稳定的三聚体流感血凝素茎作为一种广泛保护性的免疫原。
A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen.
机构信息
Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, 3210 Merryfield Row, San Diego, CA 92121, USA.
出版信息
Science. 2015 Sep 18;349(6254):1301-6. doi: 10.1126/science.aac7263. Epub 2015 Aug 24.
The identification of human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem revitalized hopes of developing a universal influenza vaccine. Using a rational design and library approach, we engineered stable HA stem antigens ("mini-HAs") based on an H1 subtype sequence. Our most advanced candidate exhibits structural and bnAb binding properties comparable to those of full-length HA, completely protects mice in lethal heterologous and heterosubtypic challenge models, and reduces fever after sublethal challenge in cynomolgus monkeys. Antibodies elicited by this mini-HA in mice and nonhuman primates bound a wide range of HAs, competed with human bnAbs for HA stem binding, neutralized H5N1 viruses, and mediated antibody-dependent effector activity. These results represent a proof of concept for the design of HA stem mimics that elicit bnAbs against influenza A group 1 viruses.
鉴定针对血凝素(HA)茎部的人源广谱中和抗体(bnAbs)重新燃起了开发通用流感疫苗的希望。我们采用合理的设计和文库方法,基于 H1 亚型序列构建了稳定的 HA 茎部抗原(“mini-HA”)。我们最先进的候选物在结构和 bnAb 结合特性方面与全长 HA 相当,完全保护小鼠免受致死性异源和异亚型挑战模型的感染,并在食蟹猴中减轻亚致死性挑战后的发热。该 mini-HA 在小鼠和非人类灵长类动物中诱导的抗体结合了广泛的 HA,与人类 bnAbs 竞争 HA 茎部结合,中和 H5N1 病毒,并介导抗体依赖的效应活性。这些结果证明了设计能够诱导针对甲型流感病毒群 1 病毒的 bnAbs 的 HA 茎模拟物的概念验证。