Since the COVID-19 pandemic began, SARS-CoV-2 viruses have mutated, causing genetic variation among circulating strains. Since Molecular, Antigen, and Serological tests are designed differently, they are affected by viral mutations differently.

In the coming content, you will learn about genetic mutations in SARS-CoV-2 and how they may impact COVID-19 tests, clinical laboratory recommendations for testing, and information regarding certain tests with potential performance issues. 

Considerations and Background on Genetic Variations

Mutations, also known as changes in genetic sequences, in SARS-CoV-2 refer to a change in genetic information compared to a reference sequence, such as WuhanHu1 (the first genetic sequence to be identified) or USA-WA1/2020 (the first sequence to be identified in the United States). In some cases, new viruses (virus variants or genetic variants) of the SARS-CoV-2 virus have at least one mutation distinct from the reference sequence or dominant virus variants currently in circulation. There are many strains of SARS-CoV-2. Compared to previous and currently circulating viruses, some viruses are more likely to spread more quickly, are resistant to current treatments, and have no effect.

If SARS-CoV-2 viruses are found in a patient sample with mutations, test results may be impacted. Many factors influence the performance of a test when a mutation occurs, including its sequence, design, and prevalence in the population.

FDA works with stakeholders to determine the impact of new SARS-CoV-2 variants on tests that are eligible for emergency use authorizations (EUAs). As part of its public health oversight, the agency has also been monitoring publicly available databases and collaborating with other agencies to evaluate the effects of new virus variants on public health.

While COVID-19 was under a public health emergency, the FDA published the Policy for Evaluating Viral Mutations on COVID-19 Tests, which gives recommendations regarding test design to minimize the impact of viral mutations and ongoing monitoring suggestions.

Health Care Providers and Clinical Laboratory Staff

SARS-CoV-2 detection by molecular tests is subject to false-negative results, especially if mutations occur in the region of the virus’ genome assessed by the test. Healthcare providers and laboratory staff should be aware of this possibility.

Changes in virus genomes can alter viral proteins and, therefore, affect the effectiveness of antigens and serology tests.

The following points are important to remember for health care providers and clinical laboratory staff using SARS-CoV-2 tests:

  • False-negative test results can occur due to genetic variant(s) of SARS-CoVID-2.
  • Analyze negative reports/results regarding patient history, clinical observations, and epidemiological data.
  • If COVID-19 is still suspected after receiving a negative test result, consider having repeat tests with different EUA-approved or molecular diagnostic tests, which must be an FDA-cleared (having separate genetic targets).
  • Certain variants may have an impact on test performance.
  • Testing with the single target(s) is more likely to fail to detect new variants due to modifications in their performances because of viral mutations.
  • Tests with various/multiple targets are more prone to maintain their performance, as mentioned in the labeling of the test, when new variants appear. A molecular test with multiple targets detects greater than one section of the SARS-CoVID-2 genome or, in the case of antigen tests, it I greater than one section of proteins making up SARS-CoV-2.

Background Information on Omicron Variant

As of November 30, 2021, the United States designated B.1.1.529, the omicron strain of SARS-CoVID-2, as a Variant of Concern (VOC). December 1, 2021, marks the first day when the first case of omicron was confirmed in the United States.

Many mutations have been found in the omicron variant, specifically in its Spike gene, encoded by its S-gene.

As part of the evaluation of the omicron variant’s impact on SARS-CoV-2 diagnostic tests, the FDA is in touch with the government partners and the test developers.

Antigen Diagnostic Tests and the Omicron Variant

The FDA has monitored and analyzed a genetic variant during the COVID-19 pandemic.

To study how antigen tests perform with patient samples that contain the omicron variant, FDA is working with the National Institute of Health (NIH) program, i.e., RADx. In recent studies performed by RADx, the performance of antigen tests using live virus samples was evaluated, representing the only short-term method to determine real test performance. Observations prove that these antigen tests trace out the omicron variant, but it may be less sensitive.

RADx performed some of the existing antigen tests using heat-inactivated samples before performing these live virus tests. These heat-inactivated samples were successful in detecting omicron variants and others (variants). When patients cannot provide live virus samples, heat-inactivated sample(s) are no doubt the best alternative.

Clinical study evaluation(s) utilizing samples of patients with live viruses is still ongoing, so these laboratory data collections are not a replacement. The FDA and RADx evaluate a series of antigen tests using live virus samples from patients.

The FDA continues authorizing these tests for use according to the authorized labels, so individuals should follow the instructions that come with these tests. Molecular tests are usually more sensitive and more prone to pick up infections early than antigen tests. Suppose, despite a negative result from antigen tests, a person experiences any symptoms or has a high probability of becoming infected due to any exposure. In that case, molecular testing should be used as a follow-up to determine whether to treat or not COVID-19. This has been the FDA’s long-standing recommendation for rapid testing since 1988. When someone tests positive for antigens, they should isolate themselves and seek follow-up advice from a healthcare provider to determine the next steps.

The agency will provide any new information or recommendations that will be provided to the public by the agency as soon as possible.

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