ACEP COVID-19 Field Guide

Author: Mark Hauswald, MS, MD, FACEP, Emeritus Professor of Emergency Medicine, Past Associate Dean for Clinical Affairs and Patient Safety, Past Director of Global Health Projects, University of New Mexico Health Sciences Center

The following information is from the CDC’s page “SARS-CoV-2 Variant Classifications and Definitions.” Visit this page for the most current information, including the current table of variants and a list of references.

Viruses like SARS-CoV-2 continuously evolve when changes in the genetic code occur during replication of the genome. The virus consistently mutated during the pandemic, creating new variants that differ from the original. Many variants are now found across the globe. Scientists use multiple classification systems to describe and communicate similarities and differences between SARS-CoV-2 viruses.

Classification types

SARS-CoV-2 viruses are classified in multiple ways, and different classifications are appropriate depending on the context. The most common classification system for lineages is Pango. Nextclade can also be used. The WHO has used Greek letters (eg, Delta, Omicron) to classify lineages or groups of related lineages in a larger context.

Variant classification

The US Department of Health and Human Services (HHS) established a SARS-CoV-2 Interagency Group (SIG) to enhance coordination between the 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 characterizes emerging variants and monitors their potential impact on vaccines, therapeutics, and diagnostics.

The SIG meets regularly to evaluate SARS-CoV-2 variants and lineages circulating in the United States and to make recommendations about the classification of variants and lineages. A group of experts assesses the available data on variant proportion at the national and regional levels. This information is shared with local and state public health officials to aid in their decision-making for community-level guidance. They also assess how these changes may affect vaccines, therapeutics, and diagnostics as well as transmission and disease severity. Variants may be reclassified as more information becomes available.

The SIG has updated its classification system and working definitions for variants of SARS-CoV-2 to better reflect the current variant landscape. The previous system classified all Omicron sublineages as part of the Omicron variant of concern and, therefore, did not provide the distinction needed to compare new descendent lineages with altered phenotypic characteristics to the Omicron parent lineages (BA.1, BA.2). These classification updates allow for independent evaluation and tracking of Omicron sublineages and forthcoming new variants when required.

The SIG uses four types of classifications:

• Variant of high consequence
• Variant of concern
• Variant of interest
• Variants being monitored

Each variant classification includes the possible attributes of lower classes (for example, a variant of concern [higher class] includes the possible attributes of a variant of interest [lower class]). US variant classifications can differ from the WHO classifications because the impact of variants can differ by location.

Variant of high consequence

A variant of high consequence demonstrates that prevention measures or medical countermeasures used against previous strains have significantly reduced effectiveness. Variants of high consequence could impact medical countermeasures by:

• Demonstrating failure of diagnostic test targets;
• Causing significant reductions in vaccine effectiveness, a disproportionately high number of infections in vaccinated persons, or very low vaccine-induced protection against severe disease;
• Significantly reducing susceptibility to multiple emergency-use-authorized or approved therapeutics; or
• Causing more severe clinical disease and increasing hospitalizations.

A variant of high consequence would require notification to WHO under the International Health Regulations and reporting to the CDC of the strategies to prevent or contain transmission and recommendations to update treatments and vaccines.

Currently, no SARS-CoV-2 variants are designated as a variant of high consequence.

Variant of concern

In addition to the possible attributes of a variant of interest, variants designated as a variant of concern have the following characteristics:

• Increased transmissibility;
• Association with more severe disease (for example, increased hospitalizations or deaths);
• Significant reduction in neutralization by antibodies generated from previous infection or vaccination; and
• Reduced response to treatments, vaccines, or diagnostic detection.

Variants of concern may require one or more appropriate public health actions, such as:

• Notifying the WHO under the International Health Regulations;
• Reporting to the CDC, local, or regional efforts;
• Increasing preventative measures, such as masking, testing, or physical distancing;
• Conducting research to determine the effectiveness of vaccines and treatments against the variant; or
• Adapting diagnostic tests, vaccines, or treatments to increase efficacy against circulating variants of concern.

