Development of a novel human rhinovirus vaccine

描述（由申请人提供）：人类鼻病毒（HRV）在美国每年6000万“普通感冒”病例中约占三分之一，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原因。大量的HRV血清型（bbb100）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衣壳的单克隆抗体和多克隆抗体的作用相似，并且反复导致病毒衣壳中氨基酸变化的范围相当窄且相似。其次，血清学图谱数据表明，宿主反应主要局限于位于保守细胞受体结合区侧翼衣壳最高度可变区域的免疫显性表位。第三，一组独特的单克隆抗体已被证明可以在多种血清型中中和。因此，有可能病毒中存在的抗原表位可以诱导更广泛的保护性抗体，但不易被免疫系统发现。最后，在与有蹄类动物相关的小核糖核酸病毒（口蹄疫病毒）的初步研究中，将免疫重聚焦突变引入四个免疫优势抗原位点中的一个，即VP1的gh环，产生刺激交叉中和抗体的抗原。我们建议1)设计和生产一组免疫显性表位发生突变的HRV39候选疫苗；2)测试交叉中和抗体刺激的候选物；3)研究“天然样”衣壳蛋白折叠和有效抗原呈递到免疫系统的递送系统。

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.