SARS-CoV-2 Omicron BA.5: Evolving tropism and evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern.
SARS-CoV-2 Omicron BA.5: Evolving tropism and evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern.
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DOI：
10.1016/j.ebiom.2022.104270
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发表时间：
2022-10
期刊：
影响因子：
11.1
通讯作者：
Turville, Stuart G.
中科院分区：
文献类型：
--
作者：
Aggarwal, Anupriya;Akerman, Anouschka;Milogiannakis, Vanessa;Silva, Mariana Ruiz;Walker, Gregory;Stella, Alberto Ospina;Kindinger, Andrea;Angelovich, Thomas;Waring, Emily;Amatayakul-Chantler, Supavadee;Roth, Nathan;Manni, Sandro;Hauser, Thomas;Barnes, Thomas;Condylios, Anna;Yeang, Malinna;Wong, Maureen;Jean, Tyra;Foster, Charles S. P.;Christ, Daniel;Hoppe, Alexandra Carey;Munier, Mee Ling;Darley, David;Churchill, Melissa;Stark, Damien J.;Matthews, Gail;Rawlinson, William D.;Kelleher, Anthony D.;Turville, Stuart G.
自2020年1月以来，已记录到严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）的遗传上不同的病毒变体。全球疫苗计划的引入有助于降低COVID-19的住院率和死亡率，尤其是在发达国家。2021年底，Omicron BA.1出现，与其他令人担忧的变体相比，其遗传差异和临床影响发生了重大改变。在2022年初主导全球传播后不久，BA.1被遗传上不同的Omicron谱系BA.2所取代。BA.2的一个亚系，命名为BA.5，目前具有优于BA.2和其他BA.2亚系的生长优势。在这里，我们研究了Omicron BA.1，BA.2和BA.5和前Omicron变体的中和作用，使用一系列疫苗和恢复期血清和治疗性单克隆抗体，使用活病毒中和试验。使用初级鼻咽拭子，我们还测试了BA.5与前Omicron和Omicron病毒谱系相比在其使用ACE 2-TMPRSS 2途径的能力方面的相对适合性。使用进化枝A.2.2、Beta、Delta、BA.1、BA.2和BA.5的低传代临床分离株，我们使用从数千名血浆供体合并的浓缩人IgG和许可的单克隆抗体疗法，在接种疫苗和恢复期队列中测定了体外体液中和。然后，我们在存在和不存在TMPRSS 2抑制剂萘莫司他的情况下，在基因工程化ACE 2/TMPRSS 2细胞系中测定了原代鼻咽样品和扩增的低传代分离株中的感染性与颗粒比率。对3剂BNT 162 b2疫苗的峰值应答与Omicron谱系BA.1、BA.2和BA.5的中和降低9倍相关。来自恢复期和接种供体的浓缩合并人IgG和BA.1突破性感染的BNT 162 b2疫苗接种与更大的中和宽度相关，尽管在所有Omicron谱系中效价仍降低7倍。临床级抗体的检测显示，对于BA，使用Evushold时降低14.3倍，使用Sotrovimab时降低16.8倍。虽然BA.1和BA.2的感染性在ACE 2/TMPRSS 2进入中减弱，但观察到BA.5与2020年初的循环进化枝相当，并且对TMPRSS 2抑制剂萘莫司他具有更高的敏感性。观察结果支持所有Omicron变体在一系列疫苗接种和/或恢复期应答中显著逃避中和抗体。治疗性单克隆抗体的效力也降低，并且在Omicron谱系中存在差异。BA.5与其他Omicron亚变体的关键区别是回归性恢复到使用众所周知的ACE 2-TMPRSS 2途径，前Omicron谱系有效地利用该途径。监测这些变化是否影响传播和/或疾病严重程度将是全球持续跟踪和管理Omicron波的关键。这项工作主要由澳大利亚医学基金会研究资助MRF 2005760（ST，GM和WDR），MRF 2001684（ADK和ST）和医学研究未来基金抗病毒发展呼吁资助（WDR），医学研究未来基金COVID-19资助（MRF 2001684，ADK和SGT）和新南威尔士州卫生COVID-19研究赠款第2轮（SGT）支持。
Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. The introduction of global vaccine programs has contributed to lower COVID-19 hospitalisation and mortality rates, particularly in developed countries. In late 2021, Omicron BA.1 emerged, with substantially altered genetic differences and clinical effects from other variants of concern. Shortly after dominating global spread in early 2022, BA.1 was supplanted by the genetically distinct Omicron lineage BA.2. A sub-lineage of BA.2, designated BA.5, presently has an outgrowth advantage over BA.2 and other BA.2 sub-lineages. Here we study the neutralisation of Omicron BA.1, BA.2 and BA.5 and pre-Omicron variants using a range of vaccine and convalescent sera and therapeutic monoclonal antibodies using a live virus neutralisation assay. Using primary nasopharyngeal swabs, we also tested the relative fitness of BA.5 compared to pre-Omicron and Omicron viral lineages in their ability to use the ACE2-TMPRSS2 pathway. Using low passage clinical isolates of Clade A.2.2, Beta, Delta, BA.1, BA.2 and BA.5, we determined humoral neutralisation in vitro in vaccinated and convalescent cohorts, using concentrated human IgG pooled from thousands