Mucosal RSV vaccine using CpG oligodeoxynucleotides

描述（由申请人提供）：含有某些未甲基化CpG序列的寡脱氧核苷酸（CpG ODN）在与多种抗原共同施用时是强有力的免疫刺激剂，使它们成为预防性（例如传染病）和治疗性（例如癌症）疫苗的有吸引力的佐剂。 除了在肠胃外给药时有用之外，它们在局部应用于粘膜组织时也有效。这使得它们在呼吸道合胞病毒（RSV）疫苗的开发中具有潜在的用途，该疫苗将是热稳定的并且不需要无菌针头和注射器。 除了在这个国家使用外，这种疫苗在发展中国家也有巨大的用途，在这些国家，RSV的疾病负担最高，缺乏冷藏和无菌针头和注射器，无法使用其他方法。 在初步研究中，我们已经表明，从RSV纯化的融合糖蛋白（F）是没有免疫原性鼻内给药时，没有佐剂;然而，F和CpG ODN（F/CpG）的共同管理刺激棉花大鼠肺中的高效免疫应答。 虽然这一结果非常令人鼓舞，但受保护动物的肺部显示出非典型组织病理学，这让人想起早期福尔马林灭活（FI-RSV）疫苗。 我们发表的关于FI-RSV的工作表明，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，因此我们认为，伴随F/CpG免疫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对F/CpG的细胞因子、趋化因子和细胞应答，将它们与原发性RSV感染和FI-RSV免疫进行比较。 第二阶段的活动将利用这些信息来配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.