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  6. SARS-CoV-2 Viral Mutations: Impact on COVID-19 Tests
  1. Coronavirus (COVID-19) and Medical Devices

SARS-CoV-2 Viral Mutations: Impact on COVID-19 Tests

The SARS-CoV-2 virus has mutated over time, resulting in genetic variation in the population of circulating viral strains over the course of the COVID-19 pandemic. Molecular, antigen, and serology tests are affected by viral mutations differently due to the inherent design differences of each test.

This page provides information about the impact of viral mutations on COVID-19 tests, recommendations for clinical laboratory staff and health care providers, and information about certain tests for which the FDA has identified potential impacts on performance due to SARS-CoV-2 genetic mutations. The FDA will list tests on this page as the FDA's analyses identify tests for which performance may be impacted for known SARS-CoV-2 variants. For consumer information on COVID-19 testing and SARS-CoV-2 variants, visit Coronavirus Disease 2019 Testing Basics.

The FDA will update this page as significant new information becomes available.

On this page:

Genetic Variations: Background and Considerations

A mutation (also referred to as viral mutation or genetic mutation) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is a change in the genetic sequence of the SARS-CoV-2 virus when compared with a reference sequence such as Wuhan-Hu1 (the first genetic sequence identified) or USA-WA1/2020 (the first identified in the United States). A new variant (virus variant or genetic variant) or sub-lineage of SARS-CoV-2 may have one or more mutations that differentiate it from the reference sequences or predominant virus variants already circulating in the population. Variants of SARS-CoV-2 can have different characteristics. For example, some may spread more easily or show signs of resistance to existing treatment options and some may have no impact when compared with previous and currently circulating virus.

The presence of mutations in the SARS-CoV-2 virus in a patient sample can potentially impact test performance. The impact of mutations on a test's performance is influenced by several factors, including the sequence of the variant, the design of the test, and the prevalence of the variant in the population.

The FDA has collaborated with stakeholders to better understand the public health impact of new SARS-CoV-2 variants and their impact on test performance, has been routinely monitoring publicly available databases, and has coordinated efforts to evaluate the impact of new virus variants on tests that have received Emergency Use Authorization (EUA).

In February 2021, the FDA issued the Policy for Evaluating Impact of Viral Mutations on COVID-19 Tests to provide a policy and recommendations on evaluating the potential impact of emerging and future viral mutations of SARS-CoV-2 on COVID-19 tests for the duration of the COVID-19 public health emergency, including considerations for test designs to minimize the impact of viral mutations and recommendations for ongoing monitoring.

On September 23, 2021, the FDA revised the EUAs of certain authorized molecular, antigen, and serology tests to establish additional Conditions of Authorization in response to the continued emergence of new variants of SARS-CoV-2. These conditions have also been included in other EUAs, such that all EUAs previously issued for COVID-19 molecular, antigen, and serology tests include these conditions, and they continue to be included in new EUAs. These conditions require test developers to update their authorized labeling and evaluate the impact of SARS-CoV-2 viral mutations on their test's performance, among other things.

The FDA will update this page as significant new information becomes available, including the information provided by EUA holders in their authorized labeling.

General Information for Clinical Laboratory Staff and Health Care Providers (As of 12/22/2021)

Clinical laboratory staff and health care providers should be aware that false negative results may occur with any molecular test for the detection of SARS-CoV-2, particularly if a mutation occurs in the part of the virus' genome assessed by that test.

Changes in the viral genome can result in changes to viral proteins and, therefore, can also impact the performance of an antigen or serology test.

The FDA recommends clinical laboratory staff and health care providers who use SARS-CoV-2 tests note the following:

  • Genetic variants of SARS-CoV-2 arise regularly, and false negative test results can occur.
  • Consider negative results in combination with clinical observations, patient history, and epidemiological information.
  • Consider repeat testing with a different EUA authorized or FDA cleared molecular diagnostic test (with different genetic targets) if COVID-19 is still suspected after receiving a negative test result.
  • Test performance may be impacted by certain variants.
  • Tests with single targets are more susceptible to changes in performance due to viral mutations, meaning they are more likely to fail to detect new variants.
  • Tests with multiple targets are more likely to continue to perform as described in the test's labeling as new variants emerge. Multiple targets means that a molecular test is designed to detect more than one section of the SARS-CoV-2 genome or, for antigen tests, more than one section of the proteins that make up SARS-CoV-2.

In addition to these general recommendations, the FDA is providing information related to specific variants and recommendations for the use of specific tests that may be impacted by genetic variation in the sections below.

Omicron Variant: Background (As of 12/22/2021)

The omicron variant, B.1.1.529, of SARS-CoV-2, was designated by the United States as a Variant of Concern (VOC) on November 30, 2021. The first confirmed case of omicron in the United States was identified on December 1, 2021.

The omicron variant has significantly more mutations than previous SARS-CoV-2 variants, particularly in its S-gene, the gene that encodes the virus's spike protein.

The FDA is working with our government partners and test developers to evaluate the impact of the omicron variant on SARS-CoV-2 diagnostic tests.

Omicron Variant: Impact on Antigen Diagnostic Tests (As of 12/28/2021)

Throughout the ongoing COVID-19 pandemic, the FDA has been monitoring and evaluating the potential impact of genetic variants on antigen tests.

The FDA is collaborating with the National Institutes of Health's (NIH) RADx program to study the performance of antigen tests with patient samples that have the omicron variant. RADx recently performed preliminary studies evaluating the performance of some antigen tests using patient samples containing live virus, which represents the best way to evaluate true test performance in the short-term. Early data suggests that antigen tests do detect the omicron variant but may have reduced sensitivity.

