In the USA, over 853,000 people were hospitalized for Covid-19 in May, 20211. About 0.1% (less than 1200) of them were fully vaccinated. Of the 18,000 Covid-19 deaths in May, only 150 (0.8%) were people who were fully vaccinated1. Meanwhile, the more transmissible Delta variant of the SARS-CoV-2 virus has been detected in at least 98 countries2. It was designated a Variant of Concern (VOC) by the World Health Organization (WHO) on 11 May, 20213. It has become the dominant strain in India, Bangladesh, the UK, USA, Singapore, Russia, Indonesia, Portugal, Luxembourg, the Netherlands, Denmark, South Africa and Australia3. The goals of this month’s article are to describe VOCs and Variants of Interest (VOIs) as well as the evolution of the SARS-CoV-2 virus.
Variants of Concern (VOCs) and Variants of Interest (VOIs)
The WHO defines a VOC as a variant that has been demonstrated to be associated with one or more of the following changes3:
- increase in transmissibility or detrimental change in COVID-19 epidemiology;
- increase in virulence or change in clinical disease presentation;
- decrease in effectiveness of public health and social measures or available diagnostics, vaccines, therapeutics.
The WHO has designated Alpha, Beta, Gamma and Delta variants as VOCs. Their evolutionary lineages are defined by Phylogenetic Assignment of Named Global Outbreak LINeages, also known as Pango5-7. It is a software tool. Its purpose is to implement a dynamic nomenclature to classify genetic lineages for SARS-CoV-28. A user with a full genome sequence of a SARS-CoV-2 genome can use the tool to submit that sequence. It is then compared with other genome sequences, and assigned the most likely lineage8.
There are also some Epsilon variants that the WHO has designated as are VOIs. A VOI is a variant which, if compared to a reference variant, has important mutations in its genome. These mutations have either established or suspected implications on the phenotype. VOIs also either cause community transmission of the virus with multiple Covid-19 cases or clusters, or have been detected in multiple countries. A VOI can also be designated to be a VOI by the WHO SARS-CoV-2 Virus Evolution Working Group3.
The U.S. Centers for Disease Control (CDC) has slightly different definitions9. To them, a VOC is a variant for which there is evidence of an increase in transmissibility, more severe disease (e.g. increased hospitalizations or deaths), a significant reduction in neutralization by antibodies generated during previous infection or vaccination, reduced effectiveness of treatments or vaccines, or diagnostic detection failures. The B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.427 (Epsilon), B.1.429 (Epsilon), and B.1.617.2 (Delta) variants circulating in the United States are classified as variants of concern. They have the following mutations in the part of their genome that codes for the Spike protein.
- B.1.1.7 (Alpha) Spike Protein Substitutions: 69del, 70del, 144del, (E484K), (S494P), N501Y, A570D, D614G, P681H, T716I, S982A, D1118H (K1191N*);
- B.1.351 (Beta) Spike Protein Substitutions: D80A, D215G, 241del, 242del, 243del, K417N, E484K, N501Y, D614G, A701V;
- P.1 (Gamma) Spike Protein Substitutions: L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G, H655Y, T1027I;
- B.1.617.2 (Delta) Spike Protein Substitutions: T19R, (G142D*), 156del, 157del, R158G, L452R, T478K, D614G, P681R, D950N;
- B.1.427 (Epsilon) Spike Protein Substitutions: L452R, D614G;
- B.1.429 (Epsilon) Spike Protein Substitutions: S13I, W152C, L452R, D614G.
The one letter abbreviations for amino acids are listed in the Appendix. The first very significant mutation was in amino acid 614. The original virus had a D-aspartate (D) in this position. A mutant emerged early in which 614 is a glycine (G). This is called a D614G mutation. This mutation in the S protein made it more stable and the virus more infective. It became the dominant variant as it spread to the Americas. In the South Africa Beta variant, a K417N (lysine to asparagine) mutation appeared independently in the U.S. and several European countries. This mutation is associated with escape from neutralization by monoclonal and polyclonal antibodies in blood serum10. It has also had E484K and N501Y mutations. The P.1 Gamma variant has K417T, E484K and N501Y mutations.
There is also a Delta Plus also a variant that has a K417N mutation. It is also known as AY.111.
