Immunizations with diverse sarbecovirus receptor-binding domains elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability.
Immunizations with diverse sarbecovirus receptor-binding domains elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability.
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具有不同SARBECOVIRUS受体结合结构域的免疫接种引起了SARS-COV-2中和抗体，以抵抗保守的脆弱性位点。
DOI：
10.1016/j.immuni.2021.10.019
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发表时间：
2021-12-14
期刊：
影响因子：
32.4
通讯作者：
Goodnow CC
中科院分区：
文献类型：
--
作者：
Burnett DL;Jackson KJL;Langley DB;Aggrawal A;Stella AO;Johansen MD;Balachandran H;Lenthall H;Rouet R;Walker G;Saunders BM;Singh M;Li H;Henry JY;Jackson J;Stewart AG;Witthauer F;Spence MA;Hansbro NG;Jackson C;Schofield P;Milthorpe C;Martinello M;Schulz SR;Roth E;Kelleher A;Emery S;Britton WJ;Rawlinson WD;Karl R;Schäfer S;Winkler TH;Brink R;Bull RA;Hansbro PM;Jäck HM;Turville S;Christ D;Goodnow CC
病毒突变是降低 SARS-CoV-2 疫苗接种效果的一个新问题。第二代疫苗需要针对 sarbecovirus 亚属进化上保守的位点引发中和抗体。在这里，我们对含有不同 sarbecovirus 受体结合域 (RBD) 的人类抗体库的小鼠进行了免疫接种，以识别针对保守脆弱位点的抗体。针对针对保守的 4 类表位的不同进化枝 B RBD 具有广泛反应性的抗体，具有重复的 IGHV/IGKV 对，很容易引发，但不是中和性的。然而，结合这个保守的 RBD 超级位点的罕见 4 类抗体显示出对 SARS-CoV-2 和所有相关变体的有效中和作用。结构分析显示，交叉反应抗体的中和能力仅保留给那些具有延长的 CDRH3 的抗体，CDRH3 延长了反向平行的 β-片层 RBD 核心并定向抗体轻链以阻碍 ACE2-RBD 相互作用。这些结果确定了一种结构明确的疫苗策略途径，可引发抗逃逸的 SARS-CoV-2 中和抗体。病毒突变是降低 SARS-CoV-2 疫苗接种效果的一个新问题。伯内特等人。使用不同的 sarbecovirus RBD 对人源化小鼠进行免疫，以引发针对保守位点的抗体。很容易引发针对保守的 4 类表位的非中和交叉反应抗体。中和能力仅保留给通过阻碍 ACE2-RBD 相互作用的延长 CDRH3 结合此保守超级位点的抗体。
Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Second-generation vaccines will need to elicit neutralizing antibodies against sites that are evolutionarily conserved across the sarbecovirus subgenus. Here, we immunized mice containing a human antibody repertoire with diverse sarbecovirus receptor-binding domains (RBDs) to identify antibodies targeting conserved sites of vulnerability. Antibodies with broad reactivity against diverse clade B RBDs targeting the conserved class 4 epitope, with recurring IGHV/IGKV pairs, were readily elicited but were non-neutralizing. However, rare class 4 antibodies binding this conserved RBD supersite showed potent neutralization of SARS-CoV-2 and all variants of concern. Structural analysis revealed that the neutralizing ability of cross-reactive antibodies was reserved only for those with an elongated CDRH3 that extends the antiparallel beta-sheet RBD core and orients the antibody light chain to obstruct ACE2-RBD interactions. These results identify a structurally defined pathway for vaccine strategies eliciting escape-resistant SARS-CoV-2 neutralizing antibodies. Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Burnett et al. immunized humanized mice with different diverse sarbecovirus RBDs to elicit antibodies targeting conserved sites. Non-neutralizing cross-reactive antibodies targeting the conserved class 4 epitope were readily elicited. Neutralizing ability was reserved only for antibodies binding this conserved supersite through an elongated CDRH3 that obstructed ACE2-RBD interactions.
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DOI：
10.1107/s090744491003982x
发表时间：
2011-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Evans PR
通讯作者：
Evans PR
影响因子：
46.9
作者：
Bolotin DA;Poslavsky S;Davydov AN;Frenkel FE;Fanchi L;Zolotareva OI;Hemmers S;Putintseva EV;Obraztsova AS;Shugay M;Ataullakhanov RI;Rudensky AY;Schumacher TN;Chudakov DM
通讯作者：
Chudakov DM
影响因子：
3
作者：
Moorhouse MJ;van Zessen D;IJspeert H;Hiltemann S;Horsman S;van der Spek PJ;van der Burg M;Stubbs AP
通讯作者：
Stubbs AP
DOI：
10.1126/science.aao3859
发表时间：
2018-04-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Burnett DL;Langley DB;Schofield P;Hermes JR;Chan TD;Jackson J;Bourne K;Reed JH;Patterson K;Porebski BT;Brink R;Christ D;Goodnow CC
通讯作者：
Goodnow CC
影响因子：
64.8
作者：
Barnes CO;Jette CA;Abernathy ME;Dam KA;Esswein SR;Gristick HB;Malyutin AG;Sharaf NG;Huey-Tubman KE;Lee YE;Robbiani DF;Nussenzweig MC;West AP Jr;Bjorkman PJ
通讯作者：
Bjorkman PJ