Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants.
Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants.
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DOI：
10.1126/science.abh1766
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发表时间：
2021-08-13
期刊：
影响因子：
56.9
通讯作者：
Misasi, John
中科院分区：
文献类型：
--
作者：
Wang, Lingshu;Zhou, Tongqing;Zhang, Yi;Yang, Eun Sung;Schramm, Chaim A.;Shi, Wei;Pegu, Amarendra;Oloniniyi, Olamide K.;Henry, Amy R.;Darko, Samuel;Narpala, Sandeep R.;Hatcher, Christian;Martinez, David R.;Tsybovsky, Yaroslav;Phung, Emily;Abiona, Olubukola M.;Antia, Avan;Cale, Evan M.;Chang, Lauren A.;Choe, Misook;Corbett, Kizzmekia S.;Davis, Rachel L.;DiPiazza, Anthony T.;Gordon, Ingelise J.;Helmold-Hait, Sabrina;Hermanus, Tandile;Kgagudi, Prudence;Laboune, Farida;Leung, Kwanyee;Liu, Tracy;Mason, Rosemarie D.;Nazzari, Alexandra F.;Novik, Laura;O'Connell, Sarah;O'Dell, Sijy;Olia, Adam S.;Schmidt, Stephen D.;Stephens, Tyler;Stringham, Christopher D.;Talana, Chloe Adrienna;Teng, I-Ting;Wagner, Danielle A.;Widge, Alicia T.;Zhang, Baoshan;Roederer, Mario;Ledgerwood, Julie E.;Ruckwardt, Tracy J.;Gaudinski, Martin R.;Moore, Penny L.;Doria-Rose, Nicole A.;Baric, Ralph S.;Graham, Barney S.;McDermott, Adrian B.;Douek, Daniel C.;Kwong, Peter D.;Mascola, John R.;Sullivan, Nancy J.;Misasi, John
我们对抗COVID-19疫情的关键防御措施是通过自然感染或接种疫苗产生的SARS-CoV-2病毒中和抗体。最近出现的病毒变异引起了人们的关注，因为它们有可能逃避抗体中和。Wang等人从早期爆发的恢复期供体中鉴定出四种抗体，这些抗体对23种变体（包括令人担忧的变体）有效，并表征了它们与严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的刺突蛋白的结合。Yuan等人检查了刺突蛋白受体结合结构域中出现的突变对与宿主受体ACE 2和一系列抗体结合的影响。这些研究可能有助于开发更广泛有效的疫苗和治疗性抗体。来自第一波SARS-CoV-2恢复期供体的有效中和抗体中和了最近关注的变体。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变异的关注（VOC）与增加的传播性和耐药性的治疗性抗体的世界各地的出现，有必要发现广泛的反应性抗体。我们分离了受体结合结构域（RBD）靶向抗体，其有效地中和23种变体，包括B.1.1.7、B.1.351、P.1、B.1.429、B.1.526和B.1.617 VOC。结构和功能研究揭示了抗体结合的分子基础，并表明抗体组合减少了逃逸突变体的产生，这表明了减轻治疗抗性发展的潜在手段。对来自感染华盛顿-1（WA-1）菌株的恢复期受试者的抗体应答针对WA-1和VOC的反应性的研究可以为疫苗设计和治疗的改进提供信息。对22名从SARS-CoV-2 WA-1感染中恢复的恢复期受试者的血液进行中和和结合活性筛选，并选择对WA-1变体具有高反应性的4名受试者进行抗体分离。SARS-CoV-2刺突（S）反应性抗体通过基于S蛋白的探针的B细胞分选来鉴定。WA-1活病毒中和试验鉴定了四种具有高效价的RBD靶向抗体[半最大抑制浓度（IC 50）2.1至4.8 ng/ml]，其中两种来自相同的IGHV 1 -58种系，但来自不同的供体。这些抗体的抗原结合片段（Fab）表现出对S的纳摩尔亲和力（2.3至7.3 nM）。竞争分析和电子显微镜表明，两个最有效的抗体阻断血管紧张素转换酶2（ACE 2）和开放构象的RBD的绑定，而其他两个绑定的RBD的向上和向下的构象和阻断ACE 2的结合。针对13种循环VOC或感兴趣变体的结合和慢病毒中和试验，包括B.1.1.7、B.1.351、B.1.427、B.1.429、B.1.526、P.1、P.2、B.1.617.1、和B.1.617.2-表明，尽管这些抗体是从感染早期祖先SARS-CoV的受试者中分离出来的，但它们对VOC具有高度效力。2种病毒。对与S复合的两种最有效的抗体的Cryo-EM研究表明，这些抗体靶向RBD上的脆弱位点，但与突变热点的接触最少，这定义了它们对新兴VOC的高有效性的结构基础，并进一步描绘了IGHV 1 -58抗体超位点。为了研究逃逸的潜在机制，我们将抗体选择压力应用于表达WA-1 SARS-CoV-2 S（rcVSV-SARS 2）的复制型水泡性口炎病毒（rcVSV），并鉴定了赋予体外抗性的S突变。我们评估了这些抗体单独或组合预防rcVSV-SARS 2逃逸的能力，发现与RBD互补识别模式的抗体组合降低了耐药风险。我们的研究表明，以前感染了祖先变异SARS-CoV-2的康复期受试者产生的抗体可以交叉中和新出现的高效力VOC。结构和功能分析表明，抗体宽度介导的靶向从主要的突变热点在挥发性有机化合物的RBD尖端偏移的脆弱性的网站。针对特定RBD表位（如这些抗体定义的位点）的免疫反应的选择性增强可能会诱导针对当前和未来VOC的广度。从感染了祖先SARS-CoV-2病毒的供体中分离出的抗体显示出对新出现的VOC的超强中和作用。两种最有效的抗体共享IGHV 1 -58基因的使用，并以与VOC突变热点的最小接触靶向RBD。具有互补结合模式的抗体混合物抑制抗体逃逸。对治疗性抗体具有抗性的高度传播性SARS-CoV-2变异体（VOC）的出现突出了继续发现广泛反应性抗体的必要性。我们从三个早期爆发的恢复期供体中鉴定了四种受体结合结构域靶向抗体，其对23种变体具有有效的中和活性，包括B.1.1.7，B.1.351，P.1，B.1.429，B.1.526和B.1.617 VOC。两种抗体是超强效的，具有亚纳摩尔中和滴度[半数最大抑制浓度（IC 50）为0.3至11.1纳克/毫升; IC 80为1.5至34.5纳克/毫升）。我们定义了所有四种VOC靶向抗体结合的结构和功能决定因素，并表明两种抗体的组合减少了逃逸突变体的体外产生，表明它们在减轻耐药性发展方面的潜力。
