State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen 361102, China.
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen 361102, China.
Viruses. 2022 Jun 14;14(6):1305. doi: 10.3390/v14061305.
Two lineages of influenza B viruses (IBV) co-circulating in human beings have been posing a significant public health burden worldwide. A substantial number of broadly neutralizing antibodies (bnAbs) have been identified targeting conserved epitopes on hemagglutinin (HA) stem domain, posing great interest for universal influenza vaccine development. Various strategies to design immunogens that selectively present these conserved epitopes are being explored. However, it has been a challenge to retain native conformation of the HA stem region, especially for soluble expression in prokaryotic systems. Here, using a structure prediction tool AlphaFold2, we rationally designed a stable stem antigen "B60-Stem-8071", an HA stem vaccine derived from B/Brisbane/60/2006 grafted with a CR8071 epitope as a linker. The B60-Stem-8071 exhibited better solubility and more stable expression in the system compared to the naïve HA stem antigen. Immunization with B60-Stem-8071 in mice generated cross-reactive antibodies and protected mice broadly against lethal challenge with Yamagata and Victoria lineages of influenza B virus. Notably, soluble expression of B60-stem-8071 in the system showed the potential to produce the influenza B vaccine in a low-cost way. This study represents a proof of concept for the rational design of HA stem antigen based on structure prediction and analysis.
两种乙型流感病毒（IBV）在人类中共同循环，给全球公共卫生带来了重大负担。已经发现了大量针对血凝素（HA）茎域保守表位的广谱中和抗体（bnAbs），这对通用流感疫苗的开发具有很大的兴趣。目前正在探索各种设计免疫原的策略，以选择性地呈现这些保守表位。然而，保留 HA 茎区的天然构象一直是一个挑战，特别是在原核系统中的可溶性表达。在这里，我们使用结构预测工具 AlphaFold2，合理设计了一种稳定的茎抗原“B60-Stem-8071”，这是一种源自 B/Brisbane/60/2006 的 HA 茎疫苗，通过一个 CR8071 表位作为接头进行基因拼接。与原始的 HA 茎抗原相比，B60-Stem-8071 在 系统中表现出更好的可溶性和更稳定的表达。B60-Stem-8071 免疫小鼠后产生了交叉反应性抗体，并能广泛保护小鼠免受致命性的乙型流感病毒 Yamagata 和 Victoria 谱系的攻击。值得注意的是，B60-stem-8071 在 系统中的可溶性表达表明了以低成本方式生产乙型流感疫苗的潜力。本研究代表了基于结构预测和分析的 HA 茎抗原合理设计的概念验证。
