Identification of broad, potent antibodies to functionally constrained regions of SARS-CoV-2 spike following a breakthrough infection.
Identification of broad, potent antibodies to functionally constrained regions of SARS-CoV-2 spike following a breakthrough infection.
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DOI：
10.1073/pnas.2220948120
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发表时间：
2023-06-06
影响因子：
11.1
通讯作者：
Overbaugh, Julie
中科院分区：
文献类型：
--
作者：
Guenthoer, Jamie;Lilly, Michelle;Starr, Tyler N.;Dadonaite, Bernadeta;Lovendahl, Klaus N.;Croft, Jacob T.;Stoddard, Caitlin I.;Chohan, Vrasha;Ding, Shilei;Ruiz, Felicitas;Kopp, Mackenzie S.;Bloom, Jesse D.;Chu, Helen Y.;Lee, Kelly K.;Overbaugh, Julie
SARS-CoV-2感染可导致多种临床结局，包括严重疾病。单克隆抗体（mAb）已被用于治疗感染，但变体的出现已经损害了它们的疗效。因此，鉴定在面对SARS-CoV-2进化时更持久的mAb是迫切需要的。在这里，我们描述了从Delta突破感染中分离的四种mAb，它们可以有效地中和多种变体，包括多种Omicron变体。此外，一种mAb显示出更广泛的抗冠状病毒活性。这些mAb的广度是由于它们集中在病毒蛋白抗原的高度保守区域，包括病毒进入细胞所需的区域。这些特性使它们成为治疗用途的有希望的候选者。抗体的抗病毒益处可能会受到病毒逃逸的影响，特别是对于快速进化的病毒。因此，持久有效的抗体必须既广泛又有效，以对抗新出现的不同菌株。这种抗体的发现对于SARS-CoV-2至关重要，因为全球出现的新的关注变体（VOC）已经损害了治疗性抗体和疫苗的功效。我们描述了一个广泛和有效的中和单克隆抗体（mAb）的集合，从经历了突破性感染的三角洲VOC的个人分离。在基于假病毒和真实病毒的试验中，4种mAb可有效中和Wuhan-Hu-1疫苗株Delta VOC，并通过BA.4/BA.5保留对Omicron VOC的效力。三种mAb还保留了对最近循环的VOC XBB.1.5和BQ.1.1的效力，一种mAb还有效地中和SARS-CoV-1。这些mAb对Omicron VOC的效力大于除一种之外的所有已批准用于治疗应用的mAb。mAb靶向刺突糖蛋白上的不同表位，三个在受体结合结构域（RBD）中，一个在亚结构域1（SD 1）中RBD下游的不变区中。我们在单个氨基酸分辨率下定义的逃逸途径与深度突变扫描显示它们靶向糖蛋白的保守的、功能受限的区域，这表明逃逸可能产生适应性成本。总体而言，这些mAb在VOC范围内的宽度、表位特异性方面是独一无二的，并且包括一种针对SD 1中RBD之外的罕见表位的高效mAb。
SARS-CoV-2 infections can result in diverse clinical outcomes, including severe disease. Monoclonal antibodies (mAbs) have been used therapeutically to treat infection, but the emergence of variants has compromised their efficacy. Thus, identifying mAbs that are more durable in the face of SARS-CoV-2 evolution is a pressing need. Here, we describe four mAbs isolated from a Delta-breakthrough infection that can potently neutralize diverse variants, including multiple Omicron variants. In addition, one mAb shows broader activity against coronaviruses. The breadth of these mAbs is due to their focus on highly conserved regions of the viral protein antigen, including regions that are required for the virus to enter the cell. These properties make them promising candidates for therapeutic use. The antiviral benefit of antibodies can be compromised by viral escape especially for rapidly evolving viruses. Therefore, durable, effective antibodies must be both broad and potent to counter newly emerging, diverse strains. Discovery of such antibodies is critically important for SARS-CoV-2 as the global emergence of new variants of concern (VOC) has compromised the efficacy of therapeutic antibodies and vaccines. We describe a collection of broad and potent neutralizing monoclonal antibodies (mAbs) isolated from an individual who experienced a breakthrough infection with the Delta VOC. Four mAbs potently neutralize the Wuhan-Hu-1 vaccine strain, the Delta VOC, and also retain potency against the Omicron VOCs through BA.4/BA.5 in both pseudovirus-based and authentic virus assays. Three mAbs also retain potency to recently circulating VOCs XBB.1.5 and BQ.1.1 and one also potently neutralizes SARS-CoV-1. The potency of these mAbs was greater against Omicron VOCs than all but one of the mAbs that had been approved for therapeutic applications. The mAbs target distinct epitopes on the spike glycoprotein, three in the receptor-binding domain (RBD) and one in an invariant region downstream of the RBD in subdomain 1 (SD1). The escape pathways we defined at single amino acid resolution with deep mutational scanning show they target conserved, functionally constrained regions of the glycoprotein, suggesting escape could incur a fitness cost. Overall, these mAbs are unique in their breadth across VOCs, their epitope specificity, and include a highly potent mAb targeting a rare epitope outside of the RBD in SD1.
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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
两种抗体鸡尾酒中和中和的遗传和结构基础。
影响因子：
28.3
作者：
Dong J;Zost SJ;Greaney AJ;Starr TN;Dingens AS;Chen EC;Chen RE;Case JB;Sutton RE;Gilchuk P;Rodriguez J;Armstrong E;Gainza C;Nargi RS;Binshtein E;Xie X;Zhang X;Shi PY;Logue J;Weston S;McGrath ME;Frieman MB;Brady T;Tuffy KM;Bright H;Loo YM;McTamney PM;Esser MT;Carnahan RH;Diamond MS;Bloom JD;Crowe JE Jr
通讯作者：
Crowe JE Jr
DOI：
10.1056/nejmoa2119451
发表时间：
2022-04-21
期刊：
The New England journal of medicine
影响因子：
--
作者：
Andrews N;Stowe J;Kirsebom F;Toffa S;Rickeard T;Gallagher E;Gower C;Kall M;Groves N;O'Connell AM;Simons D;Blomquist PB;Zaidi A;Nash S;Iwani Binti Abdul Aziz N;Thelwall S;Dabrera G;Myers R;Amirthalingam G;Gharbia S;Barrett JC;Elson R;Ladhani SN;Ferguson N;Zambon M;Campbell CNJ;Brown K;Hopkins S;Chand M;Ramsay M;Lopez Bernal J
通讯作者：
Lopez Bernal J
影响因子：
5.4
作者：
Doepker, Laura E.;Simonich, Cassandra A.;Overbaugh, Julie M.
通讯作者：
Overbaugh, Julie M.
DOI：
10.1126/science.abq3773
发表时间：
2022-08-12
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
通讯作者：
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