Our key defense against the COVID-19 pandemic is neutralizing antibodies against the SARS-CoV-2 virus elicited by natural infection or vaccination. Recent emerging viral variants have raised concern because of their potential to escape antibody neutralization. Wang et al. identified four antibodies from early-outbreak convalescent donors that are potent against 23 variants, including variants of concern, and characterized their binding to the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Yuan et al. examined the impact of emerging mutations in the receptor-binding domain of the spike protein on binding to the host receptor ACE2 and to a range of antibodies. These studies may be helpful for developing more broadly effective vaccines and therapeutic antibodies. —VV Potently neutralizing antibodies from convalescent donors from the first wave of SARS-CoV-2 neutralize recent variants of concern. Worldwide appearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) with increased transmissibility and resistance to therapeutic antibodies necessitates the discovery of broadly reactive antibodies. We isolated receptor binding domain (RBD) targeting antibodies that potently neutralize 23 variants, including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, and B.1.617 VOCs. Structural and functional studies revealed the molecular basis for antibody binding and showed that antibody combinations reduce the generation of escape mutants, suggesting a potential means to mitigate development of therapeutic resistance. Investigation of antibody responses from convalescent subjects infected with the Washington-1 (WA-1) strain for reactivity against WA-1 and VOCs can inform improvements to vaccine design and therapeutics. Blood from 22 convalescent subjects who recovered from SARS-CoV-2 WA-1 infection was screened for neutralizing and binding activity, and four subjects with high reactivity against the WA-1 variant were selected for antibody isolation. SARS-CoV-2 spike (S)–reactive antibodies were identified through B cell sorting with S protein–based probes. WA-1 live-virus neutralization assays identified four RBD-targeting antibodies with high potency [half-maximal inhibitory concentration (IC50) 2.1 to 4.8 ng/ml], two of which were derived from the same IGHV1-58 germline but from different donors. Antigen-binding fragments (Fabs) of these antibodies exhibited nanomolar affinity to S (2.3 to 7.3 nM). Competition assays and electron microscopy indicated that two of the most potent antibodies blocked angiotensin-converting enzyme 2 (ACE2) and bound open conformation RBD, whereas the other two bound both up and down conformations of RBD and blocked ACE2 binding. Binding and lentivirus neutralization assays against 13 circulating VOCs or variants of interest—including B.1.1.7, B.1.351, B.1.427, B.1.429, B.1.526, P.1, P.2, B.1.617.1, and B.1.617.2—indicated that these antibodies were highly potent against VOCs despite being isolated from subjects infected with early ancestral SARS-CoV-2 viruses. Cryo-EM studies of the two most potent antibodies in complex with S revealed that these antibodies target a site of vulnerability on RBD but have minimal contacts with mutational hotspots, defining the structural basis for their high effectiveness against the emerging VOCs and further delineating an IGHV1-58 antibody supersite. To