High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape.
High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape.
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DOI：
10.1038/s41586-021-04005-0
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发表时间：
2021-12
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
在SARS-CoV-2恢复期和接种疫苗的个体中，多克隆抗体靶向的中和表位的数量和变异性是中和宽度和病毒逃逸的遗传屏障的关键决定因素。使用HIV-1假型和血浆选择实验与水泡性口炎病毒/SARS-CoV-2嵌合体，在这里，我们表明，多个中和表位，内部和外部的受体结合域，被人类多克隆抗体的非靶向。抗体靶标与天然SARS-CoV-2群体中丰富多样性的刺突序列一致。通过结合血浆选择的刺突置换，我们产生了合成的“多突变体”刺突蛋白假型，其抵抗多克隆抗体中和的程度与所关注的循环变体相似。通过将关注相关的和抗体选择的刺突置换的变体聚集成单个多突变刺突蛋白，我们表明SARS-CoV-2刺突蛋白中的20个天然突变足以产生假型，所述假型对恢复期个体或接受mRNA疫苗的受体产生的多克隆中和抗体具有接近完全的抗性。然而，来自已被感染并随后接受mRNA疫苗接种的个体的血浆中和了携带这种高度耐药的SARS-CoV-2多突变刺突或不同的Sarbecovirus刺突蛋白的假型。因此，针对SARS-CoV-2的最佳引发的人多克隆抗体应该对未来的SARS-CoV-2变异具有弹性，并且可以提供针对潜在的未来Sarbecovirus大流行的保护。
The number and variability of the neutralizing epitopes targeted by polyclonal antibodies in individuals who are SARS-CoV-2 convalescent and vaccinated are key determinants of neutralization breadth and the genetic barrier to viral escape, , –. Using HIV-1 pseudotypes and plasma selection experiments with vesicular stomatitis virus/SARS-CoV-2 chimaeras, here we show that multiple neutralizing epitopes, within and outside the receptor-binding domain, are variably targeted by human polyclonal antibodies. Antibody targets coincide with spike sequences that are enriched for diversity in natural SARS-CoV-2 populations. By combining plasma-selected spike substitutions, we generated synthetic ‘polymutant’ spike protein pseudotypes that resisted polyclonal antibody neutralization to a similar degree as circulating variants of concern. By aggregating variant of concern-associated and antibody-selected spike substitutions into a single polymutant spike protein, we show that 20 naturally occurring mutations in the SARS-CoV-2 spike protein are sufficient to generate pseudotypes with near-complete resistance to the polyclonal neutralizing antibodies generated by individuals who are convalescent or recipients who received an mRNA vaccine. However, plasma from individuals who had been infected and subsequently received mRNA vaccination neutralized pseudotypes bearing this highly resistant SARS-CoV-2 polymutant spike, or diverse sarbecovirus spike proteins. Thus, optimally elicited human polyclonal antibodies against SARS-CoV-2 should be resilient to substantial future SARS-CoV-2 variation and may confer protection against potential future sarbecovirus pandemics.
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影响因子：
15.3
作者：
Gaebler, Christian;Lorenzi, Julio C. C.;Nussenzweig, Michel C.
通讯作者：
Nussenzweig, Michel C.
影响因子：
15.3
作者：
Schmidt, Fabian;Weisblum, Yiska;Bieniasz, Paul D.
通讯作者：
Bieniasz, Paul D.
影响因子：
32.4
作者：
Muecksch F;Weisblum Y;Barnes CO;Schmidt F;Schaefer-Babajew D;Wang Z;C Lorenzi JC;Flyak AI;DeLaitsch AT;Huey-Tubman KE;Hou S;Schiffer CA;Gaebler C;Da Silva J;Poston D;Finkin S;Cho A;Cipolla M;Oliveira TY;Millard KG;Ramos V;Gazumyan A;Rutkowska M;Caskey M;Nussenzweig MC;Bjorkman PJ;Hatziioannou T;Bieniasz PD
通讯作者：
Bieniasz PD
影响因子：
64.8
作者：
Cho A;Muecksch F;Schaefer-Babajew D;Wang Z;Finkin S;Gaebler C;Ramos V;Cipolla M;Mendoza P;Agudelo M;Bednarski E;DaSilva J;Shimeliovich I;Dizon J;Daga M;Millard KG;Turroja M;Schmidt F;Zhang F;Tanfous TB;Jankovic M;Oliveria TY;Gazumyan A;Caskey M;Bieniasz PD;Hatziioannou T;Nussenzweig MC
通讯作者：
Nussenzweig MC
影响因子：
7.7
作者：
Weisblum, Yiska;Schmidt, Fabian;Bieniasz, Paul D
通讯作者：
Bieniasz, Paul D