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Commentary: Coronavirus Variants and the COVID-19 Pandemic

Commentary
06/24/2021 Matthew E. Levison, MD, Drexel University College of Medicine|Drexel University;

The coronavirus RNA genome is composed of 30,000 nucleotides. When a virus replicates, mistakes, called mutations, sometimes occur in the sequence of nucleotides. Many of the mutations are inconsequential; some mutations weaken the virus; others give the virus a survival advantage, such as by enhancing transmission. Mutants with a survival advantage eventually become the dominant version of the virus. Over time, a virus may accumulate multiple mutations. A group of viruses that share the same inherited set of distinctive mutations is called a variant. Variants have also been called lineages or clades.

 

Variants of SARS-CoV-2, the coronavirus that causes COVID-19, have been given different names by various organizations, but the WHO has recently resolved this problem by naming variants with letters of the Greek alphabet. Of the first 5, the alpha variant, first detected in the UK, is also known as B.1.1.7; beta, first detected in South Africa, is also known as B.1.351; gamma, first detected in Brazil, is also known as P.1; delta, first detected in India, is also known as B.1.617.2; and epsilon, first detected in US (California), is also known as B.1.427 and B.1.429 (1).

 

Variants of concern (VOC) are those variants that have public health consequences, typically because they have one or more of the following properties:

  • More transmissible
  • Cause more severe disease
  • Not as easily neutralized by antibodies (including those generated by previous infection or vaccination, and therapeutic monoclonal antibodies)
  • Not as easily detected by diagnostic tests, such as a PCR (polymerase chain reaction) test (2)

The alpha, beta, gamma, delta, and epsilon variants have been designated as VOC in the US (1).

 

Many VOCs involve one or more mutations in the SARS-CoV-2 spike protein, which is a string of 1273 amino acids. The spike protein interacts with the host cell surface receptors, angiotensin-converting enzyme 2 (ACE2), and protease TMPRSS2, allowing the virus to bind and then fuse with the host cell. Once fused, the virus releases its RNA into the host cytoplasm, where it replicates. The spike protein has two subunits, S1 and S2. S1 contains the receptor-binding domain (RBD), which is particularly important for binding to human ACE2 receptors. S2 mediates membrane fusion. Mutations that affect the spike protein, especially its RBD (amino acid positions 319–541), can affect virus infectivity. Although it is as yet not known how many particles of SARS-CoV-2 have to be inhaled to cause infection, that number would likely be lower for a virus that is better at binding to the ACE2 receptor. Furthermore, because the spike protein also is one of the main SARS-CoV-2 viral components recognized by both the immune system and molecular diagnostic tests, changes in the spike protein may impair the ability of antibodies (natural or therapeutic) to neutralize the virus and also impair identification by molecular diagnostic tests.

 

Spike protein mutations may involve amino acid deletions or substitutions. Substitutions are described in terms of the specific amino acid substitution and its position in the amino acid sequence of the spike protein. For example, in the D614G mutation, aspartic acid (D) at position 614 in the spike protein’s amino acid sequence is replaced by glycine (G). A given mutation may be present in multiple variants, and each variant may have multiple mutations.

 

SOME COMMON VARIANTS OF CONCERN

NAME

MUTATION

EFFECT*

VARIANTS

D614G

Aspartic acid (D) at position 614 replaced by glycine (G)

First emerged in Europe in February 2020

Enhanced binding to the ACE-2 receptor, higher numbers of infectious virus in the respiratory tract, and increased transmissibility

Not associated with increased disease severity or reduced antibody binding

Alpha, beta, gamma, delta, and epsilon

E484K

Glutamate (E) at position 484 is replaced by lysine (K)

Impaired immunity from prior infection or vaccination and reduced susceptibility to some monoclonal antibody treatments

Beta, gamma, and, in the UK, some alpha

L452R

Leucine (L) at position 452 is replaced by arginine (R)

Increased transmission; decreased susceptibility to some monoclonal, convalescent, and post-vaccination antibodies

Delta and epsilon

N501Y

Asparagine (N) at position 501 is replaced by tyrosine (Y)

Enhanced binding to the ACE2 receptor

Alpha, beta, and gamma

*Compared to the original SARS-CoV-2 virus

 

Because of their increased transmissibility, the alpha, beta, gamma, and delta variants have spread worldwide the presence of the alpha variant having been confirmed in 155, beta in 144, gamma in 61, and delta in 66 countries (3).

 

Alpha Variant (B.1.1.7)

The alpha variant was first detected in Kent, a county in South East England, and in London in September 2020 (4). Over the next several months, this variant, which transmitted faster than other variants circulating at the time, rapidly became dominant in the UK (only to be later overtaken by the even more transmissible delta variant). The alpha variant arrived in the US late in November 2020. By January 2021, it had spread to at least 30 US states, doubling about every week and a half to become the dominant variant in many US states by March 2021 (5). On May 8, 2021, the alpha variant peaked at 70% of new infections in the US and then fell to 60.5% of new infections on June 5, 2021, and fell again to 52.2% of new infections on June 19, 2021, as it is being replaced by a more transmissible variant, delta (6).

