SARS-CoV-2 Variant Classifications and Definitions

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 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 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 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 in the table below. The table will be updated when a new variant of interest is identified.

(*) = detected in some sequences but not all

⁺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^].

a – Phylogenetic Assignment of Named Global Outbreak (PANGO) Lineages is software tool developed by members of the Rambaut Lab. The associated web application was developed by the Centre for Genomic Pathogen Surveillance in South Cambridgeshire and is intended to implement the dynamic nomenclature of SARS-CoV-2external icon lineagesexternal icon, known as the PANGO nomenclature.

b – Nextstrain, a collaboration between researchers in Seattleexternal icon, USA and Baselexternal icon, Switzerland, provides open-sourceexternal icon tools for visualizing the genetics of outbreaksexternal icon. The goal is to support public health surveillance by facilitating understanding of the spread and evolution of pathogensexternal icon.

c – 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.

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 table below. The table will be updated when a new variant of concern is identified.

(*) = detected in some sequences but not all
⁺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 ^[12].

a – Phylogenetic Assignment of Named Global Outbreak (PANGO) Lineages is software tool developed by members of the Rambaut Lab. The associated web application was developed by the Centre for Genomic Pathogen Surveillance in South Cambridgeshire and is intended to implement the dynamic nomenclature of SARS-CoV-2 lineages, known as the PANGO nomenclature.

b – Nextstrain, a collaboration between researchers in Seattle, USA and Basel, Switzerland, provides open-source tools for visualizing the genetics of outbreaks. The goal is to support public health surveillance by facilitating understanding of the spread and evolution of pathogens.

c – 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.

d  – Attributes listed are based on data available from pseudoviruses or recombinant viruses containing combinations of substitutions characteristic of specific lineages or from reference virus isolates.

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.

Monoclonal antibody treatment considerations for healthcare providers

Substitutions of Concern for SARS-CoV-2 Monoclonal Antibody Therapies

In the United States, there are two anti-SARS-CoV-2 monoclonal antibody treatments with FDA Emergency Use Authorization (EUA) for the treatment of COVID-19: bamlanivimab plus etesevimabexternal icon and casirivimab plus imdevimab.external 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 the L452R or E484K substitution in the spike protein cause a marked reduction in susceptibility to bamlanivimab and may have lower sensitivity to etesevimab and casirivimab.

The table below shows the national and regional unweighted proportions of SARS-CoV-2 that contain the L452R or E484K substitution. As new data become available, additional substitutions may be added to the table below. The national and regional proportions provided in the table below will be updated weekly.

Resources

Monoclonal Antibody COVID-19 Infusionexternal icon

Statement on Anti-SARS-CoV-2 Monoclonal Antibodies EUA | COVID-19 Treatment Guidelines (nih.gov)external icon

a – The unweighted proportion of SARS-CoV-2 circulating in the United States that contain the designated substitution, based on >20,000 sequences collected through CDC’s national genomic surveillance during the two-week period ending April 24, 2021.

b – The unweighted regional proportion of SARS-CoV-2 circulating in each HHS region that contain the designated substitution, based on >20,000 sequences collected through CDC’s national genomic surveillance during the two-week period ending April 24, 2021.

c – The lineages listed are the most common lineages within CDC’s national genomic surveillance with these substitutions, but this list is not intended to be a complete list of the lineages that contain the spike protein substitutions.

References

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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
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14. FACT SHEET FOR HEALTH CARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) OF REGEN-COV (fda.gov)external icon
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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
22. Xie X, Liu Y, Liu J, et al. SARS-CoV-2 spike E484K mutation reduces antibody neutralisation. The Lancet 2021. doi:  https://doi.org/10.1016/S2666-5247(21)00068-9external icon
23. Garcia-Beltran W, Lam EC, St. Denis K, et al. Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity. Cell 2021. doi: https://doi.org/10.1016/j.cell.2021.03.013external icon
24. *Annavajhala MK, Mohri H, Zucker JE, at al. A Novel SARS-CoV-2 Variant of Concern, B.1.526, Identified in New York. MedRxiv 2021. DOI: 10.1101/2021.02.23.21252259external icon
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*Non-peer-reviewed