Viruses such as SARS-CoV-2 evolve throughout a time when changes in the genetic code (genetic mutations) occur during genome replication.

A lineage is a group of virus variants that have a common ancestor and are genetically related. A variant of the SARS-CoV-2 virus has one or more mutations that distinguish it from other SARS-CoV-2 virus variants.

Throughout the epidemic, several variants of SARS-CoV-2 have been identified in the United States and around the world, as expected. Scientists evaluate genetic differences across viruses to find variants and how they are related to one another in order to inform local outbreak investigations and comprehend national patterns.

TABLE OF CONTENT

1. Important Definitions
2. Classification of Variants
3. Tracking SARS-CoV-2 variants
4. Naming SARS-CoV-2 variants
5. Variants of concern (VOC)
6. Variants of interest (VOI)
7. Reclassification Of VOIs/ VOCs
8. Variants under monitoring (VUM)

1. Important Definitions

• Mutation: It refers to a single change in a virus’s genome (genetic code). Mutations occurs often, but only a small percentage of the time do they modify the virus’s properties.

• Lineage: A lineage is a collection of closely related viruses that share a common ancestor. SARS-CoV-2 has a number of lineages, all of which induce COVID-19.

• Variant: A variant is a viral genome (genetic code) that may contain one or more mutations. Due to shared qualities and characteristics that may necessitate public health action, public health organisations may designate a set of variants with similar genetic changes, such as a lineage or group of lineages, as a Variant of Concern (VOC) or a Variant of Interest (VOI).

Since the beginning of the COVID-19 pandemic, SARS-CoV-2 genetic lineages have emerged and circulated over the world.

In the United States, epidemiological investigations, virus genetic sequence-based surveillance, and laboratory research are frequently conducted to track SARS-CoV-2 genetic lineages.

2. Classification of Variants

The SIG Variant classification scheme divides SARS-CoV-2 variants into four categories:

a) Variant Being Monitored (VBM)

• Alpha (B.1.1.7 and Q lineages)
• Beta (B.1.351 and descendent lineages)
• Gamma (P.1 and descendent lineages)
• Epsilon (B.1.427 and B.1.429)
• Eta (B.1.525)
• Iota (B.1.526)
• Kappa (B.1.617.1)
• 1.617.3
• Mu (B.1.621, B.1.621.1)
• Zeta (P.2)

The Centers for Disease Control and Prevention (CDC) keeps track of all variants that are circulating in the United States.

Variants designated as VBM are those for which data indicate a potential or clear impact on approved or authorized medical countermeasures, or those that have been linked to more severe disease or increased transmission but are no longer detected or circulating at extremely low levels in the United States. In the United States, these variants do not constitute a serious or urgent threat to public health.

A Variant of Concern may be moved to this list after a significant and sustained reduction in its national and regional proportions over time, or other evidence indicates that a variant does not pose a significant risk to public health in the United States.

These variants are being continuously examined to see if their proportions are changing, and new data is being processed all the time.

If the statistics indicate that a VBM should be given more attention, the categorization will be revised based on the SIG’s evaluation of the variant’s characteristics and the risk to public health in the United States.

b. Variant of Interest (VOI)

A genetic mutation is associated with changes in receptor binding, lower neutralization by antibodies developed against previous infection or vaccination, reduced treatment efficacy, potential diagnostic impact, or projected increase in transmissibility or disease severity.

Possible characteristics of a Variant of Interest:

• Specific genetic markers that are believe to affect transmission, diagnostics, therapeutics, or immune escape.
• Evidence indicating it is the source of an unusually high number of cases or outbreak clusters.
• In the United States and other nations, there is a limited prevalence or expansion.

A Variant of Interest may require one or more appropriate public health actions, such as increased sequence surveillance, improved laboratory characterization, or epidemiological investigations to determine how easily the virus spreads to others, the severity of disease, therapeutic efficacy, and whether currently approved or authorized vaccines provide protection.

c. Variant of Concern (VOC)

• Delta (B.1.617.2 and AY lineages)
• Omicron (B.1.1.529 and BA lineages)

There is evidence of increased transmissibility, more severe disease (for example, increased hospitalizations or deaths), a significant reduction in neutralization by antibodies generated during previous infection or vaccination, reduced effectiveness of treatments or vaccines, or diagnostic detection failures for this variant.

