SARS-CoV-2 Variant Classifications and Definitions

SARS-CoV-2 Variant Classifications and Definitions

Key Points:

  • Genetic variants of SARS-CoV-2 have been emerging and circulating around the world throughout the COVID-19 pandemic.
  • Viral mutations and variants in the United States are routinely monitored through sequence-based surveillance, laboratory studies, and epidemiological investigations.
  • A US government interagency group developed a Variant Classification scheme that defines three classes of SARS-CoV-2 variants:
  • The B.1.1.7, B.1.351, P.1, B.1.427, and B.1.429 variants circulating in the United States are classified as variants of concern

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 Department of Health and Human Services (HHS) established a SARS-CoV-2 Interagency Group (SIG) to improve coordination among the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), US 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.

In collaboration with the SIG, CDC established a classification scheme for variants of SARS-CoV-2. These classifications include definitions and attributes of the variants. Resulting public health actions are also described in the sections below.

Notes: Each class of variant includes the possible attributes of lower classes; variant status might escalate or deescalate based on scientific evidence. This page will be updated as needed to show the variants that belong to each class. The World Health Organization (WHO) also classifies variant viruses as Variants of Concern and Variants of Interest; US classifications may differ from those of WHO since the importance of variants may differ by location.

See Variant Proportions in the U.S.

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 demonstrates 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 risk of reinfection, and whether currently authorized vaccines offer protection.

Current variants of interest in the United States that are being monitored and characterized are listed in the table below. The table will be updated when a new variant of interest is identified.

Selected Characteristics of SARS-CoV-2 Variants of Concern
Name
(
Pango lineage) 
Substitution Name
(Nextstraina)
First Detected BEI Reference Isolateb

Predicted Attributes

B.1.526 Spike: (L5F*), T95I, D253G, (S477N*), (E484K*), D614G, (A701V*)
ORF1a: L3201P, T265I, Δ3675/3677
ORF1b: P314L, Q1011H
ORF3a: P42L, Q57H
ORF8: T11I
5’UTR: R81C
20C New York/November 2020
  • Potential reduction in neutralization by monoclonal antibody treatments
  • Potential reduction in neutralization by convalescent and post-vaccination sera
B.1.525 Spike: A67V, Δ69/70, Δ144, E484K, D614G, Q677H, F888L
ORF1b: P314F
ORF1a: T2007I
M: I82T
N: A12G, T205I
5’UTR: R81C
20C New York/December 2020
  • Potential reduction in neutralization by monoclonal antibody treatments
  • Potential reduction in neutralization by convalescent and post-vaccination sera
P.2 Spike: E484K, D614G, V1176F
ORF1a: L3468V, L3930F
ORF1b: P314L
N: A119S, R203K, G204R, M234I
5’UTR: R81C
20J Brazil/April 2020
  • Potential reduction in neutralization by monoclonal antibody treatments
  • Potential reduction in neutralization by convalescent and post-vaccination sera

 

(*)=detected in some sequences but not all
a – Nextstrainexternal icon
b – The Biodefense and Emerging Infections Research Resources (BEI Resources) is a NIAID-funded repository to provide reagents, tools, and information to the research community. The reference viruses proposed here facilitate the harmonization of information among all stakeholders in the COVID-19 pandemic research community. Please note that the reference viruses provided in the tables below are based on what is currently available through the BEI resources.

 These variants share one specific mutation called D614G. This mutation was one of the first documented in the US in the initial stages of the pandemic, after having initially circulated in Europe[13]. There is evidence that variants with this mutation spread more quickly than viruses without this mutation [12external icon].

Variant of Concern

A variant for which there is evidence of an increase in transmissibility, more severe disease (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, and vaccines
    • Widespread interference with diagnostic test targets
    • Evidence of substantially increased resistance 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 table below. The table will be updated when a new variant of concern is identified.

Selected Characteristics of SARS-CoV-2 Variants of Concern
Name
(Pango lineage)
Spike Protein Substitutions

Name
(Nextstraina)

First Detected BEI Reference Isolateb

Known Attributes

B.1.1.7 Δ69/70
Δ144Y
(E484K*)
(S494P*)
N501Y
A570D
D614G
P681H
20I/501Y.V1 United Kingdom NR-54000external icon
  • ~50% increased transmission 5
  • Likely increased severity based on hospitalizations and case fatality rates 6
  • Minimal impact on neutralization by EUA monoclonal antibody therapeutics 7, 14
  • Minimal impact on neutralization by convalescent and post-vaccination sera 8,9,10,11,12,13,19

 

P.1 K417N/T
E484K
N501Y
D614G
20J/501Y.V3 Japan/
Brazil
NR-54982external icon
  • Moderate impact on neutralization by EUA monoclonal antibody therapeutics 7,14
  • Reduced neutralization by convalescent and post-vaccination sera 15
B.1.351 K417N
E484K
N501Y
D614G
20H/501.V2 South Africa NR-54009external icon
  • ~50% increased transmission16
  •  Moderate impact on neutralization by EUA monoclonal antibody therapeutics 7,14
  • Moderate reduction on neutralization by convalescent and post-vaccination sera 8,12,18,19,20
B.1.427 L452R
D614G
20C/S:452R US-California
  • ~20% increased transmissibility 21
  • Significant impact on neutralization by some, but not all, EUA therapeutics
  • Moderate reduction in neutralization using convalescent and post-vaccination sera 21
B.1.429 S13I
W152C
L452R
D614G
20C/S:452R US-California
  • ~20% increased transmissibility 21
  • Significant impact on neutralization by some, but not all, EUA therapeutics
  • Moderate reduction in neutralization using convalescent and post-vaccination sera 21

(*)=detected in some sequences but not all
a – Nextstrainexternal icon
b – The Biodefense and Emerging Infections Research Resources (BEI Resources) is a NIAID-funded repository to provide reagents, tools, and information to the research community. The reference viruses proposed here facilitate the harmonization of information among all stakeholders in the COVID-19 pandemic research community. Please note that the reference viruses provided in the tables below are based on what is currently available through the BEI resources.