of plasma donors, and licensed monoclonal antibody therapies. We then determined infectivity to particle ratios in primary nasopharyngeal samples and expanded low passage isolates in a genetically engineered ACE2/TMPRSS2 cell line in the presence and absence of the TMPRSS2 inhibitor Nafamostat. Peak responses to 3 doses of BNT162b2 vaccine were associated with a 9-fold reduction in neutralisation for Omicron lineages BA.1, BA.2 and BA.5. Concentrated pooled human IgG from convalescent and vaccinated donors and BNT162b2 vaccination with BA.1 breakthrough infections were associated with greater breadth of neutralisation, although the potency was still reduced 7-fold across all Omicron lineages. Testing of clinical grade antibodies revealed a 14.3-fold reduction using Evusheld and 16.8-fold reduction using Sotrovimab for the BA.5. Whilst the infectivity of BA.1 and BA.2 was attenuated in ACE2/TMPRSS2 entry, BA.5 was observed to be equivalent to that of an early 2020 circulating clade and had greater sensitivity to the TMPRSS2 inhibitor Nafamostat. Observations support all Omicron variants to significantly escape neutralising antibodies across a range of vaccination and/or convalescent responses. Potency of therapeutic monoclonal antibodies is also reduced and differs across Omicron lineages. The key difference of BA.5 from other Omicron sub-variants is the reversion in tropism back to using the well-known ACE2-TMPRSS2 pathway, utilised efficiently by pre-Omicron lineages. Monitoring if these changes influence transmission and/or disease severity will be key for ongoing tracking and management of Omicron waves globally. This work was primarily supported by Australian Medical Foundation research grants MRF2005760 (ST, GM & WDR), MRF2001684 (ADK and ST) and Medical Research Future Fund Antiviral Development Call grant (WDR), Medical Research Future Fund COVID-19 grant (MRFF2001684, ADK & SGT) and the New South Wales Health COVID-19 Research Grants Round 2 (SGT).
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DOI：
10.1126/science.abq0203
发表时间：
2022-08-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
通讯作者：
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影响因子：
1.7
作者：
Stucki, M.;Boschetti, N.;Kempf, C.
通讯作者：
Kempf, C.
影响因子：
64.8
作者：
Mlcochova P;Kemp SA;Dhar MS;Papa G;Meng B;Ferreira IATM;Datir R;Collier DA;Albecka A;Singh S;Pandey R;Brown J;Zhou J;Goonawardane N;Mishra S;Whittaker C;Mellan T;Marwal R;Datta M;Sengupta S;Ponnusamy K;Radhakrishnan VS;Abdullahi A;Charles O;Chattopadhyay P;Devi P;Caputo D;Peacock T;Wattal C;Goel N;Satwik A;Vaishya R;Agarwal M;Indian SARS-CoV-2 Genomics Consortium (INSACOG);Genotype to Phenotype Japan (G2P-Japan) Consortium;CITIID-NIHR BioResource COVID-19 Collaboration;Mavousian A;Lee JH;Bassi J;Silacci-Fegni C;Saliba C;Pinto D;Irie T;Yoshida I;Hamilton WL;Sato K;Bhatt S;Flaxman S;James LC;Corti D;Piccoli L;Barclay WS;Rakshit P;Agrawal A;Gupta RK
通讯作者：
Gupta RK
影响因子：
28.3
作者：
通讯作者：
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SARS-CoV-2 Alpha、Beta 和 Delta 变体表现出增强的刺突介导的合胞体形成。
DOI：
10.15252/embj.2021108944
发表时间：
2021-12-15
期刊：
The EMBO journal
影响因子：
--
作者：
Rajah MM;Hubert M;Bishop E;Saunders N;Robinot R;Grzelak L;Planas D;Dufloo J;Gellenoncourt S;Bongers A;Zivaljic M;Planchais C;Guivel-Benhassine F;Porrot F;Mouquet H;Chakrabarti LA;Buchrieser J;Schwartz O
通讯作者：
Schwartz O