useful when administered parenterally, they are also effective when applied topically to mucosal tissues. This makes them potentially useful in development of a respiratory syncytial virus (RSV) vaccine that would be heat-stable and would not require sterile needles and syringes. In addition to use in this country, such a vaccine would have enormous utility in developing countries, where the disease burden of RSV is the highest and where lack of refrigeration and sterile needles and syringes preclude other approaches. In preliminary studies we have shown that purified fusion glycoprotein (F) from RSV is not immunogenic when administered intranasally without an adjuvant; however, co-administration of F and CpG ODN (F/CpG) stimulated a highly effective immune response in the lungs of cotton rats. While this result was highly encouraging, the lungs of protected animals showed atypical histopathology reminiscent of that seen with an earlier, formalin-inactivated (FI-RSV) vaccine. Our published work on FI-RSV demonstrated that the histologic phenotype associated with vaccine-enhanced disease could be eliminated by the addition of monophosphoryl lipid A (MPL), and thus we believe that the atypical histopathology accompanying F/CpG immunization can also be eliminated through use of supplements. The goal of this Phase I application is to characterize the cytokine, chemokine and cellular responses to F/CpG, comparing them to primary RSV infection and to immunization with FI-RSV. Phase II activities would use that information to formulate a vaccine that would be both effective and safe.