基于登革病毒Ｅ蛋白茎干区α-螺旋结构的通用登革疫苗的研发

Dengue fever is one of the top 5 most common human infectious diseases, casting wide influences and causing severe damages to public health globally. However, the only licensed DENV vaccine Dengvaxia elicited an unbalanced immune response with relatively low-efficiency, and was demonstrated a potential to increase the risk of severe diseases. To design a better vaccine, we hypothesized that the DENV E protein stem region, which is not only essential for viral infection of host cells, but also genetically highly conserved among all DENV serotypes, is an ideal antigen for making a safe universal DENV vaccine. To mimic the α-helix structure of the stem region, we designed four stem-peptides based on the spatial location of each amino acid. These rationally designed peptides can be used as vaccine antigens to simulate antibodies targeting specific epitopes on the DENV stem region, leading to a blockade of viral infection process. In the proposed studies, we will first evaluate the immunogenicity and protective efficacy of the stem vaccine in mice and monkeys. And then based on results from the initial experiments, we will perform further optimization of these vaccines. This project is significant for two reasons: (1) it explores a novel scientific strategy for developing a universal DENV vaccine; and (2) it evaluates a vaccine prototype which has potential to be developed into an innovative, high-efficiency, broad-spectrum universal DENV vaccine.

登革热是全球5大人类传染病之一，影响范围广、危害大。现有登革热疫苗保护效价低、免疫应答不均衡、副作用大、风险高。为解决登革疫苗研发中的这些难题，本研究根据登革病毒Ｅ蛋白茎干（stem）区域在病毒感染细胞时的重要作用及其在不同血清型登革病毒间的高度保守性等先天优势，提出了以stem区域α-螺旋结构为基础设计抗原有可能研发出新型通用登革热疫苗的科学假设。面临合成多肽缺乏二级结构的技术局限，我们根据stem区域α-螺旋的结构特征和每个氨基酸的空间位置，设计并合成了能模拟stem区域抗体构象表位的stem多肽疫苗。经过前期研究验证后，我们将先后选用小鼠和恒河猴模型评价stem疫苗的免疫原性、安全性、广谱性有效性，并对stem疫苗进行优化与改良。本研究不仅可以验证一个创新登革热疫苗研发策略；而且还有可能产生一种新型登革热预防疫苗，在探索关键科学问题和解决传染病防控重大需求两方面都具有十分重要的意义。

登革热是全球五大人类传染病之一，影响范围广、危害大。现有登革热疫苗(Dengvaxia)保护效价低、免疫应答不均衡、副作用大、风险高。为解决登革疫苗研发中的这些难题，本研究根据登革病毒Ｅ蛋白茎干（STEM）区域在病毒感染细胞时的重要作用及其在不同血清型登革病毒间的高度保守性等先天优势，将该区域选为了新型疫苗靶点，并通过创新的多肽设计策略，设计的到了新型的ΔSTEM多肽及免疫原。这些免疫原的免疫血清不仅可抑制二型登革病毒感染，并对其他血清型的登革病毒及寨卡病毒也具有一定抑制作用，初步实现了项目目的。此外，本研究还建立的登革病毒小鼠感染模型，研发了可诱导细胞免疫反应的多肽疫苗、研发了新型的mRNA形式的登革病毒疫苗，并取得了相应成果。