Towards a Vaccine for the Common Cold

开发普通感冒疫苗

• 批准号: 7707684
• 负责人: THOMAS JAMES. SMITH
• 金额: $ 41.25万
• 依托单位: DONALD DANFORTH PLANT SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-13 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707684
• 关键词: Acute; Antibodies; Antiviral Agents; Asthma; Attenuated; Binding; Breathing; Budgets; Capsid; Capsid Proteins; Common Cold; Complex; Contract Services; Cues; Development; Family; Funding; Gastroenteritis; Genetic Materials; Genomics; Goals; Grant; Heel; Hepatitis B Vaccines; Hospitalization; Hour; Human; Human Resources; Human poliovirus; Immune Sera; Immunologic Surveillance; Infection; Location; Methods; Monoclonal Antibodies; Nature; Norovirus; Pan Genus; Patients; Peptide Vaccines; Peptide antibodies; Peptides; Pharmaceutical Preparations; Play; Polioviruses; Process; Production; Proteins; Receptor Signaling; Resolution; Rhinovirus; Role; Scanning; Serotyping; Site; Structure; Testing; Tin; United States; Vaccines; Variant; Viral; Viral Physiology; Viral Proteins; Viral Vaccines; Virus; Virus Diseases; Work; cost; flexibility; improved; neutralizing antibody; particle; peptide based vaccine; polyclonal antibody; prevent; protein misfolding; receptor binding; structural biology; virology

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.

传统的病毒疫苗通常是通过制造用于接种的减毒病毒株（如脊髓灰质炎病毒的Sabine株）或通过向患者注射纯化的病毒蛋白（如乙型肝炎疫苗中使用的病毒蛋白）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（静态或动态）。也许不能使用传统疫苗方法的病毒的最好例子是人鼻病毒。由于有100多种血清型，研制减毒变种是不可行的。先前的研究已经确定了衣壳蛋白外部的主要抗原位点。然而，这些蛋白不能以可溶性形式表达，目前没有一种中和抗体被证明能识别这种错误折叠的蛋白。这一建议旨在通过靶向衣壳发生动态构象变化或“呼吸”的部分，制造针对具有高度变异抗原性的病毒的泛血清型疫苗。在过去的几年里，我们已经证明，人类鼻病毒会短暂地暴露被掩埋的衣壳部分，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种血清型中比病毒的任何其他区域更保守。因此，这可能代表了这种高度多样化的病毒家族的“阿喀喀斯之踵”，并允许一种基于肽的单一疫苗可以改善普通感冒。事实上，我们的初步证据表明，抗血清对这些肽确实具有泛血清型中和活性。这里的目标将是结合结构生物学，病毒学和免疫学方法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的方法来识别潜在的、保守的、针对其他抗原性不同病毒的疫苗靶点。