As the COVID-19 variants surface and spread we are learning that testing methods may be affected and may in fact become ineffective. The FDA is in a race to keep up with the changes…
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 regarding 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.
Updates will become available as new information comes to light.
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) 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 serological 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 additional 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 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 with Reduced Ability to Detect the SARS-CoV-2 Omicron Variant
Tests with S-Gene Drop Out – SARS-CoV-2 Detection Should Not Be Impacted
- The FDA’s Analysis: For each of the tests listed in the below table, one genetic target is expected to have significantly reduced sensitivity due to a mutation in the SARS-CoV-2 omicron variant (B.1.1.529). A specific deletion in the spike (S) gene (Δ69-70) results in an S-gene drop out, also referred to as an S-gene target failure (SGTF), where the genetic target that covers the portion of the S-gene where the deletion occurs fails to detect the virus.
- 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 an S-gene drop out may provide a signal that the omicron variant may be present. However, the presence of the S-gene drop out pattern does not mean an individual with SARS-CoV-2 has the omicron variant.
- 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 S-gene drop out pattern of detection (reduced sensitivity with the S-gene target) when using these tests is consistent with certain mutations, including those in the omicron variant.
- S-gene drop out has been observed in other variants and is not specific to the omicron variant. S-gene drop out has also been observed without the presence of a mutation in the S-gene, due to the sensitivity of the S-gene target. Therefore, these tests cannot be used as a diagnostic tool or specific identifier of the omicron variant.
- The presence of the S-gene drop out detection pattern can signal that sequencing should be considered to characterize the variant in that specimen.
- S-gene drop out is typically not observed in the delta variant. Since delta is the primary variant circulating in the United States, specimens with an S-gene drop out detection pattern may potentially 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.
Showing 1 to 27 of 27 entries
* The TaqPath COVID-19, FluA, FluB Combo Kit is expected to have an S-gene drop out due to the presence of a mutation in the S-gene, without a significant impact to overall test sensitivity. However, due to the design of the test, there will not be a distinct S-gene detection pattern to signal the potential presence of the omicron variant.
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:
For more information on the viral mutations of the SARS-CoV-2, please email us at: firstname.lastname@example.org and ref: COVID Viral Mutations.