Multi-clonal SARS-CoV-2 neutralization by antibodies isolated from severe COVID-19 convalescent donors.
Multi-clonal SARS-CoV-2 neutralization by antibodies isolated from severe COVID-19 convalescent donors.
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从严重COVID-19恢复期供体中分离的抗体对多克隆SARS-CoV-2的中和作用。
DOI：
10.1371/journal.ppat.1009165
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Freund NT
中科院分区：
文献类型：
--
作者：
Mor M;Werbner M;Alter J;Safra M;Chomsky E;Lee JC;Hada-Neeman S;Polonsky K;Nowell CJ;Clark AE;Roitburd-Berman A;Ben-Shalom N;Navon M;Rafael D;Sharim H;Kiner E;Griffis ER;Gershoni JM;Kobiler O;Leibel SL;Zimhony O;Carlin AF;Yaari G;Dessau M;Gal-Tanamy M;Hagin D;Croker BA;Freund NT
抗体、SARS-CoV-2和免疫细胞之间的相互作用参与了新冠肺炎的发病机制和保护性免疫。为了了解轻型和重型新冠肺炎患者抗体反应的差异，我们分析了SARS-CoV-2感染1.5个月后患者的B细胞反应。严重而不轻微的感染与高滴度的抗Spike受体结合域(RBD)的抗体有关，该抗体能够抑制ACE2：RBD。B细胞受体(BCR)测序显示，VH3-53在严重感染时富含。在从两个重症捐赠者那里克隆的22个抗体中，有六个对真正的SARS-CoV-2表现出很强的中和能力，并抑制了合胞体的形成。利用多肽文库、竞争酶联免疫吸附试验和RBD突变，我们将中和抗体(NAB)的表位定位到了棘突上的三个不同的位置。最后，我们使用针对不同免疫部位的NAB组合来有效地阻止SARS-CoV-2感染。对49个健康的BCR谱系的分析表明，NABS胚系VHJH前体占所有VHJH的2.7%。我们证明，严重的新冠肺炎与独特的bcr特征和多克隆中和反应有关，这在人群中相对频繁。此外，我们的数据支持使用联合抗体疗法来预防和治疗新冠肺炎。SARS-CoV-2感染的有效持久抗体反应的相关性仍不清楚。在这项研究中，我们使用分子和生物信息学的方法，比较了8名严重感染SARS-CoV-2和10名轻度感染SARS-CoV-2的以色列捐赠者在感染后1.5个月的B细胞受体特征。我们发现，在有严重疾病表现的献血者中，抗SARS-CoV-2受体结合域(RBD)血浆抗体滴度较高和B细胞增殖增加的两组患者具有明显的特征。我们进一步从这些供者身上分离出22株单抗，其中6株能中和活病毒并抑制感染细胞的融合。利用突变和多肽文库，我们定位了SARS-CoV-2刺突蛋白RBD上中和抗体的结合部位。接下来，我们证明了不同类别的中和单抗的组合可以完全阻止活病毒在培养中传播。最后，我们在49个健康的BCR谱系中进行了生物信息学搜索，在前30个最常见的前体中确定了这些中和抗体的前体，这表明大多数未感染的人群在抗原刺激下可以很容易地产生这些抗体。
The interactions between antibodies, SARS-CoV-2 and immune cells contribute to the pathogenesis of COVID-19 and protective immunity. To understand the differences between antibody responses in mild versus severe cases of COVID-19, we analyzed the B cell responses in patients 1.5 months post SARS-CoV-2 infection. Severe, and not mild, infection correlated with high titers of IgG against Spike receptor binding domain (RBD) that were capable of ACE2:RBD inhibition. B cell receptor (BCR) sequencing revealed that VH3-53 was enriched during severe infection. Of the 22 antibodies cloned from two severe donors, six exhibited potent neutralization against authentic SARS-CoV-2, and inhibited syncytia formation. Using peptide libraries, competition ELISA and mutagenesis of RBD, we mapped the epitopes of the neutralizing antibodies (nAbs) to three different sites on the Spike. Finally, we used combinations of nAbs targeting different immune-sites to efficiently block SARS-CoV-2 infection. Analysis of 49 healthy BCR repertoires revealed that the nAbs germline VHJH precursors comprise up to 2.7% of all VHJHs. We demonstrate that severe COVID-19 is associated with unique BCR signatures and multi-clonal neutralizing responses that are relatively frequent in the population. Moreover, our data support the use of combination antibody therapy to prevent and treat COVID-19. The correlates of effective durable antibody response to SARS-CoV-2 infection are still unclear. In this study, we compared B cell receptor signatures in 8 Severe versus 10 Mild SARS-CoV-2 infected Israeli donors, at 1.5 months post infection using molecular and bioinformatic approaches. We found distinct features between the two groups with higher anti-SARS-CoV-2 receptor binding domain (RBD) plasma IgG titers and increased B cell expansion in donors with severe disease manifestations. We further isolated 22 monoclonal antibodies from these donors, 6 of which were highly potent neutralizing the live virus and inhibited the fusion of infected cells. Using mutagenesis and peptide libraries we mapped the binding sites of the neutralizing antibodies on the RBD of the SARS-CoV-2 Spike. We next demonstrated that combinations of different classes of neutralizing mAbs can completely block the live virus from spreading in culture. Lastly, we performed a bioinformatic search in 49 healthy BCR repertoires identifying precursors for these neutralizing antibodies in the top 30 most common precursors, suggesting that these antibodies can be readily produced by the majority of the uninfected population upon antigenic stimulation.
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DOI：
10.1084/jem.20120423
发表时间：
2012-07-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Klein F;Gaebler C;Mouquet H;Sather DN;Lehmann C;Scheid JF;Kraft Z;Liu Y;Pietzsch J;Hurley A;Poignard P;Feizi T;Morris L;Walker BD;Fätkenheuer G;Seaman MS;Stamatatos L;Nussenzweig MC
通讯作者：
Nussenzweig MC
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
6.4
作者：
Lynch, Rebecca M.;Mantus, Grace;Chang, Aileen Y.
通讯作者：
Chang, Aileen Y.
影响因子：
16.8
作者：
Huo, Jiangdong;Le Bas, Audrey;Naismith, James H.
通讯作者：
Naismith, James H.
影响因子：
82.9
作者：
Amanat F;Stadlbauer D;Strohmeier S;Nguyen THO;Chromikova V;McMahon M;Jiang K;Arunkumar GA;Jurczyszak D;Polanco J;Bermudez-Gonzalez M;Kleiner G;Aydillo T;Miorin L;Fierer DS;Lugo LA;Kojic EM;Stoever J;Liu STH;Cunningham-Rundles C;Felgner PL;Moran T;García-Sastre A;Caplivski D;Cheng AC;Kedzierska K;Vapalahti O;Hepojoki JM;Simon V;Krammer F
通讯作者：
Krammer F