Development of a plant-derived virus-like particle vaccine against SARS-CoV

描述(申请人提供)：严重急性呼吸系统综合症(SARS)是由一种新出现的冠状病毒引起的。在2002/2003年暴发期间，该病在国际上传播，导致总死亡率约为10%，老年人的死亡率高得多，约为40%。与其他冠状病毒一样，尖峰蛋白(S)是中和抗体的主要目标。SARS-CoV S蛋白通过其受体结合区与血管紧张素转换酶2受体结合。RBD具有免疫原性，是一个主要的中和决定簇。已经针对疫苗开发进行了重大研究，但目前还没有可用的研究。对于SARS未来爆发的可能性，人们仍然感到担忧。病毒的宿主尚未确定。SARS冠状病毒是一种生物防御性C类优先病原体。也有可能发生实验室获得性感染。因此，开发有效的疫苗仍然具有重要意义。该项目的长期目标是确定呈现SARS-CoV S蛋白RBD的植物衍生病毒样颗粒是否能够有效地刺激针对SARS-CoV的保护性系统和粘膜免疫。通过在植物中将RBD表达为与乙肝表面抗原(HBs Ag)和核心抗原(HBcAg)的融合，将产生显示RBD的新型异源VLP。将评估含有RBD的VLP在小鼠中诱导强大的系统和粘膜SARS-CoV中和抗体反应和保护性免疫的能力。将使用标准的分子生物学、生化方法、疫苗接种和免疫学分析。该项目的具体目标是：1.在植物中制备呈现SARS-CoV S RBD的异源VLP；2.在小鼠模型中评价植物来源VLP的免疫原性和保护作用。 公共卫生意义：由一种新型冠状病毒(SARS-CoV)引起的严重急性呼吸综合征(SARS)是2002/2003年出现的一种新疾病，在全球范围内造成了大量感染和死亡，老年人的死亡率至少为40%。尽管全球疫情得到了控制，但人们担心病毒会再次出现，或者可能被用作生物恐怖分子，因此开发安全有效的疫苗很重要。该项目的长期目标是开发一种新的亚单位疫苗，对SARS冠状病毒具有保护作用。

DESCRIPTION (provided by applicant): Severe acute respiratory syndrome (SARS) is caused by a newly emerged coronavirus. During the outbreak in 2002/2003 the disease spread internationally resulting in an overall mortality rate of ~10% and a significantly higher rate of ~40% for elderly individuals. As is the case with other coronaviruses, the spike (S) protein is the major target for neutralizing antibodies. SARS-CoV S protein binds to the receptor, angiotensin-converting enzyme 2 (ACE2), through its receptor binding domain (RBD). The RBD is immunogenic and is a major neutralizing determinant. Significant research has been directed toward vaccine development, but none is yet available. Concerns remain over the possibility of future outbreaks of SARS. The reservoir for the virus has not been identified. SARS-CoV is a Biodefense Category C priority pathogen. There is also the potential for laboratory acquired infections. Thus, development of effective vaccines is still of significant importance. The long-term goal of this project is to determine if plant-derived virus-like particles presenting the RBD of the SARS-CoV S protein can efficiently stimulate protective systemic and mucosal immunity against SARS-CoV. Novel heterologous VLPs displaying the RBD will be generated by expressing the RBD as fusions with the hepatitis B surface (HBsAg) and core (HBcAg) antigens in plants. RBD-containing VLPs will be evaluated for their ability to elicit strong systemic and mucosal SARS-CoV-neutralizing antibody responses and protective immunity in mice. Standard molecular biology, biochemical approaches, vaccination and immunological assays will be used. The specific aims of the project are: 1. To produce heterologous VLPs presenting the SARS-CoV S RBD in plants; and 2. To evaluate the immunogenicity and protective efficacy of plant-derived VLPs in mouse models. PUBLIC HEALTH RELEVANCE: Severe acute respiratory syndrome (SARS) caused by a new coronavirus (SARS-CoV) is new disease that appeared in 2002/2003 which caused a significant number of infections and deaths worldwide, with a mortality rate of at least 40% in older individuals. Even though the global outbreak was contained, there are concerns that the virus will reemerge or that it could potentially be used as a bioterrorist agent, thus it is important to develop safe effective vaccines. The long term goal of this project is to develop a novel subunit vaccine that elicits protection against SARS coronavirus.