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

Extracted:  2021.12.21

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
• General Information for Clinical Laboratory Staff and Health Care Providers
• Omicron Variant: Molecular Tests that May Be Impacted
  • Tests Expected to Fail to Detect the SARS-CoV-2 Omicron Variant
  • Tests with Detection Patterns that May Be Associated with the SARS-CoV-2 Omicron Variant
• Other Variants: Molecular Tests that May Be Impacted
• Resources

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

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:

• Be aware that genetic variants of SARS-CoV-2 arise regularly, and false negative test results can occur.
• Be aware that molecular tests that use multiple genetic targets to determine a final result are less likely to be impacted by increased prevalence of genetic variants.
• Consider negative results in combination with clinical observations, patient history, and epidemiological information.
• Be aware of currently circulating SARS-CoV-2 variants since test performance may be impacted by certain variants.
• 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.

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

Omicron Variant: Molecular Tests That May Be Impacted

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.

Tests Expected to Fail to Detect the SARS-CoV-2 Omicron Variant

Due to the inability of these test to detect the SARS-CoV-2 omicrom variant, the FDA recommends that these test should not be used until this issues is resolved.

Tests with Detection Patterns that May Be Associated with the SARS-CoV-2 Omicron Variant

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 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 target failure 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 target failure. Therefore, the omicron variant may still be present without a target failure 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. These tests are not authorized for determining the presence or absence of the omicron variant for clinical purposes.

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.
• A target failure may occur due to different mutations in other variants and may not be specific to the omicron variant. A target failure 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 target failure detection pattern is not a definitive confirmation of the presence of the omicron variant.
• The presence of a target failure 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 target failure 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 EOCevent177@cdc.gov for additional information.

Other Variants: Molecular Tests That May Be Impacted

The FDA’s analysis to date has identified the following EUA-authorized molecular tests whose performance may be impacted by other SARS-CoV-2 viral mutations:

Resources

• Policy for Evaluating Impact of Viral Mutations on COVID-19 Tests
• Revision Concerning Viral Mutation
• Genetic Variants of SARS-CoV-2 May Lead to False Negative Results with Molecular Tests for Detection of SARS-CoV-2 – Letter to Clinical Laboratory Staff and Health Care Providers (January 8, 2021)