The Variety of Variants in COVID-19

Merriam-Webster defines variant as “manifesting variety, deviation, or disagreement.” Variant has become a normal part of our lexicon during the COVID-19 pandemic, but what does this actually mean for SARS-CoV-2?

SARS-CoV-2 is the virus that causes COVID-19 infection. It is an enveloped, nonsegmented RNA virus with an error-prone RNA polymerase that leads to accumulated mutations during periods of high viral replication. Many of these mutations will not rise to a level of clinical significance but some will confer a fitness advantage on the virus. This advantage may lead to easier transmission, immunologic escape, less response to therapeutics, or more severe clinical disease. These fitter mutant viruses have been deemed variants. They had been expected to occur and will continue to become more diverse and potentially more challenging as the pandemic persists.

The scientific community has been monitoring and assessing the evolution of SARS-CoV-2 since January 2020 when information about the virus first became available. During late 2020, investigators identified the emergence of variants that posed an increased risk to global health.¹ They have since developed a variant classification scheme that groups SARS-CoV-2 variants into 3 distinct groups based on viral and clinical characteristics: variant of interest (VOI), variant of concern (VOC), and variant of high consequence.¹ A VOI has been defined as possessing specific genetic markers that are associated with changes to receptor binding, reduced neutralization by antibodies generated from previous infection or vaccination, reduced efficacy of treatments, potential diagnostic impact, or predicted increase in transmissibility or disease severity.

A VOC is defined as showing evidence of increase in transmissibility, more severe disease, significant reduction in neutralization by antibodies, reduced effectiveness of treatment or vaccines, or diagnostic detection failures. A variant of high consequence shows clear evidence that prevention measures or medical countermeasures have significantly reduced its effectiveness relative to previously circulating variants. Currently no SARS-CoV-2 variants rise to the level of high consequence.

The variants were originally labeled with the location in which they were first detected. Those labels led to stigmatization and discrimination. Rambaut et al proposed a dynamic nomenclature for SARS-CoV-2 lineages that focuses on actively circulating virus lineages and those that spread to new locations.² This became known as the Pango classification of SARS-CoV-2. However, these labels were confusing and difficult to remember as the number of variants grew. At the end of May 2021, the World Health Organization (WHO) assigned a simple label for key variants of SARS-CoV-2 using letters of the Greek alphabet. These labels have become widely accepted.

The Centers for Disease Control and Prevention (CDC) and WHO³ lists of VOIs and VOCs vary slightly, with the CDC listing Epsilon (Pango B.1.427/B.1.429) as a VOC but the WHO listing it as a VOI. Otherwise the VOCs are similar across both agencies. Looking deeper into the VOCs on both lists shows essentially 4 main variants being closely monitored and studied. The Alpha variant (Pango B.1.1.7) was first identified in the United Kingdom and designated a VOC by the WHO in December 2020, with the first samples dating back to September 2020. Alpha shows a 43% to 90% increased transmission rate, potentially increased severity based on hospitalization and fatality rates, but no reduced response to monoclonal antibody treatments and only minimal impact on neutralization by convalescent and postvaccination sera.^4-6

The Beta variant (Pango B.1.351), first identified in South Africa, was designated a VOC by the WHO in December 2020. The first samples date to May 2020. Beta shows an increased transmission rate of approximately 50%⁷ but also shows significantly reduced susceptibility to the combination of bamlanivimab and etesevimab monoclonal antibody treatment; other emergency use authorization (EUA) monoclonal antibody treatments also are available. Beta also shows notable reduced neutralization by convalescent and postvaccination sera.

The Gamma variant (Pango P.1) dates back to samples identified in Brazil in November 2020, and was designated a VOC by the WHO in January 2021. Gamma shows significantly increased transmissibility, with a rate possibly as high as 100%.⁸ It also has been shown to possess significantly reduced susceptibility to the bamlanivimab and etesevimab combination but retains susceptibility to other EUA monoclonal antibody treatments. Gamma displays reduced neutralization by convalescent and postvaccination sera.⁹ As a result, this variant (P.1 or gamma) may cause severe disease even in persons who have been previously infected by another variant.

