Outbreaks of COVID-19 infection spread while SARS-CoV-2, the virus that causes COVID-19, evolves and circulates around the world. Given time, genetic mutations occur in the genomes of all known human viruses. For example, mutations occur rapidly in common viruses such as influenza, HIV, and hepatitis C. The high mutation rate contributes to the virus' ability to quickly adapt to changes in its environment.

Over the past year, thousands of mutations occurred within the SARS-CoV-2 genome. The genetic mutation rate of this virus is about 1:1,000 substitutions per genetic code site per year, according to a recent study published in the journal, Virus Research. This rate is slightly lower than those of influenza and HIV, for example, explains Joseph Yao, M.D., a Mayo Clinic researcher, in a recent scientific publication in Clinical Microbiology Newsletter. This virus mutated in previously uninfected humans and animals, resulting in altered viral replication and host-to-host transmission, Dr. Yao says.

"When strains of a virus with genetic sequences containing a set of commonly shared mutations are sufficiently different from the parent viral strain, they are designated as a new viral variant ― for example, delta and omicron ― whether or not these mutations cause observable differences in viral behavior," Dr. Yao says in his review. "Most viral variants do not pose a health risk and would not necessitate public health actions."

Scientists continue to study mutations in the viral spike protein of SARS-CoV-2, which is responsible for binding to the host cell receptor. The mutation types include:

• Silent mutations
  These mutations affect only the RNA sequence and not the viral proteins. With little or no ability to change the viral proteins or the virus' behavior, no substantial clinical effects occur because of silent mutations. However, silent mutations can interfere with diagnostic tests designed to detect viral RNA.
• Selective advantage mutations
  These mutations are advantageous to the virus for survival or virus reproduction, perhaps by evading the host immune system after a natural infection or after a vaccination by enhancing viral transmission or affecting host interactions.
  

SARS-CoV-2 variants raise concerns that current vaccines, therapeutic monoclonal antibody therapies, and testing need further investigation. Impact factors are:

• Increased mortality and transmissibility
  One study demonstrated an increased risk of death by 28 days postinfection when the B.1.1.7 variant of concern infections were compared to infections that were not related to this variant of concern.
• Reinfection
  One study suggested increased infection rates attributable to the B.1.351 variant among people who were fully vaccinated.
• Eluding the immune response
  The U.K., B.1.1.7; South Africa, B.1.351; and Brazil, P.1 variants have multiple changes in the spike protein that help them elude immune responses, according to an article in Nature.
• Enhanced replication
  One study found that the B.1.1.7 mutation may hinder the efficiency of existing vaccines and be better able to spread through a population with higher levels of immunity due to infection or vaccination.

Scientists rank the threat and categorize the variant according to risk, as follows:

• Variant of interest
  Requires further investigation.
• Variant of concern
  Demonstrates the potential for increased risk in lab studies, but it lacks clinical evidence proving that the risk is increased.
• Variant of high consequence
  This is the highest threat level. These variants would have strong evidence that prevention and medical countermeasures will not be as effective. A variant of high consequence impact might include a failure of diagnostic tests, a reduction in vaccine efficacy, an unusually high number of vaccine breakthrough cases, or low vaccine protection against severe disease. In other words, variants of high consequence could have reduced susceptibility to multiple therapies, and lead to increased disease severity, increased hospitalizations or evasion of testing methods. Fortunately, no SARS-CoV-2 variant is currently classified as a variant of high consequence. Identification of a new variant of high consequence would trigger the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) to create new strategies to prevent or contain the transmission, and, if needed, recommendations to update treatments and vaccines.

Common SARS-CoV-2 identified variants of concern include:

• B.1.1.7 lineage/alpha
  This strain emerged in the U.K. in September 2020 and spread through many countries, including the U.S., where it was first discovered in December 2020. The variant is associated with increased transmissibility, and increased risk of hospitalization and death, compared to other strains.
• B.1.351 lineage/beta
  This strain emerged independent of B.1.1.7 in South Africa, but it shares some mutations with the U.K. strain. Multiple reports found that vaccine-induced antibodies could not bind to or neutralize this variant as well as prior variants. No evidence suggests that this variant affects disease severity. However, it is associated with a selection advantage, meaning it is likely more transmissible. It was detected in the U.S. in January.
• B.1.617.2/delta
  This variant emerged in India in December 2020. Because of its increased transmissibility, it was found throughout the world, including the U.S., within months. This strain may be more than twice as contagious as previous strains, cause more severe illness and death, and create more breakthrough cases in people who have been vaccinated, according to the CDC. From the end of August until Dec. 4, the delta variant represented more than 99% of the cases in the U.S., according to the CDC's "Nowcast." By the week ending Dec. 11, though, the delta variant percentage dropped to 87% as the omicron variant accounted for nearly 13% of cases. By the week ending Dec. 11, the omicron variant accounted for 73% of cases while the delta variant accounted for only 27%.
• P.1 lineage/gamma
  First identified in Brazil, this strain was detected in the U.S. in January. Evidence suggests that some of the mutations in the P.1 variant may affect its transmissibility and its immunity to a vaccine. The mutations may affect the ability of antibodies to recognize and neutralize the virus. The variant's emergence and association with a higher viral density raised concerns about a potential increase in transmissibility and reinfection.
• B.1.427 and B.1.429
  These strains originated in California in October 2020. Before mutating, it likely emerged from New York via Europe early in 2020, according to a recent study in JAMA. It may be 20% more transmissible than common strains, the JAMA study suggests. Some COVID-19 treatments may not work well against the variants. Vaccines are still effective against both strains.
• B.1.1.529/omicron
  This variant was first identified on Nov. 11, 2021, according to the WHO. Because this strain has just emerged, scientists are still learning about its potential dangers. Preliminary reports suggest it is more transmissible and has a greater ability to evade preexisting immunity due to vaccination or prior infection. No current evidence suggests that it will cause more severe illnesses, the CDC reports. Because this is a new strain, however, the CDC says it is likely to cause more breakthrough cases in previously vaccinated populations. This variant went from less than 1% of cases in the U.S. before Dec. 4, to 73% by the week ending Dec. 18, according to the CDC.

Identifying the circulating and prevailing variants of SARS-CoV-2 that may be associated with increased infectivity, transmission or severity of infection in a given community or geographic region is essential for resource planning and effective mitigative measures to reduce the risk of infection. In the clinical domain, analyzing SARS-CoV-2 sequences could improve the care of an individual patient, if variants of high consequence emerge.

Dr. Yao is the senior author of the scientific publication in Clinical Microbiology Newsletter. The first author is Blake Buchan, Ph.D., a researcher at the Medical College of Wisconsin in Milwaukee.

- Adam Harringa, December 21, 2021

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