Mucosal RSV vaccine using CpG oligodeoxynucleotides

描述(由申请人提供)：含有某些未甲基化CpG序列的寡核苷酸(CpG ODN)与多种抗原共同注射时是强大的免疫刺激剂，使其成为预防(如传染病)和治疗性(如癌症)疫苗的有吸引力的佐剂。除了在非肠道给药时有用外，它们在局部应用于粘膜组织时也有效。这使它们在开发呼吸道合胞病毒(RSV)疫苗方面具有潜在的实用价值，这种疫苗将是热稳定的，不需要无菌针头和注射器。除了在这个国家使用之外，这种疫苗还将在发展中国家有巨大的用途，因为在这些国家，RSV的疾病负担最高，而且缺乏冷藏和无菌针头和注射器，排除了其他方法。在初步研究中，我们已经证明从RSV提纯的融合糖蛋白(F)在没有佐剂的情况下不具有免疫原性；然而，F和CpG ODN(F/CpG)联合给药在棉鼠的肺中激发了高效的免疫应答。虽然这一结果非常令人鼓舞，但受保护动物的肺部表现出了与早期福尔马林灭活(FI-RSV)疫苗相似的非典型组织病理学。我们发表的关于FI-RSV的工作表明，与疫苗增强型疾病相关的组织表型可以通过添加单磷酰脂A(MPL)来消除，因此我们认为也可以通过使用补充剂来消除伴随F/CpG免疫的非典型组织病理学。这一阶段应用的目标是表征细胞因子、趋化因子和细胞对F/CpG的反应，将它们与原发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研制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.