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Last reviewed: August 3, 2022
The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject.
Viruses mutate over time, and as a result, new variants of viruses tend to emerge. Most mutations do not produce clinically relevant changes for individual infections, but occasionally mutations occur that may be beneficial for the virus epidemiologically.
Multiple variants of SARS-CoV-2, the virus that causes COVID-19, have emerged or spread throughout different parts of the world, including the United States. Variant viruses may carry mutations that could be associated with differences in diagnostic test performance, changes in disease epidemiology, clinical outcomes and effectiveness of certain therapeutics or vaccines. Additionally, some forms of SARS-CoV-2 are recombinant. Recombinant viruses occur when multiple variants infect the same individual at the same time, and the variants exchange genetic material with each other, changing their formulations. Recombination events occur more frequently when community transmission levels are high. Naming conventions for recombinant variants include an “X,” referring to the intersection of genetic material from two previously distinct lineages.
In November 2021, the World Health Organization designated the Omicron variant (B.1.1.529) as a “variant of concern.” This VOC designation was determined based on the number and location of mutations present in the spike protein — many of which have been previously associated with increased transmissibility and immune evasion — as well as epidemiological data from southern Africa suggestive of high rates of reinfection and replacement of Delta by Omicron as the dominant circulating variant.
Omicron was first reported from South Africa and neighboring countries in November 2021 but has since become the dominant variant around the world. The Omicron variant differs from previous variants of SARS-CoV-2 in the increased number of mutations present in the spike protein (at least 30, including 15 in the receptor binding domain region) relative to previous variants such as Beta (10) and Delta (nine), many of which are unique. These mutations impact the performance of certain molecular tests targeting the spike protein gene, as well as viral transmissibility, and neutralization by monoclonal antibodies or antibodies elicited by COVID-19 vaccination or SARS-CoV-2 natural infection.
There are several lineages designated “Omicron,” including B.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4 and BA.5. The lineage B.1.1.529 includes BA.1 and BA.3; BA.1.1 and BA.2 are categorized separately. Omicron lineages share 39 mutations from the ancestral strain of SARS-CoV-2, and BA.1 and BA.2 also differ by 28 mutations (Colson, March 2022; Yu, April 2022) — approximately twice as many amino acid differences as those that exist between the ancestral strain of SARS-CoV-2 and the first four WHO-designated variants of concern (Alpha, Beta, Gamma and Delta).
As new subvariants of Omicron continue to emerge, the possibility increases that immunological protection from a previous Omicron infection may not protect against a new variant. Preliminary evidence from in vitro studies suggests that immunological protection from BA.1 infection may not protect against BA.4 or BA.5 infection (Khan, May 2022 – preprint, not peer-reviewed; Cao, June 2022)..
Variants and subvariants may account for an increased proportion of new cases for several reasons. Two primary reasons are:
- The variant or subvariant is able to replicate more quickly in respiratory tracts, reducing the time interval and increasing the capacity for onward transmission as well as potentially increasing viral load; and/or
- The variant or subvariant grows at a pace that is similar to other variants or subvariants but has genetic changes that allow it to evade immune system detection more easily.
Limited evidence suggests that the comparative increase in cases of BA.5 is due to an increased ability to evade immune system detection compared with other variants and subvariants (European Center for Disease Prevention and Control, May 2022). Epidemiological information about new Omicron subvariants is limited and still emerging.
The lineages BA.1 and BA.1.1, as well as BA.4 and BA.5, experience S-gene target failure: While these viruses are identifiable by PCR, some PCR tests specifically for an S-gene component that fails to be recognized for BA.1 and BA.1.1. This led to these lineages being colloquially termed “stealth” variants; however, S-gene target failure is used as a tool to identify the presence of these lineages specifically.
Within the BA.2 lineage, several subvariants have been identified, including BA.2.12, BA.2.12.1 and BA.2.75. The subvariants BA.2.12 and BA.2.12.1 are estimated to have an approximately 23%-27% growth advantage above the original BA.2 variant (New York State Department of Health, April 2022). At present, there is no evidence suggesting these subvariants cause more severe disease than the original BA.2 lineage, but outcomes after BA.2.12 and BA.2.12.1 infection continue to be monitored. Preliminary evidence about BA.2.75 suggests that, similar to BA.4 and BA.5, its susceptibility to a broad range of monoclonal antibody therapies is reduced (Yamasoba, July 2022 — preprint, not peer-reviewed).
