SARS-CoV-2 Variants

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SARS-CoV-2 Variants

Last reviewed: January 13, 2022

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Overview

Viruses mutate over time, and as a result, new variants of viruses tend to emerge. Most mutations do not produce clinically relevant changes, but occasionally mutations occur that may be beneficial for the virus.

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.


Clinical Data Summary

Selected CDC/World Health Organization Designees with Published Clinical Data 
Version 12/24/21

Variant
(WHO label/
Pango lineage)

Treatment efficacy (in vitro)** 

mRNA vaccine clinical effectiveness

Viral vector vaccine clinical effectiveness

Nanoparticle / subunit vaccine clinical effectiveness

Omicron 
B.1.1.529  

Southern Africa 
2021 

 

 

Bamlanivimab + etesevimab: No  neutralization efficacy (CDC; Gruell, December 2021 – preprint, not peer-reviewed) 

REGEN-COV (casirivimab + imdevimab): No neutralization efficacy (Wilhelm, December 2021 – preprint, not peer-reviewed) 

Sotrovimab: Retains neutralization efficacy 

Convalescent sera: Severely reduced neutralization efficacy (from patients recovering from Alpha and some Delta infections) (Ikemura, December 2021 – preprint, not peer-reviewed) 

Evusheld: Retains neutralization efficacy (NIH OpenData, December 2021)
 

 

Pfizer-BioNTech vaccine: 

Significantly reduced effectiveness against infection in the UK (Andrews, December 2021 – preprint, not peer-reviewed) 

 

 

Oxford-AstraZeneca vaccine: 

Significantly reduced effectiveness against infection in the UK (Andrews, December 2021 – preprint, not peer-reviewed) 

 

 

No data 

Delta 
B.1.617.2 
 
India 
2020 

Bamlanivimab + 
etesevimab:  
Retains neutralization efficacy (FDA EUA)  
Bamlanivimab alone inefficacious 

REGEN-COV (casirivimab + imdevimab):  
Retains neutralization efficacy (FDA EUAPlanas, May 2021) 

Sotrovimab:  
Retains neutralization efficacy (FDA EUA) 

Convalescent sera:  
Potential moderately reduced neutralization (Planas, May 2021) 

Pfizer-BioNTech vaccine: 
Slightly reduced effectiveness against infection but preserved effectiveness*** against severe COVID-19 after 2 doses in the U.S. (Tartof, October 2021), U.K. (Bernal, July 2021Stowe, May 2021 - preprintSheikh, June 2021) and Canada (Chung, August 2021) 

Moderna vaccine: 
Slightly reduced effectiveness against infection but preserved effectiveness against severe COVID-19 in Canada (Chung, August 2021)

Oxford-AstraZeneca vaccine: 
Slightly reduced effectiveness against infection but preserved effectiveness*** against severe COVID-19 after 2 doses in the U.K. (Bernal, July 2021Stowe, May 2021 - preprintSheikh, June 2021) and Canada (Chung, August 2021) 

No data 

Gamma 
P.1 
 
Brazil 
2020 

Bamlanivimab + 
etesevimab:  
Markedly reduced neutralization (FDA EUA) 

REGEN-COV (casirivimab + imdevimab):  
Retains neutralization efficacy (FDA EUA) 

Sotrovimab:  
Retains neutralization efficacy (FDA EUA) 

Convalescent sera:  
Moderately reduced neutralization (Wang, June 2021) 
 

No data 

(Presumed to be similar to Beta variant based on relevant mutations)

No data 

(Presumed to be similar to Beta variant based on relevant mutations) 

No data 

(Presumed to be similar to Beta variant based on relevant mutations) 

Beta 
B.1.351 
 
South Africa 

2020 

Bamlanivimab + 
etesevimab: 
 
Markedly reduced efficacy (FDA EUAChen, June 2021) 

