Immunity to dengue viruses

项目摘要 ! 登革热病毒是蚊媒黄病毒，对公共卫生有巨大影响，可引起一系列 从轻微到致命的人类疾病。严重登革热的进展是由 存在调节Fc受体中病毒和细胞因子产生的非中和性抗登革热IgG- 产生细胞。我们已经表明，严重登革热疾病的进展是由抗- 具有丰富的无岩藻糖基化Fc糖型的登革热抗体，这种修饰增强Fc对 特异性激活Fc受体FcγRIIIa。因此，我们的数据指出FcγRIIIa在肿瘤的发病机制中的作用。 登革热在本提案中，我们将研究来自活的减毒四价疫苗的III期试验的样本。 登革热病毒疫苗，CYD-TDV（Dengvaxia，Sanofi Pasteur），以确定参与人体免疫的机制 登革热病毒。最近对CYD-TDV III期试验数据的分析表明， 在一些研究队列中，通过接种疫苗增加。这一发现凸显了理解的重要性 如何调节登革热疫苗接种的抗体应答以及抗体 可以增强登革热感染。本提案的目的是：a）定义抗体上Fc岩藻糖基化的调节剂 由CYD-TDV疫苗接种或由人中的天然登革热感染引起; B）定义接种后 在5年期间，疫苗接种/感染前抗登革热抗体谱和对登革热疾病的易感性 疫苗接种后的随访期; c）确定FcγRIIIa影响登革热感染的机制， 发病机理总的来说，这些目标将促进我们对机制的基本理解 调节人类对登革病毒的免疫力，并指导设计安全、有效的登革病毒疫苗。

PROJECT SUMMARY ! Dengue viruses are mosquito-borne flaviviruses of immense public health impact that cause a spectrum of disease in humans ranging from mild to fatal. Progression to severe dengue disease is promoted by the presence of non-neutralizing anti-dengue IgGs that modulate virus and cytokine production in Fc receptor- bearing cells. We have shown that progression to severe dengue disease is promoted by the presence of anti- dengue antibodies with abundant afucosylated Fc glycoforms, a modification that enhances affinity of the Fc for a specific activating Fc receptor, FcγRIIIa. Thus, our data point to a role for FcγRIIIa in the pathogenesis of dengue disease. In this proposal we will study samples from Phase III trials of a live, attenuated tetravalent dengue virus vaccine, CYD-TDV (Dengvaxia, Sanofi Pasteur), to define mechanism involved in human immunity to dengue viruses. Recent analyses of data from the Phase III trials of CYD-TDV showed that risk for disease was increased in some study cohorts by vaccination. This finding highlights the importance of understanding how antibody responses to dengue vaccination are regulated and molecular mechanisms by which antibodies can enhance dengue infections. Aims in this proposal will: a) define regulators of Fc fucosylation on antibodies elicited by CYD-TDV vaccination or by natural dengue infection in humans; b) define associations between post- vaccination/pre-infection anti-dengue antibody repertoires and susceptibility to dengue disease during a 5-year follow-up period after vaccination; c) define mechanisms by which FcγRIIIa impacts dengue infections and disease pathogenesis. Collectively, these aims will advance our fundamental understanding of mechanisms regulating human immunity to dengue viruses and guide the design of safe, effective dengue virus vaccines.