Influenza chimeric hemagglutinin structures in complex with broadly protective antibodies to the stem and trimer interface.
Influenza chimeric hemagglutinin structures in complex with broadly protective antibodies to the stem and trimer interface.
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DOI：
10.1073/pnas.2200821119
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发表时间：
2022-05-24
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
用含有相同茎但不同头部结构域的嵌合血凝素(CHAs)连续免疫，可以将抗体免疫反应定向到保守的茎区域。关于CHAS的结构信息仅限于一个包含第1族茎的例子。在这里，X射线和电子显微镜结构显示，ChaS CH4/3和cH15/3含有一个第2组茎，带有广泛保护的茎抗体31.a.83，具有完整的天然茎区域。此外，CHA头部结构域呈开放构象，暴露了保守的三聚体界面区域。31.a.83的cH15/3 HA和头部界面抗体fla-20的结构测定表明，针对保守的HA茎和头部界面都能诱导出广泛的保护性抗体。流感病毒血凝素(HA)一直是流感疫苗研制的主要靶点。针对HA保守区域的广泛保护性抗体开启了产生普遍流感免疫的可能性。两个2组甲型流感嵌合体HAD，CH4/3和cH15/3，先前被设计来诱导针对保守的HA干的抗体。在这里，我们通过X射线结晶学和负染色电子显微镜显示，广泛保护的抗干抗体可以稳定地与CH4/3和cH15/3结合，从而验证了它们作为通用疫苗免疫原的潜力。此外，在嵌合HA结构的头部区域观察到了灵活性，这表明抗体也可能与头部界面表位相互作用。我们的结构和结合研究表明，广泛保护的抗头三聚体界面抗体确实可以靶向cH15/3 HA三聚体的更开放的头域。因此，除了诱导针对保守的HA茎的广泛保护性抗体外，嵌合HAS还可能诱导针对HA头部区域保守的三聚体界面的抗体，从而提高疫苗的效力。
Sequential vaccination with chimeric hemagglutinins (cHAs) that contain the same stem, but different head domains, can direct the antibody immune response to the conserved stem region. Structural information on cHAs is limited to one example containing a group 1 stem. Here, X-ray and electron microscopy structures revealed that cHAs cH4/3 and cH15/3, which contain a group 2 stem, with broadly protective stem antibody 31.a.83, have intact, native-like stem regions. Furthermore, the cHA head domains were in an open conformation, which exposes the conserved trimer interface region. Structure determination of cH15/3 HA with 31.a.83 and head interface antibody FluA-20 suggests that broadly protective antibodies could be elicited against both the conserved HA stem and the head interface. Influenza virus hemagglutinin (HA) has been the primary target for influenza vaccine development. Broadly protective antibodies targeting conserved regions of the HA unlock the possibility of generating universal influenza immunity. Two group 2 influenza A chimeric HAs, cH4/3 and cH15/3, were previously designed to elicit antibodies to the conserved HA stem. Here, we show by X-ray crystallography and negative-stain electron microscopy that a broadly protective antistem antibody can stably bind to cH4/3 and cH15/3 HAs, thereby validating their potential as universal vaccine immunogens. Furthermore, flexibility was observed in the head domain of the chimeric HA structures, suggesting that antibodies could also potentially interact with the head interface epitope. Our structural and binding studies demonstrated that a broadly protective antihead trimeric interface antibody could indeed target the more open head domain of the cH15/3 HA trimer. Thus, in addition to inducing broadly protective antibodies against the conserved HA stem, chimeric HAs may also be able to elicit antibodies against the conserved trimer interface in the HA head domain, thereby increasing the vaccine efficacy.
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影响因子：
8.7
作者：
Julien JP;Lee PS;Wilson IA
通讯作者：
Wilson IA
影响因子：
6.1
作者：
CONNOLLY, ML
通讯作者：
CONNOLLY, ML
影响因子：
16.8
作者：
Henry C;Palm AE;Krammer F;Wilson PC
通讯作者：
Wilson PC
影响因子：
5.4
作者：
Eggink, Dirk;Goff, Peter H.;Palese, Peter
通讯作者：
Palese, Peter
DOI：
10.1073/pnas.1200039109
发表时间：
2012-02-14
影响因子：
11.1
作者：
Pica, Natalie;Hai, Rong;Palese, Peter
通讯作者：
Palese, Peter