Evidence about the severity, diagnostic performance, vaccine effectiveness and reinfection risk specifically regarding BA.2 is limited and is still being investigated. Observational evidence from the U.K. Health Security Agency suggests that cases caused by BA.2 are not more severe than cases caused by BA.1, but the relative severity of BA.2 cases is still being investigated. An observational study in Denmark using national COVID-19 surveillance systems identified 263 SARS-CoV-2-positive individuals with genomic results that had a reinfection out of a total of 1.8 million cases (1,739 cases with genomic results). This study found that reinfection with BA.2 after initial infection with BA.1 was rare (Stegger, February 2022 – preprint, not peer-reviewed). Unfortunately, in a laboratory study in Japan, most therapeutic monoclonal antibody treatments were not effective against cases caused either by BA.1 or BA.2 (Takashita, March 2022). In that study, imdevimab still had neutralizing activity against BA.2, as did a combination of imdevimab and casirivimab, though this combination did not have neutralizing activity against BA.1 or BA.1.1.
There are several recombinant forms of SARS-CoV-2 that involve Omicron genetic material, including XD (Delta-Omicron) and XE (BA.1-BA.2). Current evidence suggests that XD is not associated with higher transmissibility or more severe outcomes than its parent strains.
Source: Screenshot of CDC Nowcast data accessed November 28, 2022. Data updates via CDC weekly on Fridays.
CDC’s COVID Data Tracker illustrates the proportions of each of the lineages currently circulating in the U.S.
A number of notable transmission events and outbreaks (Gu, December 2021; Jansen, December 2021; Brandal, December 2021) and the rapid expansion of Omicron in South Africa (Viana, January 2022) and the U.S. (Lambrou, February 2022) have illustrated the epidemic importance of this variant. Early evidence suggests that the heightened transmissibility of the Omicron variant is not attributable to higher viral loads compared to previous variants (Puhach, April 2022; Hay, January 2022 – preprint, not peer-reviewed) but instead greater immune evasion.
Multiple studies have demonstrated reduced neutralization of Omicron by antibodies from vaccinated or convalescent individuals compared with previous SARS-CoV-2 variants. This includes recipients of the Pfizer-BioNTech (Cele, December 2021; Edara, February 2022; Dejnirattisai, January 2022; Muik, January 2022; Rossler, January 2022), Moderna (Rossler, January 2022), Johnson & Johnson/Janssen (Lyke, January 2022 – preprint, not peer-reviewed) and Oxford-AstraZeneca (Dejnirattisai, January 2022; Rossler, January 2022) COVID-19 vaccines. These observations also translate to reduced effectiveness of prior infection (Altarawneh, February 2022) as well as mRNA and viral vector vaccines against both infection and severe disease due to the Omicron variant. Importantly, booster doses of vaccine appear to restore in vitro neutralization titers in the short term (Nemet, December 2021; Garcia-Beltran, December 2021; Pajon, January 2022; Lyke, January 2022 – preprint, not peer-reviewed) as well as clinical effectiveness (Andrews, April 2022; Thompson, January 2022; Johnson, January 2022; Accorsi, January 2022; Gray, December 2021 – preprint, not peer-reviewed; Ferdinands, February 2022; Danza, February 2022).
COVID-19 Incidence and Death Rates Among Unvaccinated and Fully Vaccinated Adults With and Without Booster Doses During Periods of Delta and Omicron Variant Emergence — 25 U.S. Jurisdictions, April 4–December 25, 2021 (Johnson, January 2022).
In this analysis, CDC investigators used COVID-19 surveillance data from 25 jurisdictions to determine COVID-19 case and death rates among unvaccinated individuals compared with individuals who had received two or three doses of a COVID-19 vaccine across four time periods: pre-Delta (April–May 2021), Delta emergence (June 2021), Delta predominance (July–November 2021) and Omicron emergence (December 2021). Vaccinated individuals had lower rates of infection and death in all time periods, but the relative reduction in incidence was lowest during the period of Omicron emergence, consistent with significant immune escape. Fully vaccinated individuals who had received a booster dose of vaccine had the lowest case and death rates compared with both unvaccinated individuals and those who had received two doses of vaccine. The effect of a booster dose was most substantial among individuals aged >50 years of age.
