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[结构分类] 新冠病毒变体的分类和定义SARS-CoV-2 Variant Classifications

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发表于 2021-7-9 12:33:52 | 显示全部楼层 |阅读模式
Viruses constantly change through mutation, and new variants of a virus are expected to occur. Sometimes new variants emerge and disappear. COVID-19疫情自2019年底被发现以来,造成大量人群的感染。伴随着感染人数的增加和疫情的持续,SARS-CoV-2不断进化和变异,产生了大量的病毒变异株,其中一些变异株的传播能力和致病性明显提高,还有一些毒株出现抗原逃逸现象,这些变异株引起了公共卫生部门和民众的关注。Other times, new variants persist. Multiple variants of the virus that causes COVID-19 have been documented in the United States and globally during this pandemic. Genetic variants of SARS-CoV-2 have been emerging and circulating around the world throughout the COVID-19 pandemic. A US government SARS-CoV-2 Interagency Group (SIG) interagency group developed a Variant Classification scheme that defines three classes of SARS-CoV-2 variants:


    The B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and P.1 (Gamma), variants circulating in the United States are classified as variants of concern.

  • To date, no variants of high consequence have been identified in the United States.
  • Laboratory studies suggest specific monoclonal antibody treatments may be less effective for treating cases of COVID-19 caused by variants with certain substitutions or combinations of substitutions in the spike protein.

    • L452R is present in B.1.526 (Iota), B.1.427 (Epsilon), and B.1.429 (Epsilon) lineages, as well as the B.1.617 (Kappa, Delta) lineages and sub-lineages.
    • E484K is present in B.1.525 (Eta), P.2 (Zeta), P.1 (Gamma), and B.1.351 (Beta), but only some strains of B.1.526 (Iota) and B.1.1.7 (Alpha).
    • The combination of K417N, E484K, and N501Y substitutions is present in B.1.351 (Beta).
    • The combination of K417T, E484K, and N501Y substitutions is present in P.1 (Gamma).

Viruses constantly change through mutation. A variant has one or more mutations that differentiate it from other variants in circulation. As expected, multiple variants of SARS-CoV-2 have been documented in the United States and globally throughout this pandemic. To inform local outbreak investigations and understand national trends, scientists compare genetic differences between viruses to identify variants and how they are related to each other.
Variant classifications
The US Department of Health and Human Services (HHS) established a SARS-CoV-2 Interagency Group (SIG) to improve coordination among the Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), Food and Drug Administration (FDA), Biomedical Advanced Research and Development Authority (BARDA), and Department of Defense (DoD). This interagency group is focused on the rapid characterization of emerging variants and actively monitors their potential impact on critical SARS-CoV-2 countermeasures, including vaccines, therapeutics, and diagnostics.
Notes: Each classification of variant includes the possible attributes of lower classes (i.e., VOC includes the possible attributes of VOI); variant status might escalate or deescalate based on emerging scientific evidence. This page will be updated as needed to show the variants that belong to each class. The World Health Organizationexternal icon (WHO) also classifies variant viruses as Variants of Concern and Variants of Interest; US classifications may differ from those of WHO because the importance of variants may differ by location. To assist with public discussions of variants, WHO proposed using labels consisting of the Greek Alphabet, i.e., Alpha, Beta, Gamma, as a practical way to discuss variants by non-scientific audiences. The labels assigned to each variant are provided in the tables below.
See Variant Proportions in the U.S.  2019-nCoV 新型冠状病毒变异株和突变序列
Variant of Interest
A variant with specific genetic markers that have been associated with changes to receptor binding, reduced neutralization by antibodies generated against previous infection or vaccination, reduced efficacy of treatments, potential diagnostic impact, or predicted increase in transmissibility or disease severity.
Possible attributes of a variant of interest:
  • Specific genetic markers that are predicted to affect transmission, diagnostics, therapeutics, or immune escape.
  • Evidence that it is the cause of an increased proportion of cases or unique outbreak clusters.
  • Limited prevalence or expansion in the US or in other countries.