The Delta variant is the last VOC designated by the WHO, on May 11, 2021, and is rapidly becoming the most problematic variant in the United States and worldwide. The earliest sample dates back to October 2020 in India. Delta (Pango B.1.617.2) shows an increased transmissibility rate (26%-113%)¹⁰ relative to Alpha and potential reduction in neutralization by some monoclonal antibody treatments. It also demonstrates reduced neutralization by postvaccination sera, resulting in higher risks of infection and clinical progression of disease, even among those who have received vaccinations.

Hospitalization rates as high as 85%¹¹ above that seen with Alpha have been reported. A variant deemed “Delta plus” is also being monitored in England and India. It should be noted that to date none of the above variants have shown any changes in testing efficacy.

Where does this leave us? Clearly, SARS-CoV-2 will continue to evolve. Variants of concern will continue to develop, with selective advantage generally favoring those that are more transmissible.¹² Delta is becoming the predominant strain due to its increased transmissibility and is outcompeting the previously dominant Alpha variant. Vigilance in preventing transmission of infection and in monitoring for newer variants is critical, as a new VOC could evolve with even higher rates of immune evasion from vaccination or prior infection, prompting continued spread and risks of ongoing reinfection. However, such a variant would also require increased transmissibility to become the predominant circulating strain. The available vaccines continue to provide significant protection from the development of severe infection, aiding in the prevention of further variations emerging. Widespread, rapid vaccination is of paramount importance to avoid further surges in this pandemic. However, this does not negate the continued need for mask use, hand hygiene, distancing, and testing for those who are unvaccinated or may have a blunted immune response (immunocompromised patients). We may be entering a new phase of the pandemic regarding vaccines and variants, but the pandemic is not over.

References

1. ^{SARS-CoV-2 variant classifications and definitions. CDC. Updated July 13, 2021. Accessed June 24, 2021. https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.html}
2. ^{Rambaut A, Holmes EC, O’Toole Á, et al. A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology. Nat Microbiol. 2020;5(11):1403-1407. doi:10.1038/s41564-020-0770-5}
3. ^{Tracking SARS-CoV-2 variants. WHO. Updated July 6, 2021. Accessed July 24, 2021.https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/}
4. ^{Davies NG, Abbott S, Barnard RC, et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. MedRxiv. Preprint posted online March 5, 2021. doi:10.1101/2020.12.24.2024882}
5. ^{Horby P, Huntley C, Davies N, et al. NERVTAG note on B.1.1.7 severity. New & Emerging Threats Advisory Group, Jan. 21, 2021. Accessed June 24, 2021.}
6. ^{Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. bioXRiv. Preprint posted online February 12, 2021. doi:10.1101/2021.01.25.428137}
7. ^{Pearson CAB, Russell TW, Davies NG, et al. Estimates of severity and transmissibility of novel South Africa SARS-CoV-2 variant 501Y.V2. Accessed June 24. 2021.}
8. ^{Faria NR, Mellan TA, Whittaker C, et al. Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil. Science. 2021;372(6544):815-821. doi:10.1126/science.abh2644}
9. ^{Wang P, Casner RG, Nair MS, et al. Increased resistance of SARS-CoV-2 variant P.1 to antibody neutralization. bioRxiv. Preprint posted online April 9, 2021. doi:10.1101/2021.03.01.43346}
10. ^{SARS-CoV-2 variants of concern and variants under investigation in England: technical briefing 15. Public Health England. June 11, 2021. Accessed 15 June 2021. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/993879/Variants_of_Concern_VOC_Technical_Briefing_15.pdf}
11. ^{Sheikh A, McMenamin J, Taylor B, Robertson C; Public Health Scotland and the EAVE II Collaborators. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. Lancet. 2021;397(10293):2461-2462. doi:10.1016/S0140-6736(21)01358-1}
12. ^{Krause PR, Fleming TR, Longini IM, et al. SARS-CoV-2 variants and vaccines. N Engl J Med. 2021;385(2):179-186.doi:10.1056/NEJMsr2105280}