Emergence of Multiple SARS-CoV-2 Antibody Escape Variants in an Immunocompromised Host Undergoing Convalescent Plasma Treatment.
Emergence of Multiple SARS-CoV-2 Antibody Escape Variants in an Immunocompromised Host Undergoing Convalescent Plasma Treatment.
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DOI：
10.1128/msphere.00480-21
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发表时间：
2021-08-25
期刊：
影响因子：
4.8
通讯作者：
Kreiswirth BN
中科院分区：
文献类型：
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作者：
Chen L;Zody MC;Di Germanio C;Martinelli R;Mediavilla JR;Cunningham MH;Composto K;Chow KF;Kordalewska M;Corvelo A;Oschwald DM;Fennessey S;Zetkulic M;Dar S;Kramer Y;Mathema B;Germer S;Stone M;Simmons G;Busch MP;Maniatis T;Perlin DS;Kreiswirth BN
严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）变异体（VOC），携带刺突蛋白N-末端结构域（NTD）或受体结合结构域（RBD）突变，表现出对恢复期血清、商业抗体混合物和疫苗中和的体外敏感性降低，并与再感染有关。这些突变的积累可能是由于免疫功能低下的宿主中的长期感染引起的宿主内病毒进化的结果。在这项研究中，我们记录了SARS-CoV-2的微进化，从一个免疫抑制的患者接受类固醇和恢复期血浆治疗的连续气管吸出物中回收，并确定了多个NTD和RBD突变的出现。在序列水平上比较了第一个拭子（第0天）和三个气管抽吸物（第7、21和27天）的SARS-CoV-2基因组。我们从第二份气管吸出物样本（第21天）中鉴定出在NTD或RBD区域具有5种不同S蛋白突变（141至144缺失、243至244缺失、E484 K、Q493 K和Q493 R）的混合病毒群体，并且在第27天以S蛋白141至144 LGVY缺失和E484 K突变为主。抗各种S蛋白慢病毒假病毒突变体的中和抗体以及抗SARS-CoV-2总IG和IgG呈“U”形动态，支持中和抗体的内源性发展。患者的免疫状态受损，抗排斥方案，恢复期血浆治疗，中和抗体的发展可能导致独特的选择性压力的intrahost基因组进化，这一观察结果支持的假设，挥发性有机化合物可以独立出现和免疫功能低下的患者恢复期血浆治疗免疫逃逸突变体的潜在滋生地。重要性COVID-19大流行一年多来，全球多个地理区域出现了不同的严重急性呼吸系统综合征冠状病毒2（SARS-CoV-2）谱系。关注的SARS-CoV-2变体（VOC），即，在刺突蛋白N-末端结构域（NTD）或受体结合结构域（RBD）区域中携带突变和/或缺失的B.1.1.7（α）、B.1.351（β）、P.1（γ）和B.1.617.2（δ）显示出传播性和疾病严重程度增加以及可能降低疫苗效力的证据。在这项研究中，我们报告了五个不同的NTD和RBD突变出现在一个不常见的SARS-CoV-2 B.1.369谱系免疫抑制患者接受类固醇和恢复期血浆治疗。观察结果强调，VOC可以在接受抗SARS-CoV-2治疗的免疫功能低下人群中独立出现，需要加强措施以减少传播。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs), harboring spike protein N-terminal domain (NTD) or receptor-binding domain (RBD) mutations, exhibit reduced in vitro susceptibility to convalescent-phase serum, commercial antibody cocktails, and vaccine neutralization and have been associated with reinfections. The accumulation of these mutations could be the consequence of intrahost viral evolution due to prolonged infection in immunocompromised hosts. In this study, we document the microevolution of SARS-CoV-2 recovered from sequential tracheal aspirates from an immunosuppressed patient on steroids and convalescent plasma therapy and identify the emergence of multiple NTD and RBD mutations. SARS-CoV-2 genomes from the first swab (day 0) and from three tracheal aspirates (days 7, 21, and 27) were compared at the sequence level. We identified a mixed viral population with five different S protein mutations (141 to 144 deletion, 243 to 244 deletion, E484K, Q493K, and Q493R) at the NTD or RBD region from the second tracheal aspirate sample (day 21) and a predominance of the S protein 141 to 144 LGVY deletion and E484K mutant on day 27. The neutralizing antibodies against various S protein lentiviral pseudovirus mutants, as well as the anti-SARS-CoV-2 total Ig and IgG, showed “U” shape dynamics, in support of the endogenous development of neutralizing antibodies. The patient’s compromised immune status, the antirejection regiment, convalescent plasma treatment, and the development of neutralizing antibodies may have resulted in unique selective pressures on the intrahost genomic evolution, and this observation supports the hypotheses that VOCs can independently arise and that immunocompromised patients on convalescent plasma therapy are potential breeding grounds for immune escape mutants. IMPORTANCE Over a year of the COVID-19 pandemic, distinct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages have arisen in multiple geographic areas around the world. SARS-CoV-2 variants of concern (VOCs), i.e., B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), and B.1.617.2 (delta), harboring mutations and/or deletions in spike protein N-terminal domain (NTD) or receptor-binding domain (RBD) regions showed evidence of increased transmissibility and disease severity and possible reduced vaccine efficacy. In this study, we report the emergence of five different NTD and RBD mutations in an uncommon SARS-CoV-2 B.1.369 lineage from an immunosuppressed patient undergoing steroid and convalescent plasma therapy. The observation highlighted that VOCs can independently arise in immunocompromised populations undergoing anti-SARS-CoV-2 therapy, and enhanced measures will be required to reduce the transmission.