 

The alpha variant is defined by 23 mutations, of which 8 mutations (6 that encode amino acid changes and 2 deletions) are in the spike protein (7). The amino acid deletion at positions 69 and 70 within the spike protein causes “spike gene target failure” (SGTF), that is, failure of probes to detect the S-gene target with one commonly used PCR-based diagnostic assay; detection of other targets, including the nucleocapsid (N) and ORF1ab genes is unaffected by this mutation. SGTF has served as a proxy for identifying the alpha variant in patient specimens in place of whole genome sequencing (8).

 

In the UK, the alpha variant is thought to be associated with an increased risk of death (9), but more studies are thought to be needed to confirm this. The alpha variant with the E484K mutation not only spreads faster but is also better at evading immunity than alpha variants without this mutation (10).

 

The effectiveness of 2 doses of the Pfizer-BioNTech mRNA vaccine to prevent any infection with the alpha variant was 89.5% at 14 or more days after the second dose and over 97% effective at preventing severe, critical, or fatal disease (11).

 

Beta (B.1.351), Gamma (P.1), and Epsilon (B.1.427, B.1.429) Variants

The beta variant was first detected in South Africa in December 2020, and it remains dominant there. This variant was first detected in the US at the end of January 2021, but currently accounts for less than 1% of infections in the US In Qatar, the effectiveness of 2 doses of the Pfizer-BioNTech mRNA vaccine to prevent any infection with the beta variant was 75%, and over 97% at preventing severe, critical or fatal disease.

 

The gamma variant was first detected in travelers from Brazil, who were tested during routine screening at an airport in Japan, in early January 2021. This variant is dominant in Brazil and is spreading throughout South America (12); it accounted for 16.4% of infections on June 19, 2021, in the US, having almost doubled during the previous month (13). This emerging variant must be watched closely.

 

The epsilon variants were first identified in California in February 2021, but currently account for less than 1% of infections in the US (13).

 

Delta Variant (B.1.617.2)

The delta variant, which is dominant in India, has about a 40% higher transmission rate than the alpha variant, which itself is 50% more transmissible than the original strain of the virus. In the UK, the delta variant has now displaced other variants and currently accounts for 96% of all new cases genetically analyzed.

 

Symptoms with delta variant infection are noted to be different, often including headache, sore throat, and a runny nose, rather than the classic symptoms of COVID-19 (eg, cough, fever, loss of smell or taste).

 

The delta variant is more likely to lead to hospitalizations than the alpha variant, despite spreading primarily among younger people. In England, although spreading mostly in unvaccinated groups, about 6% of new cases were in fully vaccinated people and 26% of new cases had received 1 dose of vaccine (14). Of the 42 deaths recorded within 28 days of a positive test for the delta variant, 23 patients were unvaccinated, 12 were fully vaccinated, and 7 had received one dose (14). Because of the spread of the delta variant, England’s planned removal of all remaining public-health restrictions on June 21, 2021, as the final stage of a four-step reopening that began in March 2021, is now being delayed for 4 weeks.

 

The situation in the UK may portend what will happen in the US as the delta variant replaces the alpha variant as a cause of new cases; the delta variant went from 0.1% of new cases in early April 2021, to 9.5% of new cases on June 5, 2021, and 20.6% on June 19, 2021, doubling about every 10 days (13).

 

Nevertheless, there is evidence that 2 doses of the Pfizer-BioNTech and AstraZeneca vaccines retain similar effectiveness against the delta variant as against the alpha variant. In a recent press release, Public Health England said that 2 doses of the Pfizer-BioNTech vaccine are 96% effective in preventing hospitalization and 88% effective in preventing symptomatic disease, and 2 doses of the AstraZeneca vaccine are 92% effective in preventing hospitalization and 67% effective in preventing symptomatic disease (15). Data on effectiveness of these vaccines in preventing death from the delta variant were said to be forthcoming.

 

Although the full vaccine regimens appear to provide excellent protection against the delta variant, one dose of these 2-dose vaccines gives only limited protection — one dose of either the Pfizer-BioNTech or the AztraZeneca vaccine was just 33% effective against symptomatic disease caused by the delta variant compared with about 50% effectiveness against the alpha variant. This finding prompted the British government to reduce the period between the 2 doses from 12 weeks to 8 for people aged above 40 years. In France, the period has been reduced to 3 weeks from 5 for a second dose of the Pfizer-BioNTech and Moderna vaccines (16). The period between doses in the US has always been 3 weeks for Pfizer-BioNTech and 4 weeks for Moderna vaccines (17).

 

A recent study analyzed antibody levels in the blood of 250 healthy people after either one (at a median of 28 days) or 2 doses (at a median of 30 days) of the Pfizer-BioNTech COVID-19 vaccine (18). People fully vaccinated with 2 doses of the vaccine had levels of neutralizing antibodies that were more than 5 times lower against the delta variant when compared to the original strain. The antibody response was even lower in people who had only received one dose. After a single dose of Pfizer-BioNTech vaccine, 79% of people had a quantifiable neutralizing antibody response against the original strain, but this fell to 50% for the alpha variant, 32% for the delta variant, and 25% for the beta variant. Levels of neutralizing antibodies are lower with increasing age, and levels decline over time, providing additional evidence in support of plans to deliver a booster dose to vulnerable people. Partial vaccination with only one vaccine dose, therefore, may create selective pressure for emergence of new variants that even more easily escape immune control.