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 significantly reduced neutralisation by antibodies produced during prior infection or vaccination.
• Evidence of reduced vaccine-induced protection against severe disease
• There is evidence of increased transmissibility.
• There is evidence of increased disease severity

Concerning variants may require one or more appropriate public health actions, such as notification to WHO under the International Health Regulations, reporting to the Centers for Disease Control and Prevention, local or regional efforts to control spread, increased testing, or research to determine the effectiveness of vaccines and treatments against the variant.

Additional considerations may include the development of new diagnostics or the modification of vaccines or treatments based on the characteristics of the variant.

The following are current variants of concern in the United States that are being closely monitored and characterized. When a new variant of concern is discovered, this table will be updated.

d) Variant of High Consequence (VOHC)

• No variants of high consequence have been identified in the United States.
• Vaccines that have been approved and authorised for use in the United States are effective against the predominant variant circulating in the country, and effective therapeutics are available. The CDC continues to monitor all variants that are circulating in the United States.

A VOHC has clear evidence that preventive measures or medical countermeasures (MCMs) are significantly less effective than previously circulating variants.

A high-impact variant could have the following characteristics:

In addition to the possible attributes of a variant of concern.

• Impact on MCMs
• Demonstrated failure of diagnostic test targets
• Evidence pointing to a significant decrease in vaccine effectiveness, a disproportionately high number of infections among vaccinated people, or very low vaccine-induced protection against severe disease.
• Susceptibility to multiple EUAs or approved therapeutics has been significantly reduced.
• More severe clinical disease and increased hospitalizations

A high-impact variant would require notification to WHO under the International Health Regulations, reporting to the CDC, the announcement of prevention or containment strategies, and recommendations to update treatments and vaccines.

The SIG meets on a regular basis to assess the risk posed by SARS-CoV-2 variants circulating in the United States and to make recommendations on variant classification.

This assessment is carried out by a group of subject matter experts who assess available data, such as variant proportions at the national and regional levels, as well as the potential or known impact of the constellation of mutations on the effectiveness of medical countermeasures, disease severity, and ability to spread from person to person.

Given the ongoing evolution of SARS-CoV-2 and our understanding of the impact of variants on public health, variants in the United States may be reclassified based on their characteristics and prevalence.

• Variants being monitored (VBM): View current VBM in the United States that are still being monitored and classified by federal agencies.
• Variant of interest (VOI): There are currently, no SARS-CoV-2 variants are designated as VOI
• Variant of Concern (VOC): View current VOC in the United States that are being closely monitored and characterized by federal agencies
• Variant of high consequence (VOHC): There arecurrently, no SARS-CoV-2 variants are designated as VOHC

Each variant classification includes the possible attributes of lower classes (for example, VOC includes the possible attributes of VOI); variant status might escalate or deescalate based on emerging scientific evidence.

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3. Tracking SARS-CoV-2 variants

All viruses, including SARS-CoV-2, the virus responsible for COVID-19, evolve over time. The majority of changes have little to no effect on the virus’s properties.

Some changes, however, may have an impact on the virus’s properties, such as how easily it spreads, the severity of the associated disease, or the performance of vaccines, therapeutic medicines, diagnostic tools, or other public health and social measures.

Since January 2020, WHO has been monitoring and assessing the evolution of SARS-CoV-2 in collaboration with partners, expert networks, national authorities, institutions, and researchers.

The emergence of variants posing an increased risk to global public health in late 2020 prompted the identification of specific Variants of Interest (VOIs) and Variants of Concern (VOCs), in order to prioritize global monitoring and research, and ultimately to inform the ongoing response to the COVID-19 pandemic.

WHO and its international expert networks are monitoring changes to the virus in order to inform countries and the public about any changes that may be required to respond to the variant and prevent its spread.

Globally, systems for detecting signals of potential VOIs or VOCs and assessing the risk to global public health have been established and are being strengthened. Other variants of local interest/concern may be designated by national authorities.

Reduced transmission such as through established and proven disease control methods/measures, as well as avoidance of introductions into animal populations, are critical components of the global strategy to reduce the occurrence of mutations with negative public health implications.

Current WHO-recommended strategies and measures continue to be effective against virus variants discovered since the outbreak’s inception.

Evidence from multiple countries with the extensive transmission of VOCs has indicated that public health and social measures (PHSM), including infection prevention and control (IPC) measures, have been effective in reducing COVID-19 cases, hospitalizations and deaths.