There are two other variants called B.1.427 and B.1.429 that are quite concerning, even though they have not yet been designated as VOCs12. A recent study in Switzerland tested the ability of blood plasma to neutralize a pseudovirus made using the spike (S) protein from the B.1.427 and B.1.429 variants of the SARS-CoV-2 virus. This was compared to the ability of the plasma to neutralize the wild type variant that had the D614G mutation. They analyzed plasma from eleven people who received two doses of Moderna vaccine and from fourteen people who received two doses of the Pfizer/BioNtech vaccine. Blood plasma had been collected between 7 and 27 days after receiving the second injection. All vaccines had substantial plasma neutralizing activity against wildtype SARS-CoV-2 pseudoviruses. The average neutralization potency of the plasma from people who received the Moderna vaccine was reduced 2.8-fold for the B.1.427 and B.1.429 S variants, and was reduced 4-fold from people who received the Pfizer/BioNtech vaccine12. It remains to be seen whether or not this reduced potency in the laboratory will also be seen in people. In Scotland, both the Oxford–AstraZeneca and Pfizer–BioNTech Covid-19 vaccines were effective in reducing the risk of SARS-CoV-2 infection and Covid-19 hospitalization in people with the Delta VOC13. Delta VOC in Scotland was found mainly in younger, more affluent groups. Risk of Covid-19 hospital admission was approximately doubled in those with the Delta VOC when compared to the Alpha VOC, with risk of admission particularly increased in those with five or more relevant co-morbidities. Both the Oxford–AstraZeneca and Pfizer–BioNTech Covid-19 vaccines were effective in reducing the risk of SARS-CoV-2 infection and Covid-19 hospitalization in people with the Delta VOC13. On the other hand, recent data from Israel show that there has been a decrease in efficacy of Pfizer-BioNTech vaccine as the Delta variant spreads14. Between May 2 and June 5, the vaccine had a 94.3% efficacy rate. On June 6 (five days after the government canceled social restrictions) until early July, the rate decreased to 64%. A similar decline was recorded in protection against Covid-19 symptoms. At the same time, protection against hospitalization and serious illness remained strong. From May 2 to June 5, the efficacy rate in preventing hospitalization was 98.2%, compared to 93% from June 6 to July 314.
Still, the virus continues to mutate, producing new variants15. Unvaccinated people provide the virus with an ecosystem in their bodies that will continue to produce more transmissible variants.
The evolution of the SARS-CoV-2 virus
Because of a lack of funding, virologists have only been able to identify a very small fraction of the viruses that exist on Earth. It has been estimated that there are over half a million of unidentified viruses16. All that one can do is to try to find the viral genome in existing databases that most closely matches that of the original variant of the SARS-CoV-2 virus that was seen in Wuhan, China in December, 2019. However, this coronavirus almost certainly existed before it had infected and killed enough people to be noticed. Until the outbreak occurred in Wuhan, nobody was looking closely at all databases.
So, there is a data set containing SARS-CoV-2 sequences from early in the Wuhan epidemic that was been deleted from the NIH’s Sequence Read Archive17. It was found and recovered from some deleted files in the Google Cloud. The investigator reconstructed partial sequences of thirteen early versions of the coronaviruses. Phylogenetic analysis of these sequences suggests that the Hunan Seafood Market sequences that are the focus of the joint WHO-China report are not fully representative of the viruses in the epidemic. Instead, the progenitor of known SARS-CoV-2 sequences likely contained three mutations that made it more similar to bat coronavirus relatives. The genomes of the current array of variants are consistent with expansion from a single progenitor variant sequence. However, attempts to identify this progenitor have been confounded by a perplexing observation: the earliest reported sequences from Wuhan are not the sequences most similar to SARS-CoV-2’s bat coronavirus relatives. The deleted and now set of partial SARS-CoV-2 sequences from the early Wuhan epidemic were analyzed. This led to some conclusions. First, the Hunan Seafood Market sequences that were the focus of the joint WHO-China report may not be representative of all variants that were present early in the epidemic. The deleted data as well as existing sequences from Wuhan-infected patients hospitalized in Guangdong show that early Wuhan sequences often contained a thymine to cytosine mutation on base number 29095 (T29095C) and were less likely to contain two bases that are in sequences listed in the joint WHO-China report. Second, there are two plausible identities for the progenitor of all known SARS-CoV-2 variants. One of them was described by Kumar and coworkers18, and the other is a sequence that carries three mutations (C8782T, T28144C, and C29095T) relative to Wuhan-Hu-117. Regardless of which coronavirus was the progenitor of the SARS-CoV-2 virus, evolution has continued. Just as we do not know enough or have enough data to identify the true progenitor, neither can we predict where and when the next more transmissible and deadlier variant will emerge.
Children are relatively safe so far. In the USA, only about 1.7% of all the people who have tested positive for the SARS-CoV virus are children younger than 18 years (1.1% in the Netherlands, and 2.0% in the UK)19. As of April 7, 2021 only 0.0167% of all Covid-19 deaths in the USA were in the age group of 0 – 4 years, despite being about 6% of the total population20-21.