 

Conclusions

Prevention of COVID-19 becomes particularly important at this time as more highly transmissible variants are continuously emerging. The more a virus circulates in the human population, and the more people who are infected, the more opportunities the virus has to mutate. Slowing transmission thus slows emergence of mutations. However, nonpharmaceutical interventions to reduce transmission, including wearing masks, physical distancing, improving indoor ventilation, avoiding crowded places, and restricting travel are being rolled back in many locations. Also, there is no antiviral medication currently available that can be easily taken to prevent or treat early SARS-CoV-2 infection. 

 

We nevertheless are extremely fortunate to have several vaccines that are about 90% effective at preventing symptomatic infection and even more effective at preventing hospitalizations and death from COVID-19 caused by the more easily transmissible and virulent SARS-CoV-2 variants, but only when fully vaccinated with 2 doses. Partial vaccination with one dose of these vaccines has not been shown to be effective and may be deleterious. Even after 2 doses with these vaccines, a booster dose may subsequently be required as neutralizing antibody levels wane over time. The SARS-CoV-2 variants are dangerous, but manageable by fully vaccinating populations everywhere as quickly as possible.

 

References

1. Centers for Disease Control and Prevention: SARS-CoV-2 variants classifications and definitions. June 23, 2021. https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.html

2. World Health Organization (WHO): Tracking SARS-CoV-2 variants. May 31, 2021. https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/

3. Centers for Disease Control and Prevention: COVID data tracker: Global variants report. Accessed June 23, 2021. https://covid.cdc.gov/covid-data-tracker/#global-variant-report-map

4. Rambaut A, Loman N, Pybus O, et al: Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations. December 9, 2020. https://virological.org/t/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563

5. Washington NL, Gangavarapu K, Zeller M, et al: Genomic epidemiology identifies emergence and rapid transmission of SARS-CoV-2 B.1.1.7 in the United States. [PREPRINT] MedRxiv February 7, 2021 https://doi.org/10.1101/2021.02.06.21251159

6. Centers for Disease Control and Prevention: COVID data tracker. Accessed June 23, 2021. https://covid.cdc.gov/covid-data-tracker/#datatracker-home

7. Harvey WT, Carabelli AM, Jackson B, et al: SARS-CoV-2 variants, spike mutations and immune escape. Nat Rev Microbiol 19:409-424, 2021. https://doi.org/10.1038/s41579-021-00573-0 https://www.nature.com/articles/s41579-021-00573-0

8. Guerra-Assunção JA, Randell PA, Boshier FAT, et al: Reliability of spike gene target failure for ascertaining SARS-CoV-2 lineage B.1.1.7 prevalence in a hospital setting. [PREPRINT] MedRxiv April 14, 2021 doi: https://doi.org/10.1101/2021.04.12.21255084 https://www.medrxiv.org/content/10.1101/2021.04.12.21255084v1.full

9. Iacobucci G: Covid-19: New UK variant may be linked to increased death rate, early data indicate, BMJ 372:n230, 2021 doi:10.1136/bmj.n230. https://www.bmj.com/content/372/bmj.n230

10. Wise J: Covid-19: The E484K mutation and the risks it poses. BMJ 372:n359, 2021. Doi:10.1136/bmj.n359. https//www.bmj.com/content/372/bmj.359

11. Abu-Raddad LJ, Chemaitelly H Effectiveness of the BNT162b2 Covid-19 vaccine against the B.1.1.7 and B.1.351 variants. N Engl J Med May 5: NEJMc2104974, 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117967/

12. Taylor L: Covid-19: How the Brazil variant took hold of south America. BMJ 373:n1227, 2021. Doi: 10.1136/bmj.n1227. https://www.bmj.com/content/373/bmj.n1227

13. Centers for Disease Control and Prevention: COVID data tracker. Variant proportions. Accessed June 23, 2021. https://covid.cdc.gov/covid-data-tracker/#variant-proportions

14. Davis N: Delta variant causes more than 90% of new Covid cases in UK. The Guardian June 11, 2021.https://www.theguardian.com/world/2021/jun/11/delta-variant-is-linked-to-90-of-covid-cases-in-uk

15. Public Health England: Vaccines highly effective against hospitalisation from delta variant. [press release] June 14, 2021 https://www.gov.uk/government/news/vaccines-highly-effective-against-hospitalisation-from-delta-variant

16. How COVID vaccines work against the delta variant. Al Jazeera June 16, 2021. https://www.aljazeera.com/news/2021/6/16/how-covid-vaccines-work-against-delta-variant

17. Centers for Disease Control and Infection: Frequently asked questions about COVID-19 vaccination. Updated June 15, 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/faq.html

18. Wall EC, Wu M, Harvey R, et al: Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination. Lancet 397 (10292): P2331-P2333, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01290-3/fulltext

 

Matthew Levison, MD

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