National and local authorities are encouraged to continue strengthening existing PHSM and IPC measures. Authorities are also encouraged to strengthen surveillance and sequencing capabilities, as well as to use a systematic approach to provide a representative indication of the extent of SARS-CoV-2 variant transmission based on the local context, and to detect unusual epidemiological events.

4. Naming SARS-CoV-2 variants

GISAID, Nextstrain, and Pango’s established nomenclature systems for naming and tracking SARS-CoV-2 genetic lineages are currently and will continue to be used by scientists and in scientific research.

To assist with public discussions of variants, WHO convened a group of scientists from the WHO Virus Evolution Working Group (now called the Technical Advisory Group on Virus Evolution), the WHO COVID-19 reference laboratory network, representatives from GISAID, Nextstrain, Pango, and additional experts in virological, microbial nomenclature and communication from several countries and agencies to consider easy-to-pronounce and non-stigmatizing labels for VOI and VOC.

At the moment, this expert group convened by WHO has recommended using Greek Alphabet letters, such as Alpha, Beta, Gamma, and Delta, which will be easier and more practical to discuss with non-scientific audiences.

SARS-CoV-2 variants

Given the ongoing evolution of the virus that causes SARS-CoV-2 and the ongoing advances in our understanding of the effects of variants, these working definitions may be revised on a regular basis.

When necessary, variants that do not otherwise meet all of the criteria outlined in these definitions may be designated as VOCs/VOIs/VUMs, and those that pose a declining risk in comparison to other circulating variants may be reclassified in consultation with the Technical Advisory Group on Virus Evolution (formally called the Virus Evolution Working Group).

The WHO Weekly Epidemiological Updates provide regular updates on SARS-CoV-2 classifications, the geographic distribution of VOCs, and summaries of their phenotypic characteristics (transmissibility, disease severity, risk of reinfection, and impacts on diagnostics and vaccine performance) based on published studies.

5. Variants of concern (VOC)

Definition:

A variant for which there is evidence of an increase in transmissibility, more severe disease (for example, increased hospitalizations or deaths), a significant reduction in neutralization by antibodies generated during previous infection or vaccination, decreased effectiveness of treatments or vaccines, or diagnostic detection failures. Through a comparative analysis, has been shown to be associated with one or more of the following changes with global public health significance:

• In Increased transmissibility or a negative change in COVID-19 epidemiology.
• Increase in virulence or change in clinical disease presentation.
• Reduced effectiveness of public health and social measures, as well as available diagnostics, vaccines, and therapeutics.

Concerning variants may necessitate one or more appropriate public health actions, such as notification to WHO under the International Health Regulations, reporting to the Centers for Disease Control and Prevention, local or regional efforts to control spread, increased testing, or research to determine the effectiveness of vaccines and treatments against the variant. Additional considerations may include the development of new diagnostics or the modification of vaccines or treatments based on the characteristics of the variant.

a) Actions taken by WHO and Member States:

WHO actions for a potential VOC:

• WHO and the Technical Advisory Group on Virus Evolution conduct a comparative assessment of variant characteristics and public health risks.
• If determined necessary, coordinate additional laboratory investigations with Member States and partners.
• Communicate new designations and findings to Member States and the general public via established channels. 
• Evaluate WHO guidance through established WHO mechanisms and, if necessary, update. 

b) Actions by a Member State, if a VOC is identified:

• Report initial cases/clusters of VOC infection to WHO using the IHR mechanism..
• Complete genome sequences and associated metadata should be submitted to a publicly accessible database, such as GISAID.
• Perform field investigations and laboratory assessments where capacity exists and in collaboration with the international community to improve understanding of the potential impacts of the VOC on COVID-19 epidemiology, severity, effectiveness of public health and social measures, diagnostic methods, immune responses, antibody neutralisation, or other relevant characteristics.

6. Variants of interest (VOI)

Definition

A genetic mutation is associated with changes in receptor binding, lower neutralization by antibodies developed against previous infection or vaccination, reduced treatment efficacy, potential diagnostic impact, or projected increase in transmissibility or disease severity.