REGEN-COV (casirivimab + imdevimab):  
Retains neutralization efficacy (FDA EUAWang, March 2021)     
Markedly reduced neutralization with casirivimab alone 

Sotrovimab:  
Retains neutralization efficacy (FDA EUA) 

Convalescent sera:  
Moderately reduced neutralization (Planas, May 2021) 

Pfizer-BioNTech vaccine: 
Slightly reduced effectiveness against infection but preserved effectiveness against severe COVID-19 in Qatar (Abu-Raddad, May 2021) 

Moderna vaccine: 
Slightly reduced effectiveness against infection but preserved effectiveness against severe COVID-19 in Canada (Chung, August 2021)

Oxford-AstraZeneca vaccine: 
No effectiveness against infection in South Africa (Madhi, May 2021) 

Reduced effectiveness against infection but preserved effectiveness against severe COVID-19 in Canada (Chung, August 2021) 

Johnson & Johnson vaccine: 
Reduced effectiveness against infection but preserved effectiveness against severe COVID-19 in South Africa (Sadoff, May 2021) 

Novavax vaccine: 
Reduced effectiveness against infection (Shinde, May 2021) 

Alpha 
B.1.1.7 
 
U.K. 
2020 

 

Bamlanivimab + etesevimab:
Retains neutralization efficacy (FDA EUA) 

REGEN-COV (casirivimab + imdevimab):  
Retains neutralization efficacy (FDA EUA) 

Sotrovimab:  
Retains neutralization efficacy (FDA EUA) 

Convalescent sera: Retains neutralization efficacy (Planas, May 2021) 

 Pfizer-BioNTech vaccine: 
Preserved effectiveness against infection and severe COVID-19 in the U.K. (Hall, May 2021), Israel (Haas, May 2021), Qatar (Abu-Raddad, May 2021) and Canada (Chung, August 2021) 

Moderna vaccine: 
Preserved effectiveness against infection and severe COVID-19 in Canada (Chung, August 2021) 

Oxford-AstraZeneca vaccine: 
Slightly reduced effectiveness against infection but preserved effectiveness against severe COVID-19 in the U.K. (Emary, April 2021) and Canada (Chung, August 2021) 

Novavax vaccine: 
Preserved effectiveness against infection and severe COVID-19 in the U.K. (Heath, June 2021) 

*As compared with vaccine efficacy/effectiveness against wildtype or D614G variant SARS-CoV-2.
**The susceptibility results refer, as a default, to in vitro testing of sotrovimab against both pseudotyped virus-like particles and authentic SARS-CoV-2 virus. Where results are discordant, both pseudotyped and authentic virus susceptibility is presented. Where only one type of virus was tested, it was in all cases pseudotyped virus. In the case of the Delta variant, binding of the monoclonal antibodies to variant strain was tested with the S-Fuse binding assay. The extent of correlation of neutralizing activity in in vitro cell culture experiments with clinical outcomes is as yet unknown.
*** As compared with vaccine efficacy/effectiveness against Alpha/B.1.1.7 variant.

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Omicron

In late November 2021, the World Health Organization, the United States Department of Health and Human Services’ SARS-CoV-2 Interagency Group, and the European Center for Disease Prevention and Control 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 been identified in multiple countries around the world, including the United States, and among individuals with no history of travel to southern Africa. 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 [RBD] region), relative to previous variants such as Beta (10) and Delta (9) – many of which are unique. These mutations may have implications for the performance of certain molecular tests targeting the spike protein gene, as well as for transmissibility and neutralization by monoclonal antibodies or natural antibodies elicited by COVID-19 vaccination or SARS-CoV-2 natural infection. The impact of Omicron on disease severity remains to be characterized.

