Towards a Vaccine for the Common Cold

传统的病毒疫苗通常是通过创建用于接种的减毒病毒株(如脊髓灰质炎病毒的Sabine株)或向患者注射纯化的病毒蛋白(如用于乙肝疫苗)来开发的。这种方法非常有效，但仅限于抗原变异有限的病毒(无论是静态的还是动态的)。也许传统疫苗方法不能使用的病毒的最好例子是人类鼻病毒。由于有100多个血清型，开发减毒变异体是不可行的。以前的研究已经确定了衣壳蛋白外部的主要抗原点。然而，这些蛋白质不能以可溶的形式表达，目前的中和抗体都没有被证明能识别这种错误折叠的蛋白质。这项提议旨在通过瞄准衣壳的动态构象变化或“呼吸”部分，创造针对抗原性高度变异的病毒的泛血清型疫苗。在过去的几年里，我们已经证明，人类鼻病毒瞬间暴露出被掩埋的衣壳部分，这一过程对感染过程至关重要。此外，我们已经证明，在这一过程中暴露的衣壳区域在100个血清型中比病毒的任何其他区域都更保守。因此，这可能代表着这一高度多样化的病毒家族的“阿喀琉斯”之踵，并允许开发一种单一的、基于多肽的疫苗，可以改善普通感冒。事实上，我们的初步证据表明，针对这类多肽的抗血清确实具有泛血清型中和活性。这里的目标是将结构生物学、病毒学和免疫学方法结合起来，开发一种有效的普通感冒疫苗。如果成功，这里开发的方法也将产生一种快速识别潜在的、保守的、针对其他抗原性多样化病毒的疫苗靶标的方法。

Traditional viral vaccines are normally developed by either creating attenuated viral strains for inoculation, such as the Sabine strain of poliovirus, or by injecting the patients with purified viral proteins such as employed in the hepatitis B vaccine. This method is highly efficacious, but is restricted to viruses with limited antigenic variance (either static or dynamic). Perhaps the best example of a virus where traditional vaccine approaches cannot be used is human rhinovirus. With more than 100 serotypes, development of attenuated variants is not feasible. Previous studies have identified the major antigenic sites on the exterior of the capsid proteins. However, these proteins cannot be expressed in a soluble form and none of the current neutralizing antibodies have been shown to recognize such mis-folded proteins. This proposal is aimed at creating pan-serotypic vaccines against viruses with highly variant antigenicity by targeting the portions of the capsid that undergo dynamic conformational changes, or `breathing'. Over the past few years, we have shown that human rhinovirus transiently exposes buried portions of the capsid and that this process is crucial for the infection process. Further, we have shown that the region of the capsid exposed in this process is more conserved amongst the 100 serotypes than any other region of the virus. This could, therefore, represent the "Achilles'' heel" of this highly diverse family of viruses and allow for a single, peptide-based vaccine that could ameliorate the common cold. Indeed, our preliminary evidence suggests that antiserum to such peptides does have pan-serotypic neutralizing activity. The goal here will be to combine structural biology, virology, and immunological methods to develop an efficacious vaccine for the common cold. If successful, the methods developed here will also yield a rapid way to identify potential, conserved, vaccine targets for other antigenically diverse viruses as well.