Still, there are lingering effects in some. Inevitably, some young children will pay the price if enough adults don't get vaccinated. However, it’s the unvaccinated elderly who are most at risk. Some parents may not want to get their children vaccinated simply to protect older people who are too stubborn to get vaccinated. It is true, though, that some young children will suffer one way or another if enough adults aren’t vaccinated. Interestingly, Fox News recently had someone present a short talk that encouraged people to vaccinate young children22. This is the same Fox News that spread the lies of Donald Trump and the Republican Party and denies global climate change. They have a long history of endangering the lives of countless young children. So, it’s curious that they would encourage adults not to get vaccinated, but to vaccinate young children. Clinical trials on children as young as six months are being conducted. Results will probably be available this Fall.
Amino acid abbreviations: A – alanine; C – cysteine; D – aspartic acid; E – glutamic acid; F – phenylalanine; G – glycine; H – histidine; I – isoleucine; K – lysine; L – leucine; M – methionine; N – asparagine; P – proline; Q – glutamine; R – arginine; S – serine; T – threonine; V – valine; W – tryptophan; Y – tyrosine.
So, D614G is when a mutation changes an aspartic acid (D) is changed into a glycine (G), N501Y is when a mutation changes an asparagine (N) into a tyrosine (Y); L452R is when a mutation changes a leucine (L) into an arginine (R); K417N is when a mutation changes a lysine (K) into an arginine (R); P681R is when a mutation changes a proline (P) into an arginine (R).
1 Al-Arshani, S. 99% of current Covid-19 deaths have one thing in common. Science Alert, 28 June, 2021.
2 United Nations, UN News. The Delta variant has been detected in 98 countries. It continues to mutate and evolve. 2 July, 2021.
3 World Health Organization. Tracking SARS-CoV-2 variants. 2021.
4 Hadda, M. Map: Tracking the Delta variant. Al Jazeera, 6 July, 2021.
5 Pangolin. Phylogenetic Assignment of Named Global Outbreak LINeages, 2021.
6 COG Consortium. PANGO Lineages: Latest epidemiological lineages of SARS-CoV-2, 2021.
7 Rambaugh, A. et al. A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology. Nature Microbiology, Volume 5, p. 1403-1407.
8 Phylogenetic Assignment of Named Global Outbreak Lineages. Software Tool, 2021.
9 Centers for Disease Control, CDC. SARS-CoV-2 Variant Classifications and Definitions. 23 June, 2021.
10 Thomson, E.C. et al. The circulating SARS-CoV-2 spike variant N439K maintains fitness while evading antibody-mediated immunity.bioRxiv. 2020.
11 Verma, J. and Subbarao, N. Insilico study on the effect of SARS-CoV-2 RBD hotspot mutants’ interaction with ACE2 Insilico study on the effect of SARS-CoV-2 RBD hotspot mutants. Virology, Volume 561, p. 107-116, 2021.
12 McCallum, M. et al. SARS-CoV-2 immune evasion by the B.1.427/B.1.429 variant of concern. Science, 1 July, 2021.
13 Sheikh, A. et al. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. The Lancet, Volume 397, 2021.
14 Odenheimer, A. Israel data reportedly shows drop in efficacy of Pfizer-BioNTech vaccine as delta variant spreads. Bloomberg, 5 July, 2021.
15 Smith, R.E. COVID-19 News: Millions are vaccinated, while the virus mutates and produces new variants. Wall Street International, 24 Jan., 2021.
16 The Global Virome Project, 2021.
17 Kumar, S.Q. et al. An evolutionary portrait of the progenitor SARS-CoV-2 and its dominant offshoots in COVID-19 pandemic. Molecular Biology and Evolution, 24 Sept., 2020.
18 Kumar, S.Q. et al. An evolutionary portrait of the progenitor SARS-CoV-2 and its dominant offshoots in COVID-19 pandemic. Molecular Biology and Evolution, 24 Sept., 2020.
19 Viner, R.M. and Whittaker, E. Kawasaki-like disease: emerging complication during the COVID-19 pandemic. The Lancet, Volume 395, pp. 1741-1743, 2020.
20 CDC. Provisional COVID-19 deaths: focus on ages 0-18 years. 7 Apr., 2021.
21 CDC. Resident population, by age, sex, race, and Hispanic origin: United States, selected years 1950–2012.
22 Rivas, K. Foolish' not to vaccinate young kids if Covid-19 shots found safe, effective, expert says. Fox News, 13 July, 2021.