A variant of interest might require one or more appropriate public health actions, including enhanced sequence surveillance, enhanced laboratory characterization, or epidemiological investigations to assess how easily the virus spreads to others, the severity of disease, the efficacy of therapeutics and whether currently authorized vaccines offer protection.
Current variants of interest in the United States that are being monitored and characterized are listed below. This will be updated when a new variant of interest is identified.
Selected Characteristics of SARS-CoV-2 Variants of Interest
Spike Protein Substitutions: L452R, D614G
Name (Nextstrainexternal icon)b: 20C/S:452R
WHO Label: Epsilon
First Identified: United States-(California) 美国加州变异株
Attributes:
  • ~20% increased transmission21
  • Modest decrease in susceptibility to the combination of bamlanivimab and etesevimab; however, the clinical implications of this decrease are not known.7 Alternative monoclonal antibody treatments are available.14
  • Reduced neutralization by convalescent and post-vaccination sera21
  • Deescalated from a VOC on June 29, 2021, due to the significant decrease in the proportion of B.1.427 lineage viruses circulating nationally and available data indicating that vaccines and treatments are effective against this variant.

Spike Protein Substitutions: S13I, W152C, L452R, D614G
Name (Nextstrainexternal icon)b: 20C/S:452R
WHO Label: Epsilon
First Identified: United States-(California) 美国加州变异株
Attributes:
  • ~20% increased transmission21
  • Reduced susceptibility to the combination of bamlanivimab and etesevimab; however, the clinical implications of this decrease are not known.7 Alternative monoclonal antibody treatments are available.14
  • Reduced neutralization by convalescent and post-vaccination sera21.
  • Deescalated from a VOC on June 29, 2021, due to the significant decrease in the proportion of B.1.429 lineage viruses circulating nationally and available data indicating that vaccines and treatments are effective against this variant.

Spike Protein Substitutions: A67V, 69del, 70del, 144del, E484K, D614G, Q677H, F888L
Name (Nextstrainexternal icon)b: 20A/S:484K
WHO Label: Eta
First Identified: United Kingdom/Nigeria – December 2020  尼日利亚变异株
Attributes:
  • Potential reduction in neutralization by some Emergency Use Authorization (EUA) monoclonal antibody treatments 7, 14
  • Potential reduction in neutralization by convalescent and post-vaccination sera22


Spike Protein Substitutions: L5F, (D80G*), T95I, (Y144-*), (F157S*), D253G, (L452R*), (S477N*), E484K, D614G, A701V, (T859N*), (D950H*), (Q957R*)
Name (Nextstrainexternal icon)b: 20C/S:484K
WHO Label: Iota
First Identified: United States (New York) – November 2020 美国纽约变异株
BEI Reference Isolatec: NR-55359external icon
Attributes:
  • Reduced susceptibility to the combination of bamlanivimab and etesevimab monoclonal antibody treatment; however, the clinical implications of this are not known.7 Alternative monoclonal antibody treatments are available.14
  • Reduced neutralization by convalescent and post-vaccination sera22, 24
  • B.1.526.1 sublineage has been consolidated with this parent lineage


Spike Protein Substitutions: (T95I), G142D, E154K, L452R, E484Q, D614G, P681R, Q1071H
Name (Nextstrainexternal icon)b: 20A/S:154K
WHO Label: Kappa
First Identified: India – December 2020 印度变异株
Attributes:
  • Potential reduction in neutralization by some EUA monoclonal antibody treatments7, 14
  • Potential reduction in neutralization by post-vaccination sera26


Spike Protein Substitutions: T19R, G142D, L452R, E484Q, D614G, P681R, D950N
First Identified: India – October 2020 印度变异株
Attributes:
  • Potential reduction in neutralization by some EUA monoclonal antibody treatments7, 14
  • Potential reduction in neutralization by post-vaccination sera26


Spike Protein Substitutions: E484K, (F565L*), D614G, V1176F
WHO Label: Zeta
First Identified: Brazil – April 2020 巴西变异株
Attributes:
  • Potential reduction in neutralization by some EUA monoclonal antibody treatments7, 14
  • Reduced neutralization by post-vaccination sera22, 23


Variant of Concern
A variant for which there is evidence of an increase in transmissibility, more severe disease (e.g., increased hospitalizations or deaths), significant reduction in neutralization by antibodies generated during previous infection or vaccination, reduced effectiveness of treatments or vaccines, or diagnostic detection failures.
Possible attributes of a variant of concern:
In addition to the possible attributes of a variant of interest
  • Evidence of impact on diagnostics, treatments, or vaccines

    • Widespread interference with diagnostic test targets
    • Evidence of substantially decreased susceptibility to one or more class of therapies
    • Evidence of significant decreased neutralization by antibodies generated during previous infection or vaccination
    • Evidence of reduced vaccine-induced protection from severe disease