Studies from multiple countries — including the U.S. (Iuliano, January 2022; Lewnard, May 2022 – preprint, not peer-reviewed; Christensen, April 2022; Wang, January 2022 – preprint, not peer-reviewed; Wang, January 2022 – preprint, not peer-reviewed; Modes, February 2022; Lauring, March 2022), U.K. (Sheikh, April 2022) and South Africa (Abdullah, December 2021; Maslo, December 2021; Wolter, January 2022; Davies, April 2022) — indicate that infection due to the Omicron variant is associated with less severe disease (decreased risk of hospitalization and death, reduced length of stay, etc.) compared with previous variants of concern, including Delta. This may be attributable to relatively less lower respiratory tract replication (Diamond, December 2021 – preprint, not peer-reviewed; Hui, February 2022; Meng, February 2022; Suzuki, February 2022).
Trends in Disease Severity and Health Care Utilization During the Early Omicron Variant Period Compared With Previous SARS-CoV-2 High Transmission Periods — United States, December 2020–January 2022 (Iuliano, January 2022).
In this analysis, CDC investigators used data from three surveillance systems and a large health care database to characterize indicators of COVID-19 disease severity — including rates of hospitalization, ICU admission and death as well as markers of health care utilization such as need for mechanical ventilation and hospital length of stay — across three high-COVID-19 transmission periods, spanning winter 2020-2021, July 15-Oct. 31, 2021 (Delta surge) and Dec. 19, 2021-Jan. 15, 2022 (Omicron surge). They found that overall COVID-19 cases, ED visits and admissions were significantly higher during the Omicron period than during previous high COVID-19 transmission periods, but deaths were significantly lower. Additionally, hospitalized COVID-19 patients had a shorter length of stay, a smaller proportion required ICU admission or mechanical ventilation, and fewer died during the Omicron period. Notably, rates of ED visits and hospitalization were higher for those aged under 18 years, presumably related to their lower rates of vaccination.
Omicron cases of all lineages can be detected using a molecular method such as RT-PCR in two ways. The first is to assess for spike gene target failure in PCR assays that assess for presence of the spike gene. The BA.2 lineage lacks the mutation that results in spike gene target failure and therefore would not be detected using this method. The second way to identify these cases is to use a PCR designed to look for the major mutations specific to the Omicron variant. This method would be able to detect all lineages.
With respect to rapid antigen tests, three independent studies have shown no change in the analytic sensitivity of one of the most widely used rapid antigen tests in the U.S., the Abbott BinaxNOW COVID-19 Antigen test. The first study was from Australia and showed no attenuation in sensitivity relative to detection of the Delta variant using samples obtained from viral culture (Deerain, December 2021). The study also evaluated nine other rapid antigen tests available in Australia and found no attenuation in sensitivity. A second study used 32 Omicron and 30 Delta samples previously collected as part of a university screening program and also showed no difference in analytic sensitivity for the BinaxNOW test by variant. The authors also found that the limit of detection of the assay was in the range of prior estimates made during earlier pandemic waves (Kanjilal, January 2022 – preprint, not peer-reviewed). A third study at a community testing center in San Francisco compared nasal swabs to nasal RT-PCR and showed that the BinaxNOW test had a sensitivity of 95% for detecting virus below a cycle threshold value of 30 (Schrom, March 2022). The study did not provide an estimate of the viral copy number associated with a cycle threshold value <30. However, an additional independent laboratory-based study found reduced ability to detect cases caused by Omicron compared to Delta, using nine rapid antigen tests available in Germany (Osterman, February 2022).
In December 2021, FDA announced that studies from independent laboratories have shown that rapid antigen tests can still detect cases caused by the Omicron variant, but the analytic sensitivity may be decreased by an unspecified amount. The data supporting this announcement has not yet been published.
The clinical sensitivity of rapid antigen tests varies depending on when the test is performed in the illness course. Tests performed too early may be falsely negative because the amount of virus at the time of sampling is below the limit of detection for the assay. Thus, if people infected with the Omicron variant are developing symptoms earlier, or in the throat before the nasopharynx, then sampling from the nose at the time when symptoms begin may lead to a false negative result (Adamson, January 2022 - preprint, not peer-reviewed). Testing may be repeated within 24 to 48 hours per CDC's suggestion. Conversely, performing a throat swab, which is off-label use, later in the course of illness may also be falsely negative.
Most rapid antigen tests in current use in the United States are not validated — and are therefore not interpretable — for specimen types OTHER than the anterior nares, such as throat specimens. This includes the Abbott BinaxNOW COVID-19 Antigen Self-Test, the Quidel QuickVue SARS Antigen Test, ACON FlowFlex COVID-19 Antigen Home Test and the iHealth COVID-19 Antigen Rapid Test.