As information continues to emerge, we collect key timely resources here and provide key literature reviews on Omicron transmissibility, immunity and severity:

Transmissibility

Probable Transmission of SARS-CoV-2 Omicron Variant in Quarantine Hotel, Hong Kong, China, November 2021 (Gu, December 2021). 
This was a report of two successive SARS-CoV-2 infections due to the Omicron variant among guests of a quarantine hotel in Hong Kong. Both individuals had completed their Pfizer COVID-19 vaccine series 5-6 months earlier, had tested negative for SARS-CoV-2 by PCR within 72 hours of arrival, and arrived in Hong Kong from different originating sites – case A arrived from South Africa on November 11 and case B arrived from Canada on November 10. Case A was found to have asymptomatic SARS-CoV-2 infection on November 13 (cycle threshold value of 18) and Case B was subsequently found to have symptomatic SARS-CoV-2 infection on November 18 (cycle threshold value of 19). Both patients’ viruses underwent whole genome sequencing and were identified as the Omicron variant, differing by only 1 nucleotide, strongly suggestive of airborne transmission from case A to case B. 

 

Immunity

Effectiveness of COVID-19 vaccines against the Omicron (B.1.1.529) variant of concern (Andrews, December 2021 – pre-print, not peer-reviewed). 
In this analysis the authors used a test-negative case control design to evaluate COVID-19 vaccine effectiveness against symptomatic COVID-19 due to the Omicron variant compared to the Delta variant in the UK from October 16 to December 6, 2021. Cases of COVID-19 were identified as due to the Omicron or Delta variant based on the results of whole genome sequencing or S gene target status (from November 27 onwards, close to 90% of S gene target failure cases were confirmed to be due to Omicron by whole genome sequencing). A total of 581 cases of Omicron, 56,439 cases of Delta, and 130,867 test negative controls were identified over the study time period. The investigators separately analyzed individuals who had received two doses of the Oxford-AstraZeneca COVID-19 vaccine, two doses of the Pfizer-BioNTech COVID-19 vaccine, or two doses of either vaccine followed by a Pfizer-COVID-19 vaccine booster.  

The authors found no protective effect of two doses of the Oxford-AstraZeneca vaccine against Omicron from 15 weeks after the second dose. For individuals who received two doses of the Pfizer-BioNTech COVID-19 vaccine, vaccine effectiveness was 88.0% (95% CI, 65.9-95.8%) 2-9 weeks after dose 2, 48.5% (95% CI, 24.3-65.0%) at 10-14 weeks post dose 2, and 34-37% from 15 weeks post dose 2. Two weeks after a booster dose with the Pfizer COVID-19 vaccine, vaccine effectiveness was 71.4% (95% CI, 41.8-86.0%) among previous recipients of the Oxford-AstraZeneca vaccine and 75.5% (95% CI, 56.1-86.3%) among previous recipients of the Pfizer-BioNTech COVID-19 vaccine.  

As a comparison, the vaccine effectiveness of the Pfizer-BioNTech COVID-19 vaccine against Delta fell from 88.2% (95% CI, 86.7-89.5%) 2-9 weeks after dose 2 to 63.5% (95% CI, 61.4-65.5%) 25+ weeks after dose 2, and increased back to 92.6% (95% CI, 92.0-93.1%) 2 weeks after the booster. 

Reduced neutralisation of SARS-COV-2 Omicron-B.1.1.529 variant by post-immunisation serum (Dejnirattisai, December 2021 – pre-print, not peer reviewed).
In this study, the investigators measured antibody neutralization against an isolate of Omicron obtained from an infected case in the UK using post-vaccination sera from nucleocapsid seronegative individuals who had received two doses of either the Oxford-AstraZeneca (N=22) or Pfizer-BioNTech COVID-19 vaccine (n=21) – individuals received their vaccine doses on an extended interval schedule as part of the Com-COV2 study, with the second dose administered 8-11 (median 9.0) weeks after the first, and serum samples for this analysis being collected four weeks after the second dose. In this analysis, neutralizing titers against Omicron were only detectable in one recipient of the Oxford-AstraZeneca vaccine, and dropped 29.8 fold (compared with the parent SARS-CoV-2 strain) among recipients of the Pfizer-BioNTech COVID-19 vaccine. 

