Epstein-Barr virus antigen design and characterisation

Epstein-Barr 病毒抗原设计和表征

• 批准号: 2743752
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2743752
• 关键词: Epstein; Barr; virus; antigen; design

The Epstein-Barr virus (EBV) is a human herpesvirus that infects epithelial cells and B lymphocytes; and transforms B cells to remain latent and can spontaneously reactivate. The virus infects over 90% of adults, and in most cases causes no problems or relatively mild symptoms (typically infectious mononucleosis, also known as glandular fever). In a small minority of those who are infected, however, EBV is associated with the development of multiple sclerosis or certain cancers. These diseases are often associated with poor prognoses and often require expensive treatment interventions, posing a significant issue to society. Indeed, data from Cancer Research UK suggests that EBV infection accounts for 200,000 new cases of cancer each year resulting in more than 140,000 deaths yearly. Therefore, there is an urgent need to design an efficacious vaccine that prevents EBV infection with the aim in the long run to reduce the onset of these more severe EBV associated pathologies. To date there is no approved EBV vaccine candidate, in part due to the inability to select an appropriate antigen that elicits robust neutralising antibodies to block infection. Recently there has been increasing support and research towards EBV vaccine development, with Moderna having initiated Phase I trials of their mRNA candidate targeting four key EBV envelope glycoproteins gH, gL, gp42 and gp220. The supervisor's group have taken a different approach in targeting the class III fusogen protein, glycoprotein B (gB), which is crucial for mediating membrane fusion to both epithelial cells and B lymphocytes. However, the gB protein very rapidly switches conformation from a pre-fusion state (natural conformation on the viral membrane) towards a post-fusion structure. A high-resolution structure of the pre-fusion state has not yet been established. Defining the pre-fusion state of gB would largely promote its use as a vaccine antigen.The project will use a library of gB mutants to establish which residues within the protein are involved in the stability of the pre-fusion conformation, and hence to attempt to design a pre-fusion stabilised form of the protein. It is hypothesised that a stabilised pre-fusion gB could elicit stronger immune responses upon immunisation, analogous to the 2P-based vaccines that target SARS-CoV-2. Furthermore, this project could provide further insight into the molecular architecture and dynamics that drive gB fusion and thus EBV infection.

EB病毒（EBV）是一种感染上皮细胞和B淋巴细胞的人疱疹病毒;并转化B细胞以保持潜伏并可自发地再活化。该病毒感染超过90%的成年人，在大多数情况下不会引起任何问题或相对轻微的症状（通常是传染性单核细胞增多症，也称为腺热）。然而，在少数感染者中，EBV与多发性硬化症或某些癌症的发展有关。这些疾病往往与贫困有关，往往需要昂贵的治疗干预，给社会带来重大问题。事实上，英国癌症研究中心的数据表明，EBV感染每年导致20万例新的癌症病例，每年导致14万多人死亡。因此，迫切需要设计预防EBV感染的有效疫苗，其目的是从长远来看减少这些更严重的EBV相关病理的发作。到目前为止，还没有批准的EBV候选疫苗，部分原因是无法选择合适的抗原，从而产生强大的中和抗体来阻断感染。最近，对EBV疫苗开发的支持和研究越来越多，Moderna已经启动了针对四种关键EBV包膜糖蛋白gH、gL、gp 42和gp 220的mRNA候选物的I期试验。主管小组采取了不同的方法靶向III类融合蛋白，糖蛋白B（gB），它对介导上皮细胞和B淋巴细胞的膜融合至关重要。然而，gB蛋白非常快速地将构象从融合前状态（病毒膜上的天然构象）转换为融合后结构。尚未建立聚变前状态的高分辨率结构。该项目将利用gB突变体库来确定蛋白质中哪些残基参与融合前构象的稳定性，从而尝试设计融合前稳定形式的蛋白质。假设稳定的融合前gB可以在免疫后引发更强的免疫应答，类似于靶向SARS-CoV-2的基于2 P的疫苗。此外，该项目可以进一步深入了解驱动gB融合和EBV感染的分子结构和动力学。