Currently, no SARS-CoV-2 variants are designated as a variant of concern.

Variant of interest

A variant of interest is a variant that has:

• Reduced neutralization by antibodies generated from previous infection or vaccination;
• Less response to diagnostic tests or FDA-approved treatments; and
• Predicted increases in transmissibility or disease severity.

 Possible attributes of a variant of interest include:

• Specific genetic markers that are predicted to affect transmission, diagnostics, therapeutics, or immune escape; and
• Evidence that it is the cause of an increased proportion of cases or unique outbreak clusters.

Although a variant of interest may have limited prevalence in the United States, it could potentially expand in other countries. It may require one or more public health actions. The CDC may increase surveillance or epidemiologic investigations to evaluate the risk a variant of interest may have on the United States.

Variants being monitored

Variants designated as variants being monitored include:

• Lineages with a potential impact on available medical countermeasures based on analysis of genetic sequence data;
• Lineages that previously caused more severe disease or increased transmission but are no longer detected;
• Lineages with an unusually large number of antigenic mutations and presence in multiple countries with collection dates within 4 weeks; and
• Lineages previously designated as a variant of interest, concern, or high consequence that are currently circulating at very low levels in the United States.

A variant of interest or a variant of concern can be downgraded to a variant being monitored once it is no longer circulating at sustained levels and no longer poses significant risk to public health in the United States. Classifications can change over time, based on the evolving situation and information available.

Pango lineage system

The Pango lineage system is hierarchical. Lineages are evolutionarily descendants of a “parent” lineage. A lineage can be described as a sublineage when it is discussed in relation to its parent lineage.

Lineages are named using an alphabetical prefix (such as B or BA) and numerical suffix (such as .1 or .1.1.5). When a new lineage is defined, the Pango system assigns an additional number to the name of its parent lineage (eg, BA.2.75 is a sublineage of BA.2). As the virus continues to change, the Pango lineage names can become very long. Lineages with longer names may be given alphabetic aliases as the numbering continues (eg, BA stands for B.1.1.529; thus, BA.2 is the same as B.1.1.529.2).

For more information on the Pango lineage system and its nomenclature, see the Pango Network. For a full list of the current Pango lineages, see cov-lineages.org.

Nextclade

Nextclade is a tool that is used to classify SARS-CoV-2 sequences according to their genetic relatedness. Potentially important branches of the SARS-CoV-2 family tree are given names, indicating members of that branch are a “clade” and are thought to arise from a common ancestor.

Members of a clade share many features with each other, reflecting their common ancestry. Not every SARS-CoV-2 virus is assigned its own clade by Nextclade. Each potential clade must circulate at a certain frequency for a period of time, show consistent growth in a region, or be assigned a WHO classification. The Nextclade team outlines their clade designation rubric in the Nextstrain publication “SARS-CoV-2 Clade Naming Strategy for 2022.” These broader definitions offer an alternative naming solution that is meant to reflect significant differences in biology or circulation.

Nextclade clade names consist of the two-digit year of assignment followed by a letter that indicates the order of assignment within the year. For example, “22A” is the first clade designated in 2022 and corresponds to the group of Pango lineages that descended from BA.4, which was circulating in early 2022. More information about the various clades and their relationship to the various Pango lineages is detailed at covariants.org.

Recombinants

All coronaviruses have the potential to undergo a natural process called recombination, which can occur when two different lineages infect the same cell in someone at the same time. This rare phenomenon can affect the characteristics of the virus, including its ability to spread, cause severe disease, or make treatments or vaccines less effective. In many cases, recombinant viruses do not have competitive advantages that help them rise.

The CDC’s genomic surveillance systems can reliably detect and monitor the spread of variants, including recombinants. When a recombinant does emerge, CDC scientists evaluate and monitor the new recombinant just like any other variant lineage — including how it might be classified or when it should be presented on the CDC’s COVID Data Tracker.