  • Evidence of increased transmissibility
  • Evidence of increased disease severity

Variants of concern might require one or more appropriate public health actions, such as notification to WHO under the International Health Regulations, reporting to CDC, local or regional efforts to control spread, increased testing, or research to determine the effectiveness of vaccines and treatments against the variant. Based on the characteristics of the variant, additional considerations may include the development of new diagnostics or the modification of vaccines or treatments.
Current variants of concern in the United States that are being closely monitored and characterized by federal agencies are included in the below. This table will be updated when a new variant of concern is identified.
Selected Characteristics of SARS-CoV-2 Variants of Concern
Spike Protein Substitutions: 69del, 70del, 144del, (E484K*), (S494P*), N501Y, A570D, D614G, P681H, T716I, S982A, D1118H (K1191N*)
Name (Nextstrainexternal icon)b: 20I/501Y.V1
WHO Label: Alpha
First Identified: United Kingdom 英国变异株 N501Y.V1
BEI Reference Isolatec: NR-54000external icon
Attributes:
  • ~50% increased transmission5
  • Potential increased severity based on hospitalizations and case fatality rates6
  • No impact on susceptibility to EUA monoclonal antibody treatments7,14
  • Minimal impact on neutralization by convalescent and post-vaccination sera8-13,19


Spike Protein Substitutions: D80A, D215G, 241del, 242del, 243del, K417N, E484K, N501Y, D614G, A701V
Name (Nextstrainexternal icon)b: 20H/501.V2
WHO Label: Beta
First Identified: South Africa 南非变异株  N501Y.V2
BEI Reference Isolatec: NR-55282external icon
Attributes:
  • ~50% increased transmission16
  • Significantly reduced susceptibility to the combination of bamlanivimab and etesevimab monoclonal antibody treatment,7 but other EUA monoclonal antibody treatments are available 14
  • Reduced neutralization by convalescent and post-vaccination sera8,12,18,19,20


Spike Protein Substitutions: T19R, (V70F*), T95I, G142D, E156-, F157-, R158G, (A222V*), (W258L*), (K417N*), L452R, T478K, D614G, P681R, D950N
Name (Nextstrainexternal icon)b: 20A/S:478K
WHO Label: Delta
First Identified: India   印度德尔塔变异株
Attributes:
  • Increased transmissibility 29
  • Potential reduction in neutralization by some EUA monoclonal antibody treatments 7, 14
  • Potential reduction in neutralization by post-vaccination sera 21
  • AY.1 and AY.2 are currently aggregated with B.1.617.2. As data are available, CDC will continue to evaluate the independent classification of AY.1 and AY.2.


Spike Protein Substitutions: L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G, H655Y, T1027I
Name (Nextstrainexternal icon)b: 20J/501Y.V3
WHO Label: Gamma
First Identified: Japan/Brazil  巴西变异株 N501Y.V3
BEI Reference Isolatec: NR-54982external icon
Attributes:
  • Significantly reduced susceptibility to the combination of bamlanivimab and etesevimab monoclonal antibody treatment,7 but other EUA monoclonal antibody treatments are available 14
  • Reduced neutralization by convalescent and post-vaccination sera15


Variant of High Consequence
A variant of high consequence has clear evidence that prevention measures or medical countermeasures (MCMs) have significantly reduced effectiveness relative to previously circulating variants.
Possible attributes of a variant of high consequence:
In addition to the possible attributes of a variant of concern
  • Impact on Medical Countermeasures (MCM)

    • Demonstrated failure of diagnostics
    • Evidence to suggest a significantly reduction in vaccine effectiveness, a disproportionately high number of vaccine breakthrough cases, or very low vaccine-induced protection against severe disease
    • Significantly reduced susceptibility to multiple Emergency Use Authorization (EUA) or approved therapeutics
    • More severe clinical disease and increased hospitalizations

A variant of high consequence would require notification to WHO under the International Health Regulations, reporting to CDC, an announcement of strategies to prevent or contain transmission, and recommendations to update treatments and vaccines.
Currently, there are no SARS-CoV-2 variants that rise to the level of high consequence.