A Variant of Interest may necessitate one or more appropriate public health actions, such as increased sequence surveillance, improved laboratory characterization, or epidemiological investigations to determine how easily the virus spreads to others, the severity of disease, therapeutic efficacy, and whether currently approved or authorized vaccines provide protection.

a) A SARS-CoV-2 variant:

• With predicted or known genetic changes that affect virus characteristics such as transmissibility, disease severity, immune escape, diagnostic or therapeutic escape.
• Identified to cause considerable community transmission or several COVID-19 clusters in different countries with increasing relative incidence alongside increasing number of cases over time, or other obvious epidemiological implications to signal an emerging worldwide public health issue.
  
  

b) Actions by a Member State, if a new potential VOI is identified:

•  Inform WHO about VOI-related cases using established WHO Country or Regional Office reporting channels and supporting documentation.
• Submit complete genome sequences and associated metadata to a publicly available database, such as GISAID.
• Conduct field investigations to gain a better understanding of the potential impacts of the VOI on COVID-19 epidemiology, severity, the efficacy of public health and social measures, and other relevant characteristics.
• Perform laboratory assessments in accordance with available resources, or contact WHO for assistance in conducting laboratory assessments on the impact of the VOI on relevant topics.

c) Actions by WHO for a potential VOI

• Comparative assessment of variant characteristics and public health risks by WHO.
• If determined necessary, coordinated laboratory investigations with Member States and partners. 
• Review global epidemiology of VOI.
• Monitor and track global spread of VOI

7. Reclassification Of VOIs/ VOCs

A previously designated Variant of Interest (VOI) or Variant of Concern (VOC) has been conclusively demonstrated to pose no significant additional risk to global public health when compared to other circulating SARS-CoV-2 variants.

This is accomplished through a critical expert assessment of several criteria, such as the observed incidence/relative prevalence of variant detections among sequenced samples over time and between geographical locations, the presence/absence of other risk factors, and any ongoing impact on control measures, in collaboration with the Technical Advisory Group on Virus Evolution.

VOC and VOI-defining constellation of mutations in the spike protein

The profile of amino acid changes compared to the wild-type virus (GISAID Accession ID: EPI ISL 402124) was created for each variant based on the first 1,000 genomes available in GISAID (genomes with less than 29,000 nucleotides and >5% Ns were excluded). Amino acid changes that occur in 85 percent of the examined sequences are depicted. It should be noted that relevant amino acid changes may exist in other regions of the SARS-CoV-2 genome, and not all amino acid changes in the spike protein are associated with potential changes in the virus variant’s characteristics.

8. Variants under monitoring (VUM)

Definition

A SARS-CoV-2 variant with genetic changes suspected to affect virus characteristics, with some indication that it may pose a future risk, but evidence of phenotypic or epidemiological impact is currently unclear, necessitating increased monitoring and reassessment in the absence of new evidence.

It is anticipated that our understanding of the effects of these variants will rapidly evolve, and designated Variants under Monitoring may be easily added/removed; thus, WHO labels will not be assigned at this time.

Former VOIs/VOCs, on the other hand, maybe monitored for an extended period of time under this category and will keep their assigned WHO label until further notice.

a) Actions by the Member States:

• Complete genome sequences and associated metadata should be submitted to a publicly accessible database, such as GISAID
• Conduct field investigations to gain a better understanding of the VUM characteristics on COVID-19.
• Epidemiology.
• Monitor the spread of VUM and its interactions with other circulating variants for the possibility of outcompeting or thriving in the presence of a known dominant VOC/VOI.
• Conduct laboratory studies to better understand the VUM’s phenotypic implications.

b) Variants that were previously monitored

Former VOCs/VOIs/VUMs, as well as their descendent lineages, have been reclassified using at least one of the following criteria:

(1) The variant is no longer circulating at global public health significance levels;

(2) The variant has been circulating for a long time with no impact on the overall epidemiological situation.

(3) Scientific evidence shows that the variant is not linked to any concerning characteristics.

According to preliminary evidence from Case Western Reserve University, the risk of being admitted to the hospital or intensive care unit during the omicron surge in the United States is roughly half that observed during the delta surge. And this is consistent with what doctors across the country are witnessing firsthand with their patients.

As with any variant of SARS-CoV-2, your absolute risk is determined by a variety of factors, including whether you’ve been vaccinated and boosted, your age, overall health, and financial situation.

According to data from the Department of Health and Human Services, hospitalizations in the United States have surpassed 126,000, with more than one in every four ICU beds occupied by a COVID-19 patient.

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