Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
J Virol. 2012 Nov;86(21):11686-97. doi: 10.1128/JVI.01694-12. Epub 2012 Aug 15.
The discovery of broadly neutralizing antibodies that recognize highly conserved epitopes in the membrane-proximal region of influenza virus hemagglutinin (HA) has revitalized efforts to develop a universal influenza virus vaccine. This effort will likely require novel immunogens that contain these epitopes but lack the variable and immunodominant epitopes located in the globular head of HA. As a first step toward developing such an immunogen, we investigated whether the 20-residue A-helix of the HA2 chain that forms the major component of the epitope of broadly neutralizing antibodies CR6261, F10, and others is sufficient by itself to elicit antibodies with similarly broad antiviral activity. Here, we report the multivalent display of the A-helix on icosahedral virus-like particles (VLPs) derived from the capsid of Flock House virus. Mice immunized with VLPs displaying 180 copies/particle of the A-helix produced antibodies that recognized trimeric HA and the elicited antibodies had binding characteristics similar to those of CR6261 and F10: they recognized multiple HA subtypes from group 1 but not from group 2. However, the anti-A-helix antibodies did not neutralize influenza virus. These results indicate that further engineering of the transplanted peptide is required and that display of additional regions of the epitope may be necessary to achieve protection.
广谱中和抗体的发现,这些抗体能够识别流感病毒血凝素(HA)膜近侧区域高度保守的表位,这重新激发了开发通用流感病毒疫苗的努力。这项工作可能需要新型免疫原,这些免疫原包含这些表位,但缺乏位于 HA 球状头部的可变和免疫显性表位。作为开发这种免疫原的第一步,我们研究了 20 个残基的 HA2 链 A 螺旋本身是否足以引发具有类似广谱抗病毒活性的抗体,该 A 螺旋是广谱中和抗体 CR6261、F10 和其他抗体的主要表位组成部分。在这里,我们报告了来自禽痘病毒衣壳的二十面体病毒样颗粒(VLPs)上 A 螺旋的多价展示。用展示 180 个拷贝/颗粒 A 螺旋的 VLPs 免疫的小鼠产生了能够识别三聚体 HA 的抗体,并且诱导的抗体具有与 CR6261 和 F10 相似的结合特性:它们识别来自 1 组的多个 HA 亚型,但不识别来自 2 组的 HA 亚型。然而,抗 A 螺旋抗体不能中和流感病毒。这些结果表明需要进一步对移植肽进行工程改造,并且可能需要展示表位的其他区域才能实现保护。
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