Treatment considerations for healthcare providers
Substitutions of Concern for SARS-CoV-2 Monoclonal Antibody Therapies
In the United States, there are three anti-SARS-CoV-2 monoclonal antibody treatments with FDA Emergency Use Authorization (EUA) for the treatment of COVID-19: bamlanivimab plus etesevimabexternal icon, casirivimab plus imdevimab,external icon, and sotrovimabexternal icon.
CDC’s national genomic surveillance program identifies new and emerging SARS-CoV-2 variants to determine implications for COVID-19 diagnostics, treatments, or vaccines authorized for use in the United States. Sequences with similar genetic changes are grouped into lineages, and multiple lineages can have the same substitutions. For example, the E484K substitution is found in lineages B.1.351, P.1, B.1.526, and many others. Genomic surveillance efforts provide the capability to detect viruses that have reduced susceptibility to treatments more quickly.
In laboratory studies, SARS-CoV-2 variants that contain certain substitutions in the spike protein cause a marked reduction in susceptibility to bamlanivimab and may have reduced sensitivity to etesevimab and casirivimab. The L452R substitution found in the B.1.427 and B.1.429 lineages has been shown to cause a significant reduction in susceptibility to bamlanivimab and a modest decrease in susceptibility to the combination of bamlanivimab and etesevimab, although the clinical implications of this modest decrease are not known. 7 The E484K substitution found in the B.1.351, P.1, and B.1.526 lineages also results in a marked reduction in susceptibility to bamlanivimab, as well as the combination of bamlanivimab and etesevimab.7  Laboratory studies also suggest that the K417N and K417T substitutions, which are present in the B.1.351 and P.1 variants, respectively, along with the E484K mutation, reduces virus susceptibility to casirivimab, although the combination of casirivimab and imdevimab appears to retain activity.14 There is no reported reduction in susceptibility of variants to sotrovimab.28
The data below shows the national and regional unweighted proportions of SARS-CoV-2 that contain the L452R or E484K substitution, individually, as well as the unweighted proportions of SARS-CoV-2 that contain the combination of K417N, E484K, and N501Y substitutions or the combination of K417T, E484K, and N501Y substitutions. As new data become available, additional substitutions may be added below.


另外可以参考英国Public Health England定期发布的: Technical briefing documents on novel SARS-CoV-2 variants:

PANGO Lineages网站:



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 楼主| 发表于 2021-7-10 21:03:59 | 显示全部楼层
新冠变异毒株中的“四大天王”
原创 左脑 [url=]病毒学界[/url]
新冠疫情的全球大流行对全球经济增长,文化交流以及世界人民的日常生活造成了巨大损失和影响。截至目前,虽然全球疫情的发展得到有效防控。但是,随着新冠病毒的变异,一些国家出现了传播更加迅速的变异毒株。其中分别发生英国、南非、巴西、印度等的新冠变种病毒可谓是变异毒株中的“四大天王”。

  • Alpha 这种变体于 2020 年 9 月在英格兰出现,并导致冬季病例激增,使英国在 1 月重新进入封锁状态。其他国家紧随其后,特别是在欧洲。据世界卫生组织称,它于 4 月初成为美国的主要毒株,截至 5 月 25 日,至少有 149 个国家报告了这种毒株。
  • Beta 这个于 2020 年 8 月出现在南非,导致 Covid-19 病例卷土重来,席卷了南部非洲。截至 5 月 25 日,至少有 102 个国家/地区报告了这种情况。
  • Gamma 这种变异于 2020 年 12 月首次在亚马逊城市马瑙斯发现,导致病例激增,使巴西的卫生系统紧张并导致氧气短缺。截至 5 月 25 日,至少有 59 个国家/地区报告了这种情况。
  • Delta  2020 年 10 月在印度首次发现,截至 5 月下旬,至少在 54 个国家/地区发现了这种病毒。英国紧急情况科学咨询小组 5 月 13 日表示,它的传播率可能比 alpha 变体高 50%。(数据来源:WHO)