investigate potential mechanisms of escape, we applied antibody selection pressure to replication-competent vesicular stomatitis virus (rcVSV) expressing the WA-1 SARS-CoV-2 S (rcVSV-SARS2) and identified S mutations that conferred in vitro resistance. We evaluated these antibodies individually or in combinations for their capacity to prevent rcVSV-SARS2 escape and discovered that antibody combinations with complementary modes of recognition to the RBD lowered the risk of resistance. Our study demonstrates that convalescent subjects previously infected with ancestral variant SARS-CoV-2 produce antibodies that cross-neutralize emerging VOCs with high potency. Structural and functional analyses reveal that antibody breadth is mediated by targeting a site of vulnerability at the RBD tip offset from major mutational hotspots in VOCs. Selective boosting of immune responses targeting specific RBD epitopes, such as the sites defined by these antibodies, may induce breadth against current and future VOCs. Antibodies isolated from donors infected with ancestral SARS-CoV-2 viruses showed ultrapotent neutralization of emerging VOCs. The two most potent antibodies shared usage of the IGHV1-58 gene and targeted the RBD with minimal contact to VOC mutational hotspots. Cocktails of antibodies with complementary binding modes suppressed antibody escape. The emergence of highly transmissible SARS-CoV-2 variants of concern (VOCs) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identified four receptor binding domain–targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 23 variants, including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, and B.1.617 VOCs. Two antibodies are ultrapotent, with subnanomolar neutralization titers [half-maximal inhibitory concentration (IC50) 0.3 to 11.1 nanograms per milliliter; IC80 1.5 to 34.5 nanograms per milliliter). We define the structural and functional determinants of binding for all four VOC-targeting antibodies and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting their potential in mitigating resistance development.
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影响因子：
64.5
作者：
Hou, Yixuan J.;Okuda, Kenichi;Baric, Ralph S.
通讯作者：
Baric, Ralph S.
DOI：
10.1056/nejmoa2029849
发表时间：
2021-01-21
期刊：
The New England journal of medicine
影响因子：
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BLAZE-1 Investigators
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
SARS-COV-2血统的估计可传播和影响B.1.1.7在英国。
DOI：
10.1126/science.abg3055
发表时间：
2021-04-09
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Davies NG;Abbott S;Barnard RC;Jarvis CI;Kucharski AJ;Munday JD;Pearson CAB;Russell TW;Tully DC;Washburne AD;Wenseleers T;Gimma A;Waites W;Wong KLM;van Zandvoort K;Silverman JD;CMMID COVID-19 Working Group;COVID-19 Genomics UK (COG-UK) Consortium;Diaz-Ordaz K;Keogh R;Eggo RM;Funk S;Jit M;Atkins KE;Edmunds WJ
通讯作者：
Edmunds WJ
DOI：
10.1126/science.abe8499
发表时间：
2020-12-18
期刊：
Science (New York, N.Y.)
影响因子：
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Hou YJ;Chiba S;Halfmann P;Ehre C;Kuroda M;Dinnon KH 3rd;Leist SR;Schäfer A;Nakajima N;Takahashi K;Lee RE;Mascenik TM;Graham R;Edwards CE;Tse LV;Okuda K;Markmann AJ;Bartelt L;de Silva A;Margolis DM;Boucher RC;Randell SH;Suzuki T;Gralinski LE;Kawaoka Y;Baric RS
通讯作者：
Baric RS