Emergence of the E484K mutation in SARS-COV-2-infected immunocompromised patients treated with bamlanivimab in Germany.
Emergence of the E484K mutation in SARS-COV-2-infected immunocompromised patients treated with bamlanivimab in Germany.
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DOI：
10.1016/j.lanepe.2021.100164
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Luedde T
中科院分区：
文献类型：
--
作者：
Jensen B;Luebke N;Feldt T;Keitel V;Brandenburger T;Kindgen-Milles D;Lutterbeck M;Freise NF;Schoeler D;Haas R;Dilthey A;Adams O;Walker A;Timm J;Luedde T
单克隆抗体（Monoclonal antibodies，mAb）作为一种新型的抗SARS病毒的治疗手段，已被广泛应用于临床。目前，关于其在临床试验中代表性不足的患者人群（例如免疫功能低下患者）中的临床效果的经验很少。此外，目前还不清楚单克隆抗体治疗SARS-CoV-2在多大程度上可以触发免疫逃逸病毒变异体的选择。在确定了免疫功能低下的患者在接受bamlanivimab治疗后出现病毒反弹后，我们通过全基因组测序对SARS-CoV-2分离株进行了鉴定。在bamlanivimab给药前后连续进行病毒载量测量和序列分析。在病毒载量最初降低后，接受bamlanivimab治疗的6名免疫功能低下患者中有5名未实现病毒清除。相反，病毒复制在接下来的一到两周内再次增加。在这5名患者中，E484 K置换-已知可赋予免疫逃逸-在病毒反弹时检测到，但在bamlanivimab治疗前未检测到。在免疫功能低下的患者中使用bamlanivimab治疗SARS-CoV-2导致在相当大比例的病例中快速发展免疫逃逸变体。鉴于E484 K突变会阻碍自然免疫力、疫苗接种的有效性以及基于抗体的治疗，这些发现不仅对个体治疗决策具有重要意义，而且可能对一般预防和治疗策略构成风险。所有作者都是由政府、联邦州或其他公共资助机构雇用的，所有费用都由这些机构承担。
Monoclonal antibodies (mAb) have been introduced as a promising new therapeutic approach against SARS-CoV-2. At present, there is little experience regarding their clinical effects in patient populations underrepresented in clinical trials, e.g. immunocompromised patients. Additionally, it is not well known to what extent SARS-CoV-2 treatment with monoclonal antibodies could trigger the selection of immune escape viral variants. After identifying immunocompromised patients with viral rebound under treatment with bamlanivimab, we characterized the SARS-CoV-2-isolates by whole genome sequencing. Viral load measurements and sequence analysis were performed consecutively before and after bamlanivimab administration. After initial decrease of viral load, viral clearance was not achieved in five of six immunocompromised patients treated with bamlanivimab. Instead, viral replication increased again over the course of the following one to two weeks. In these five patients, the E484K substitution – known to confer immune escape – was detected at the time of viral rebound but not before bamlanivimab treatment. Treatment of SARS-CoV-2 with bamlanivimab in immunocompromised patients results in the rapid development of immune escape variants in a significant proportion of cases. Given that the E484K mutation can hamper natural immunity, the effectiveness of vaccination as well as antibody-based therapies, these findings may have important implications not only for individual treatment decisions but may also pose a risk to general prevention and treatment strategies. All authors are employed and all expenses covered by governmental, federal state, or other publicly funded institutions.
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DOI：
10.1126/science.aaf0972
发表时间：
2016-05-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Schoofs T;Klein F;Braunschweig M;Kreider EF;Feldmann A;Nogueira L;Oliveira T;Lorenzi JC;Parrish EH;Learn GH;West AP Jr;Bjorkman PJ;Schlesinger SJ;Seaman MS;Czartoski J;McElrath MJ;Pfeifer N;Hahn BH;Caskey M;Nussenzweig MC
通讯作者：
Nussenzweig MC
影响因子：
64.8
作者：
Kemp SA;Collier DA;Datir RP;Ferreira IATM;Gayed S;Jahun A;Hosmillo M;Rees-Spear C;Mlcochova P;Lumb IU;Roberts DJ;Chandra A;Temperton N;CITIID-NIHR BioResource COVID-19 Collaboration;COVID-19 Genomics UK (COG-UK) Consortium;Sharrocks K;Blane E;Modis Y;Leigh KE;Briggs JAG;van Gils MJ;Smith KGC;Bradley JR;Smith C;Doffinger R;Ceron-Gutierrez L;Barcenas-Morales G;Pollock DD;Goldstein RA;Smielewska A;Skittrall JP;Gouliouris T;Goodfellow IG;Gkrania-Klotsas E;Illingworth CJR;McCoy LE;Gupta RK
通讯作者：
Gupta RK
影响因子：
8.7
作者：
Margolis DM;Koup RA;Ferrari G
通讯作者：
Ferrari G
影响因子：
82.9
作者：
Wibmer, Constantinos Kurt;Ayres, Frances;Moore, Penny L.
通讯作者：
Moore, Penny L.
影响因子：
120.7
作者：
Gottlieb, Robert L.;Nirula, Ajay;Skovronsky, Daniel M.
通讯作者：
Skovronsky, Daniel M.