新型冠状病毒(2019-nCoV)属于β属的冠状病毒,具有囊膜的单股正链RNA病毒,颗粒呈圆形或椭圆形,直径60-140nm。具有5个必需基因,分别编码翻译核蛋白(N)、病毒包膜(E)、基质蛋白(M)和刺突蛋白(S)4种结构蛋白以及RNA依赖性的RNA聚合酶(RdRp)。核蛋白(N)包裹RNA基因组构成稳定的核衣壳,核衣壳外面围绕着一层病毒包膜(E)起着保护作用,在病毒包膜里有基质蛋白(M)和刺突蛋白(S)等蛋白。其中新冠病毒利用表面的刺突蛋白结合细胞受体,进而入侵细胞。刺突蛋白也是免疫系统识别病毒、以抗体中和病毒的重要结构。这四种新冠病毒变异株正是因为刺突蛋白(S)的一些关键位点发生突变,从而导致了变异毒株在与细胞受体或者与中和抗体的亲和力发生了明显变化。进一步导致这四种突变株成为当前流行的主要毒株。Alpha与Beta 突变体S蛋白的主要特点:哈佛医学院和波士顿儿童医院陈冰教授带领的团队于近期在顶尖学术期刊《科学》上连续发表研究结果显示,最早发现于alpha变种,其氨基酸的变化A570D和S982A有助于刺突蛋白三聚体让其受体结合域保持在一个与受体结合的位置,同时N501Y增加了受体结合域与ACE2受体结合的亲和力。研究人员推测,这些变化可能使alpha变种感染那些ACE2受体较少的细胞类型。 该团队的研究结果同时表明在 Beta 病毒中,S 蛋白在很大程度上保留了 G614 三聚体的结构,具有几乎相同的生化稳定性。RBD 中的 N501Y、K417N 和 E484K 没有引起重大的结构变化,但 K417 和 ACE2 Asp30 以及 Glu484 和 ACE2 Lys31 之间盐桥的丢失减轻了 N501Y 赋予的受体亲和力增加。K417N 和 E484K 可能导致靶向 RBD-2 表位的抗体失去结合和中和作用。NTD 中伴随的突变重塑了抗原表面并大大降低了针对 NTD-1 表位的中和抗体的效力。Beta 变种很可能是在一定程度的免疫压力下被选中的, Gamma突变体S蛋白的主要特点:2021年4月14日刊登在《科学》杂志上的一项研究,一国际研究人员小组对在巴西地区出现的Gamma(P.1)新型冠状病毒变异株进行相关研究分析。结果表明Gamma(P.1)病毒具有17个独特的氨基酸变化,其中10个存在于棘突蛋白中,包括三个最令人担忧的变体:N501Y,E484K,K417T。N501Y和K417T与人类血管紧张素转换酶2(ACE2)相互作用,而E484K位于人类ACE2接口外部的环路区域。值得注意的是,这三个变体也存在于备受关注的南非变异体(Beta, B.1.351)中,且N501Y存在于英国变异体(Alpha, B.1.1.7)中。因为它们似乎使该病毒变异体与人细胞更紧密地结合,在某些情况下,以帮助逃避抗体。
Delta 突变体S蛋白的主要特点:2021年6月17日刊登在bioRxiv平台上的一篇文章通过对delta(B.1.617) 变体的研究,确定了P681R 突变在delta(B.1.617)谱系中高度保守。通过深入的研究发现,由于P681R的突变促进了弗林蛋白酶介导的刺突蛋白的切割,加速了细胞-细胞融合。并且促使P681 突变增强病毒对中和抗体的逃逸能力。

根据新冠病毒突变株的“四大天王”的流行病学特点和病原学特点,我没可以看出疫情的局部流行将是全球疫情发展的常态。积极响应国际防疫政策,寻求广谱有效的新冠疫苗将成为我们对抗疫情的有力武器。
参考文献:
1. SARS-CoV-2 Infection of Airway Cells,Camille Ehre,N Engl J Med. 2020 Sep 3;383(10):969. doi: 10.1056/NEJMicm2023328.
2. Yongfei Cai et al., (2021) Structural basis forenhanced infectivity and immune evasion of SARS-CoV-2 variants. Science Doi:10.1126/science.abi9745
3. Jun Zhang et al., (2021) Structural impact onSARS-CoV-2 spike protein by D614G substitution. Science Doi: 10.1126/science.abf2303
4. Boopathi, Subramanian et al. Novel 2019 coronavirus structure, mechanism of action, antiviral drug promises and rule out against its treatment.” Journal of biomolecular structure & dynamics vol. 39,9 (2021): 3409-3418. doi:10.1080/07391102.2020.1758788
5. Nuno R. Faria et al. 2021, Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil, Science. DOI: 10.1126/science.abh2644
6. Akatsuki Saito et al. SARS-CoV-2 spike P681R mutation enhances and accelerates viral fusion.bioRxiv.2021. doi: https://doi.org/10.1101/2021.06.17.448820

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