Prior to completing these live virus tests, RADx conducted initial laboratory tests using heat-inactivated samples for some of the currently available antigen tests, which were able to detect the omicron variant, with similar performance when detecting other variants. Heat-inactivated samples are patient samples with omicron variant that have been heat-treated so that the virus is no longer live. Heat-inactivated samples are the best available option when patient samples with live virus are not available.

It is important to note that these laboratory data are not a replacement for clinical study evaluations using patient samples with live virus, which are ongoing. The FDA and RADx are continuing to further evaluate the performance of antigen tests using patient samples with live virus.

The FDA continues to authorize the use of these tests as directed in the authorized labeling and individuals should continue to use them in accordance with the instructions included with the tests. Antigen tests are generally less sensitive and less likely to pick up very early infections compared to molecular tests. In following the FDA's long-standing rapid test recommendations, if a person tests negative with an antigen test but is suspected of having COVID-19, such as experiencing symptoms or have a high likelihood of infection due to exposure, follow-up molecular testing is important for determining a COVID-19 infection. If a person tests positive with an antigen test, they should self-isolate and seek follow-up care with a health care provider to determine the next steps.

The FDA, our partners, and test developers continue to evaluate test sensitivity, when tests should be performed, and the frequency of testing. The agency is also coordinating with our international regulatory counterparts who are also evaluating the impact of omicron on antigen tests used in their countries.

The agency will provide updated information and any needed recommendations to the public should they become available.

Omicron Variant: Impact on Molecular Tests (As of 12/22/2021) 

The FDA's analysis to date has identified certain EUA-authorized molecular tests whose performance may be impacted by mutations in the SARS-CoV-2 omicron variant. These tests fall into two categories, as described below: those that are expected to fail to detect the SARS-CoV-2 omicron variant, and those that are expected to detect the SARS-CoV-2 omicron variant with a specific gene drop out detection pattern.

Tests Expected to Fail to Detect the SARS-CoV-2 Omicron Variant (As of 12/27/2021)

Due to the inability of these tests to detect the SARS-CoV-2 omicron variant, the FDA recommends that these tests should not be used until this issue of these tests' inability to detect the omicron variant is resolved.

Issue Resolved: Tests Previously Expected to Fail to Detect the SARS-CoV-2 Omicron Variant (As of 12/27/2021)

These tests have been modified or otherwise have addressed the issue of their inability to detect the omicron variant.

Tests with Detection Patterns that May Be Associated with the SARS-CoV-2 Omicron Variant (As of 12/22/2021)

These tests are expected to detect the SARS-CoV-2 omicron variant. Due to mutations found in the SARS-CoV-2 omicron variant, these tests may be useful in identifying samples where omicron may be present so that sequencing can be considered to characterize the variant.

  • The FDA's Analysis: Certain mutations in the SARS-CoV-2 omicron variant (B.1.1.529) lead to significantly reduced sensitivity in an N-gene or S-gene genetic target that covers the portion of the gene where the mutation occurs. In tests that are designed to detect multiple genetic targets, where only one genetic target has reduced sensitivity due to a mutation, the tests are still expected to detect the SARS-CoV-2 omicron variant. The detection pattern, showing the drop out, or failure of the affected target, may help to signal the presence of the omicron variant in a patient sample with a positive result so that sequencing can be considered to characterize the variant.
  • Potential Impact: Since these tests are designed to detect multiple genetic targets, the overall test sensitivity should not be impacted. The pattern of SARS-CoV-2 detection with one gene drop out may provide a signal that the omicron variant may be present so that sequencing can be considered to characterize the variant. However, testing positive for SARS-CoV-2 with one of these tests does not mean an individual is infected with the omicron variant. Further, not all patient samples with the omicron variant display a mutation that leads to a gene drop out. Therefore, the omicron variant may still be present without a gene drop out detection pattern.
  • Notes: These tests are identified based on initial bioinformatics analyses and may not yet have been evaluated against the omicron variant in the laboratory. 

Recommendations for Clinical Laboratory Staff and Health Care Providers Using These Tests

  • Be aware that the target failure or gene drop out pattern of detection (reduced sensitivity with the one genetic target) when using these tests is consistent with certain mutations, including those in some samples of the omicron variant. If a laboratory reports a gene drop out detection pattern when providing test results, we encourage laboratories to explain what the pattern may or may not mean.
  • A gene drop out may occur due to different mutations in other variants and may not be specific to the omicron variant. A gene drop out may also be observed without the presence of a mutation in the target area, due to the sensitivity of the genetic target. Therefore, the presence of a gene drop out detection pattern is not a definitive confirmation of the presence of the omicron variant.
  • The presence of a gene drop out detection pattern can signal that sequencing should be considered to characterize the variant in that specimen.
  • N-gene and S-gene drop outs are typically not observed in the delta variant. Specimens with a gene drop out detection pattern may be omicron variants and should be prioritized for sequencing confirmation.
  • If local or state clinical laboratories have access to quick turnaround whole genome sequencing services, these labs should consider further characterizing the specimen with genetic sequencing when this pattern is identified. If such services are not readily available, local or state clinical laboratories should consider reaching out to the Centers for Disease Control and Prevention at [email protected] for additional information.

Other Variants: Impact on Diagnostic Tests (As of 12/15/2021)

Several variants have been in circulation in the United States at various times during the pandemic. As part of the FDA's analysis of the impact of viral mutations on COVID-19 tests, the FDA has identified certain tests whose performance may be impacted by SARS-CoV-2 viral mutations. Note that the variants discussed in this section may no longer be the predominantly circulating variants in the United States, which are discussed in the above sections of this webpage.

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