SARS-CoV-2 B.1.1.529 variant (Omicron) evades neutralization by sera from vaccinated and convalescent individuals (Roessler, December 2021 – pre-print, not peer reviewed). 
In this study, the investigators measured neutralizing antibody titers in sera from individuals who were either previously infected with SARS-CoV-2, who had been vaccinated with the Oxford-AstraZeneca (N=10), Moderna (N=10), Pfizer-BioNTech (N=20) or heterologous (Oxford-AstraZeneca then Pfizer-BioNTech) (N=20) vaccine, or both infected and vaccinated (N=10). They compared titers against the Alpha, Beta, Delta, and Omicron variants using replication competent SARS-CoV-2 variants. They found that sera from individuals vaccinated with the Oxford-AstraZeneca and Moderna vaccines neutralized Omicron to a much lesser extent than any other variant analyzed, with only some cross-neutralization in sera from individuals vaccinated with either homologous Pfizer-BioNTech or heterologous Oxford-AstraZeneca/Pfizer-BioNTech COVID-19 vaccination. Sera from individuals with “hybrid” immunity – infected then vaccinated or vice-versa – demonstrated the best cross-neutralization against Omicron, though still reduced compared with all other tested variants. 

SARS-CoV-2 Omicron has extensive but incomplete escape of Pfizer BNT162b2 elicited neutralization and requires ACE2 for infection (Cele, December 2021 - pre-print, not peer-reviewed).
In this small study, the investigators evaluated neutralizing antibody titers against the Omicron variant of SARS-CoV-2 using plasma samples from 12 individuals previously vaccinated with the Pfizer-BioNTech COVID-19 vaccine. The individuals were aged 41-68 years, mostly women (n=8) and had all received their COVID-19 vaccine in the preceding 6 weeks. Half the participants had a history of SARS-CoV-2 infection 12-15 months prior to vaccination. The investigators used a live virus neutralization assay and reported the reciprocal plasma dilution (FRNT50) that caused a 50% reduction in the number of infection foci seen on H1299-E3 cells – this same group of investigators has used this approach previously to describe decreased neutralization of the Beta variant by convalescent plasma (Cele, March 2021). In this study, the investigators found a 41-fold reduction in neutralizing antibody titers against the Omicron variantwhen compared with titers against the ancestral strain of SARS-CoV-2. Notably, in five of the participants with a history of prior infection, neutralizing antibody titers remained high. Though these preliminary data have important limitations – small number of participants, underlying conditions not specified, uncertainty if plasma timepoints were after the first or second dose of vaccine or if the individuals even received two doses of vaccine and no pre-vaccination titers reported – these findings suggest significant immune escape by the Omicron variant.

Reduced neutralization of SARS-CoV-2 Omicron variant by vaccine sera and monoclonal antibodies (Wilhelm, December 2021 – pre-print, not peer-reviewed). 
In this study, the investigators evaluated neutralizing antibody titers against the Omicron variant of SARS-CoV-2 using plasma samples from individuals who had previously completed a 2-dose Pfizer-BioNTech or Moderna COVID-19 vaccine series, some of whom had also received a Pfizer-BioNTech COVID-19 booster, as well as individuals who had received a mixed product vaccine series with the Oxford-AstraZeneca and Pfizer-BioNTech COVID-19 vaccines. The total sample size was 117, with each group including 8-20 individuals. Data on underlying comorbidities were not reported and the age range of these groups varied – for example, the median age was 51 years for the two-dose Pfizer-BioNTech COVID-19 vaccine recipients, 28 years for the two-dose Moderna COVID-19 vaccine recipients, and 87.5 years for the two-dose Pfizer-BioNTech COVID-19 vaccine recipients with a history of SARS-CoV-2 infection. The investigators used a live virus neutralization assay and reported the reciprocal dilutions of SARS-CoV-2 microneutralization titers resulting in 50% virus neutralization as seen on A549-AT cells – this same group of investigators has used this approach previously to describe neutralization against other SARS-CoV-2 variants (Wilhelm, August 2021). In this study, the investigators found significant reductions in neutralizing antibody titers against the Omicron variant (10- to 40-fold reduction depending on study group) when compared with titers against the Delta variant – a booster dose of the Pfizer-BioNTech COVID-19 vaccine did increase neutralizing antibody concentrations against Omicron compared with individuals who had completed their 2-dose Pfizer-BioNTech or Moderna COVID-19 vaccine series 6 months earlier. Furthermore, using this same assay the investigators evaluated the efficacy of the monoclonal antibodies casirivimab and imdevimab, against the Delta and Omicron variants, and found no neutralization of Omicron by these agents. These findings suggest significant immune escape by Omicron and the potential role of booster doses in augmenting immunity against this variant. 

