消除ADE表位的寨卡疫苗设计及其免疫保护特性的研究

Zika virus (ZIKV) infection can cause severe clinical consequences, including microcephaly in fetuses and newborns. The 2015 outbreak of Zika epidemic has explosively spilled over 84 countries and regions worldwide. China also has imported cases and has ZIKV isolation in local vector. Zika now is the worldwide threat to the public health. So far, no prophylactics or therapeutics are available. Although progresses have been made in vaccine development against ZIKV, the potential antibody-dependent enhancement (ADE) of infection of dengue virus (DENV) caused by ZIKV vaccine has become a widespread safety concern. In particular, these two viruses are mainly transmitted by the same vector and endanger population usually in the same regions. In order to solve this problem, the applicant will base on the insight of previous ZIKV research to rational design of ZIKV immunogen. The strategy is to eliminate the major epitopes that cause ADE effect from the immunogen, but maintain the sufficient protein expression and intact folding at other neutralizing epitopes. The optimized immunogen will be further developed as the recombinant chimpanzee adenovirus vector (AdC7) vaccine. The vaccine efficacy and DENV ADE potential would be further evaluated by ex vivo and in vivo experiment. This project will push forward the development of efficient ZIKV vaccine with reduced ADE risk and have promising application potential. Moreover, this project will also provide new evidence for the immunological interplay between ZIKV/DENV.

人感染寨卡病毒可引发多种严重疾病，包括新生儿小头症。2015年寨卡疫情暴发，传播至全球84个国家和地区，我国既有输入病例也从本土病媒中分离到病毒。寨卡病毒严重威胁全球公共卫生。尽管寨卡疫苗研发取得了一些进展，但寨卡对登革病毒感染的抗体依赖感染增强（ADE）效应使得寨卡疫苗的安全性成为一个普遍担心的问题。尤其这两种病毒主要由同样的病媒传播，且威胁的人群常处于同一地区。为解决这一问题，在前期研究的基础上申请本项目。项目将对寨卡抗原进行重新设计和优化，消除引起ADE的关键表位并维持抗原的足够表达和其它中和表位的完整，获得的优化抗原将进一步构建成重组黑猩猩腺病毒载体AdC7疫苗。通过细胞和动物模型验证疫苗的效果，再评估其对登革病毒感染的ADE风险。该研究将有助于获得ADE风险大幅降低、且有效的寨卡疫苗，为研制更安全的疫苗奠定基础，有较高的应用潜力。也将为寨卡/登革病毒之间的免疫互作规律提供新依据。

寨卡病毒是一类蚊媒传播病原，感染孕妇可引起新生儿小头症。寨卡与登革病毒同为黄病毒属一个超血清家族。血清型之间的抗体依赖增强(ADE)是疫苗研制亟需解决的焦点安全问题。本项目我们通过反向疫苗学来理性设计新型寨卡疫苗的策略。我们基于ADE抗体的结构基础，对寨卡抗原E蛋白进行了理性改造，消除了寨卡抗原引发登革ADE的关键表位，同时维持了疫苗的中和表位。新疫苗可诱导清除性免疫应答，阻断寨卡病毒的母婴传播，转换免疫优势，不引起登革病毒ADE。结构解析揭示了改造后免疫原的分子基础。该研究朝着开发安全、有效的寨卡病毒疫苗迈出了关键的一步。