Development of a novel human rhinovirus vaccine

描述(申请人提供)：人类鼻病毒(HRV)导致美国每年6000万例“普通感冒”病例中的大约三分之一，因此是发达国家最重要的经济人类疾病之一。虽然鼻病毒通常不被认为是“杀手”病毒，但最近的研究表明，鼻病毒是哮喘和慢性肺部疾病患者住院治疗的一个重要来源。大量的HRV血清型(&gt；100)是疫苗开发的主要障碍。然而，过去和最近的三项发展表明，设计第一代鼻病毒疫苗现在可能成为可能。首先，体外进化逃逸实验表明，针对HRV衣壳的单抗和多克隆抗体的作用相似，并反复导致病毒衣壳内相当窄和相似范围的氨基酸变化。其次，血清学图谱数据表明，宿主的反应在很大程度上限于位于衣壳最高度可变区域的免疫优势表位，这些表位位于保守的细胞受体结合区两侧。第三，一组独特的单抗已经被证明可以中和多种血清型。因此，可能存在于病毒中的表位可以诱导更广泛的保护性抗体，但不容易被免疫系统发现。最后，在与有蹄目动物相关的小核糖核酸病毒，口蹄疫病毒的初步研究中，免疫重聚焦突变只引入了四个免疫优势抗原位点之一，即VP1的GH环，导致了一种能刺激交叉中和抗体的抗原。我们建议1)设计和生产一组具有免疫优势表位突变的HRV39候选疫苗；2)测试刺激交叉中和抗体的候选疫苗；3)研究“类天然”衣壳蛋白折叠和有效的抗原呈递给免疫系统的递送系统。 公共卫生相关性：人类鼻病毒(HRV)是普通感冒的主要原因，也是哮喘和慢性肺部疾病的日益公认的病因和/或恶化因素。由于大量的血清型，开发疫苗的努力一直令人沮丧。最近在理解病原体如何利用高度可变的抗原位点来误导免疫系统对更高度保守的表位做出反应方面的进展，导致了用于新型疫苗设计的免疫重新聚焦技术的发展。我们建议应用这项技术来重定向免疫系统，以识别HRV39上的交叉反应表位。用候选疫苗免疫的小鼠的血清将被评估以增强针对异种血清型的交叉反应抗病毒活性。开发一种具有广泛保护性的HRV疫苗将极大地改善健康状况，并对与健康相关的经济节省产生直接影响。

DESCRIPTION (provided by applicant): Human Rhinoviruses (HRV) cause approximately one third of the 60 million cases of "common cold" each year in the US and therefore are one of the most economically important human diseases of developed countries. Although rhinoviruses are not generally considered "killer" viruses, more recent studies have shown that rhinoviruses are a significant source of hospitalization for those with asthma and chronic pulmonary diseases. The large number of HRV serotypes (>100) stand as a major barrier to vaccine development. However, three past and recent developments suggest that the design of a first generation rhinovirus vaccine may now be possible. First, in vitro evolutionary escape experiments indicate that both monoclonal and polyclonal antibodies made to the HRV capsid act similarly and repeatedly result in rather narrow and similar range of amino acid changes in the capsid of the virus. Second, serological mapping data suggest the host response is largely restricted to immunodominant epitopes located in the most highly variable regions of the capsid flanking the conserved cellular receptor-binding region. Third, a unique small panel of monoclonal antibodies has been shown to neutralize across multiple serotypes. Thus, it is possible that epitopes exist in the virus that can induce more broadly protective antibodies, but are not readily seen by the immune system. Finally, in preliminary studies with the related picornavirus of ungulates, Foot and Mouth Disease Virus, Immune Refocusing mutations introduced into just one of four immunodominant antigenic sites, the GH-loop of VP1, resulted in an antigen that stimulated cross-neutralizing antibodies. We propose 1) to design and produce a panel of HRV39 vaccine candidates with mutational changes to immunodominant epitopes; 2) to test the candidates for stimulation of cross-neutralizing antibodies; and 3) to investigate delivery systems for "native- like" capsid protein folding and efficient antigen presentation to the immune system. PUBLIC HEALTH RELEVANCE: Human rhinoviruses (HRVs) are a leading cause of the common cold and an increasingly recognized cause and/or exacerbater of asthma and chronic pulmonary disease. Due to the large number of serotypes, efforts to develop a vaccine have been discouraging. Recent advances in understanding how pathogens utilize highly variable antigenic sites to misdirect the immune system from responding to more highly conserved epitopes have led to the development of the Immune Refocusing Technology for novel vaccine design. We propose to apply this Technology to redirect the immune system to recognize cross-reactive epitopes on HRV39. Sera from mice immunized with the vaccine candidates will be assessed for enhanced cross-reactive antiviral activity against heterologous serotypes. The development of a broadly protective HRV vaccine would result in enormous improvements in health status and have an immediate impact on health-related economic savings.