Increased risk of SARS-CoV-2 reinfection associated with emergence of the Omicron variant in South Africa (Pulliam, December 2021 – pre-print, not peer-reviewed). 
In this analysis, the authors determined the rate of SARS-CoV-2 reinfection over time in South Africa from March 4, 2020 to November 27, 2021 using country-wide surveillance data of positive SARS-CoV-2 tests — they defined “reinfections” as any individuals who had two positive PCR tests for SARS-CoV-2 that were at least 90 days apart. They then used reinfection incidence data from the first wave of the pandemic in South Africa (June 2020 to September 2020) to develop a model to "project" the anticipated number of reinfections in each subsequent wave of SARS-CoV-2 infections, with the null hypothesis that the rate of reinfections would be proportional to incident primary infections. Thus, any increase in the relative hazard of reinfections compared with primary infections compared with the model projections from the first wave (i.e., the relative hazard ratio) may be suggestive of immune escape being a contributor to a new wave of reinfections. Using this approach, the investigators found that whereas the relative hazard ratio for reinfection during the Beta and Delta waves was <1 (not suggestive of immune escape), the relative hazard ratio for reinfection over the period November 1-27, 2021 was 2.39 (95% CI, 1.88-3.11), coincident with emergence of the Omicron variant. These findings provide early population-level evidence that the Omicron variant may be more capable of immune escape as compared with prior SARS-CoV-2 variants.

Severity

SARS-CoV-2 B.1.1.529 (Omicron) Variant — United States, December 1–8, 2021 (CDC COVID-19 Response Team, December 2021). 
This is a summary of the first 43 cases of COVID-19 due to the Omicron variant identified in the U.S. from December 1-8, 2021. The cases were identified from 22 states. Of the 43 cases, 14 (33%) occurred among those who had reported international travel in the 14 days preceding symptom onset or positive test result, 34 (79%) occurred among individuals who were fully vaccinated against COVID-19, including 14 (33%) who had received a booster dose (9 of whom had received the booster at least 14 days before symptom onset or the positive test result). Six cases occurred among individuals with a prior history of SARS-CoV-2 infection. Only one patient was hospitalized for 2 days and there were no deaths.

Impact on Testing

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 is 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 9 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, also showing no difference in analytic sensitivity for the BinaxNOW by variant. The authors also found that the limit of detection (LoD) 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, showing the BinaxNOW had a sensitivity of 95% for detecting virus below a cycle threshold (Ct) value of 30 (Schrom, January 2022 – preprint, not peer-reviewed). The study did not provide an estimate of the viral copy number associated with a Ct <30.   

In December 2021, FDA announced that studies from independent laboratories have shown that rapid antigen tests can still detect the Omicron variant but that 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 suggestion.  

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 (e.g., the throat). This includes the Abbott BinaxNOW COVID-19 Antigen Self-Test, the Quidel Quickvue SARS Antigen Test and the iHealth COVID-19 Antigen Rapid Test. 


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