PDF(Pubmed)
Abstract：
The Ebola virus causes hemorrhagic fever in humans and poses a significant threat to global public health. Although two viral vector vaccines have been approved to prevent Ebola virus disease, they are distributed in the limited ring vaccination setting and only indicated for prevention of infection from orthoebolavirus zairense (EBOV)-one of three orthoebolavirus species that have caused previous outbreaks. Ebola virus glycoprotein GP mediates viral infection and serves as the primary target of neutralizing antibodies. Here, we describe a universal Ebola virus vaccine approach using a structure-guided design of candidates with hyperglycosylation that aims to direct antibody responses away from variable regions and toward conserved epitopes of GP. We first determined the hyperglycosylation landscape on Ebola virus GP and used that to generate hyperglycosylated GP variants with two to four additional glycosylation sites to mask the highly variable glycan cap region. We then created vaccine candidates by displaying wild-type or hyperglycosylated GP variants on ferritin nanoparticles (Fer). Immunization with these antigens elicited potent neutralizing antisera against EBOV in mice. Importantly, we observed consistent cross-neutralizing activity against Bundibugyo virus and Sudan virus from hyperglycosylated GP-Fer with two or three additional glycans. In comparison, elicitation of cross-neutralizing antisera was rare in mice immunized with wild-type GP-Fer. These results demonstrate a potential strategy to develop universal Ebola virus vaccines that confer cross-protective immunity against existing and emerging filovirus species.
摘要：
埃博拉病毒导致人类出血热，对全球公共卫生构成重大威胁。尽管两种病毒载体疫苗已被批准用于预防埃博拉病毒病，它们分布在有限的环疫苗接种环境中,并且仅用于预防扎伊伦斯直推病毒(EBOV)的感染-这是引起先前暴发的三种直推病毒之一.埃博拉病毒糖蛋白GP介导病毒感染并作为中和抗体的主要靶标。这里,我们描述了一种通用的埃博拉病毒疫苗方法,该方法使用高糖基化候选物的结构指导设计,目的是将抗体应答从GP的可变区引导至保守表位.我们首先确定了埃博拉病毒GP的高糖基化景观，并将其用于生成具有2至4个额外糖基化位点的高糖基化GP变体，以掩盖高度可变的聚糖帽区。然后,我们通过在铁蛋白纳米颗粒(Fer)上展示野生型或高糖基化的GP变体来创建疫苗候选物。用这些抗原免疫在小鼠中引发针对EBOV的有效中和抗血清。重要的是,我们观察到高糖基化GP-Fer对Bundibugyo病毒和苏丹病毒具有一致的交叉中和活性,同时添加2或3个聚糖.相比之下,在用野生型GP-Fer免疫的小鼠中很少引起交叉中和抗血清。这些结果证明了开发通用埃博拉病毒疫苗的潜在策略，该疫苗赋予针对现有和新兴丝状病毒物种的交叉保护性免疫力。
