Development of a novel human rhinovirus vaccine

描述（由申请人提供）：人鼻病毒（HRV）引起美国每年6000万例“普通感冒”病例中的约三分之一，因此是发达国家经济上最重要的人类疾病之一。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重要来源。大量的HRV血清型（>100）是疫苗开发的主要障碍。然而，三个过去和最近的发展表明，第一代鼻病毒疫苗的设计现在是可能的。首先，体外进化逃逸实验表明，针对HRV衣壳制备的单克隆和多克隆抗体的作用相似，并且重复导致病毒衣壳中相当窄且相似的氨基酸变化范围。第二，血清学定位数据表明，宿主反应主要限于位于保守的细胞受体结合区侧翼的衣壳的最高度可变区域中的免疫显性表位。第三，一个独特的小组的单克隆抗体已被证明可以中和多种血清型。因此，病毒中可能存在可以诱导更广泛保护性抗体的表位，但不容易被免疫系统发现。最后，在对相关的有蹄类动物小核糖核酸病毒（口蹄疫病毒）的初步研究中，仅将免疫重聚焦突变引入四个免疫显性抗原位点之一，即VP 1的GH环，导致产生刺激交叉中和抗体的抗原。我们提出1）设计和产生一组对免疫显性表位具有突变变化的HRV 39疫苗候选物; 2）测试用于刺激交叉中和抗体的候选物;和3）研究用于“天然样”衣壳蛋白折叠和有效抗原呈递至免疫系统的递送系统。 公共卫生相关性：人鼻病毒（HRV）是普通感冒的主要原因，也是越来越多人认识到的哮喘和慢性肺病的原因和/或加重因素。由于大量的血清型，开发疫苗的努力一直令人沮丧。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最新进展已经导致了用于新型疫苗设计的免疫重聚焦技术的发展。我们建议应用该技术来重定向免疫系统以识别HRV 39上的交叉反应性表位。将评估来自用候选疫苗免疫的小鼠的血清的针对异源血清型的增强的交叉反应性抗病毒活性。广泛保护性HRV疫苗的开发将导致健康状况的巨大改善，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.