 These variants share one specific mutation called D614G. This mutation was one of the first documented in the US in the initial stages of the pandemic, after having initially circulated in Europe[13]. There is  evidence that variants with this mutation spread more quickly than viruses without this mutation [12external icon].

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 significant 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.

References

  1. Zhou, B., Thi Nhu Thao, T., Hoffmann, D. et al.SARS-CoV-2 spike D614G change enhances replication and transmission. Nature (2021). https://doi.org/10.1038/s41586-021-03361-1external icon
  2. Volz E, Hill V, McCrone J, et al. Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity. Cell 2021; 184(64-75). doi: https://doi.org/10.1016/j.cell.2020.11.020external icon 
  3. Korber B, Fischer WM, Gnanakaran S, et al. Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell 2021; 182(812-7) doi: https://doi.org/10.1016/j.cell.2020.06.043external icon
  4. Yurkovetskiy L, Wang X, Pascal KE, et al. Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant. Cell 2020; 183(3): 739-751. doi: https://doi.org/10.1016/j.cell.2020.09.032external icon
  5. Davies NG, Abbott S, Barnard RC, et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. MedRXiv 2021. doi: https://doi.org/10.1101/2020.12.24.20248822external icon
  6. Horby P, Huntley C, Davies N et al. NERVTAG note on B.1.1.7 severity. New & Emerging Threats Advisory Group, Jan. 21, 2021. Retrieved from NERVTAG note on variant severityexternal icon
  7. Fact Sheet For Health Care Providers Emergency Use Authorization (Eua) Of Bamlanivimab And Etesevimab 02092021 (fda.gov)external icon
  8. Wang P, Nair MS, Liu L, et al. Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7. BioXRiv 2021. doi: https://doi.org/10.1101/2021.01.25.428137external icon
  9. Shen X, Tang H, McDanal C, et al. SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral Spike vaccines. BioRxiv 2021.  doi:  https://doi.org/10.1101/2021.01.27.428516external icon
  10. Edara VV, Floyd K, Lai L, et al. Infection and mRNA-1273 vaccine antibodies neutralize SARS-CoV-2 UK variant. MedRxiv 2021. doi: https://doi.org/10.1101/2021.02.02.21250799external icon
  11. Collier DA, DeMarco A, Ferreira I, et al. SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies. MedRxiv 2021. doi: https://doi.org/10.1101/2021.01.19.21249840external icon
  12. Wu K, Werner AP, Moliva JI, et al. mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants. BioRxiv 2021. doi: https://doi.org/10.1101/2021.01.25.427948external icon
  13. Emary KRW, Golubchik T, Aley PK, et al. Efficacy of ChAdOx1 nCoV-19 (AZD1222) Vaccine Against SARS-CoV-2 VOC 202012/01 (B.1.1.7). 2021. The Lancet. doi:  http://dx.doi.org/10.2139/ssrn.3779160external icon
  14. FACT SHEET FOR HEALTH CARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) OF REGEN-COV (fda.gov)external icon
  15. Wang P, Wang M, Yu J, et al. Increased Resistance of SARS-CoV-2 Variant P.1 to Antibody Neutralization. BioRxiv 2021.  doi: https://doi.org/10.1101/2021.03.01.433466external icon
  16. Pearson CAB, Russell TW, Davies NG, et al. Estimates of severity and transmissibility of novel South Africa SARS-CoV-2 variant 501Y.V2. Retrieved from: pdf (cmmid.github.io)pdf iconexternal icon
  17. Liu Y, Liu J, Xia H, et al. Neutralizing Activity of BNT162b2-Elicited Serum. 2021. NEJM. DOI: 10.1056/NEJMc2102017
  18. Madhi SA, Ballie V, Cutland CL, et al. Safety and efficacy of the ChAdOx1 nCoV-19 (AZD1222) Covid-19 vaccine against the B.1.351 variant in South Africa. MedRxiv 2021. doi: https://doi.org/10.1101/2021.02.10.21251247external icon
  19. Novavax COVID-19 Vaccine Demonstrates 89.3% Efficacy in UK Phase 3 Trial | Novavax Inc. – IR Siteexternal icon
  20. Johnson & Johnson COVID-19 Vaccine Authorized by U.S. FDA For Emergency Use | Johnson & Johnson (jnj.com)external icon
  21. Deng X, Garcia-Knight MA, Khalid MM, et al. Transmission, infectivity, and antibody neutralization of an emerging SARS-CoV-2 variant in California carrying a L452R spike protein mutation. MedRxiv 2021. doi: https://doi.org/10.1101/2021.03.07.21252647external icon

*Non-peer-reviewed