The Covid-19 virus has undergone thousands of mutations since it was first identified, with some of these giving rise to variants that evade antibodies more successfully and contributing to a surge in infections. Mutant strains now remain a key concern, with a continuously evolving virus throwing up newer challenges and many countries reporting a spike in breakthrough infections among fully vaccinated people.
Classification of mutant Covid strains
It is natural for all viruses to mutate over time and such changes are particularly common in viruses that have RNA as their genetic material, as in the case of coronaviruses and influenza viruses.
Once a virus enters the human body, its genetic material — RNA or DNA — enters the cells and starts making copies of itself which can infect the other cells. Whenever an error occurs during this copying process, it triggers a mutation.
Occasionally, a mutation comes along when the genetic mistakes that are introduced while copying prove to be advantageous for the virus — these help the virus copy itself or enter human cells more easily.
Whenever a virus is widely circulating in a population, the more it spreads and replicates, its chances of mutating increases.
According to a model of classification which was developed by a US government SARS-CoV-2 Interagency Group (SIG) and followed by the Centres for Disease Control and Prevention (CDC), Covid-19 mutations of significance are divided into three types — Variant of Interest, Variant of Concern and Variant of High Consequence.
This SIG was formed to improve coordination among the CDC, National Institutes of Health (NIH), Food and Drug Administration (FDA), Biomedical Advanced Research and Development Authority (BARDA), and Department of Defense (DoD). Its function is to characterise emerging variants and study how standard treatment protocols and vaccines work against these mutant strains.
WHO also classifies significant mutant strains as Variants of Concern (VOC) and Variants of Interest (VOI). But CDC classifications can differ from that of WHO, and there can also be differences across countries and locations.
For instance, the Indian government has said that Delta Plus (AY.1) is a variant of concern, while its parental lineage — Delta — has been classified as a VOC by WHO and CDC.
WHO has proposed using Greek alphabet for VOCs and VOIs to ensure that the labels being used are “easy to pronounce” and “non-stigmatising”.
Variants of Concern (VOC)
The CDC defines a VOC as a “variant for which there is evidence of an increase in transmissibility, more severe disease (e.g., increased hospitalisations or deaths), significant reduction in neutralisation by antibodies generated during previous infection or vaccination, reduced effectiveness of treatments or vaccines, or diagnostic detection failures.”
VOCs are marked by increased transmissibility and potential to induce more severe forms of disease, decreased neutralisation by antibodies generated during previous infection and the ability to cause more breakthrough infections in vaccinated people.
Alpha variant (B.1.1.7): According to WHO, the Alpha variant was first identified in the UK in September 2020 and has now spread to at least 173 countries, according to the WHO. The variant has 23 mutations and eight of those are in the virus’s spike protein. Out of these, three spike protein mutations — N501Y, 69-70del and P681H — make the biggest impact.
The N501Y mutation helps the virus’s spike protein to attach more tightly to the ACE2 receptors of the human cells while the other two key mutations increase transmissibility. According to the CDC, the Alpha variant is 50% more transmissible than the original strain and can cause more severe infections.
Beta variant (B.1.251): First detected in South Africa in May 2020, B.1.251 was designated as a VOC in December 2020. The variant has been detected in at least 122 countries now. The strain has eight mutations, three of which are significant — N501Y, K417N and E484K.
As in the case of Alpha variant, the N501Y mutation helps the virus bind more tightly to the ACE2 receptors while the other two mutations help the virus evade immunity more easily.
The Beta variant is also about 50% more transmissible than the original strain and can cause more severe infections.
Gamma variant (P.1): The Gamma variant originated in Brazil in November 2020 after which it caused a significant surge in infections and increased hospitalisations in the South American nation. It was detected in Japan in January 2021 and subsequently spread to 74 countries.
The variant has 11 mutations in its spike protein, out of which N501Y and K417T mutations help the virus to bind more tightly onto cells while E484K makes it more resistant to antibodies.
The Gamma variant is twofold more transmissible than the original Covid-19 strain.
Delta variant (B.1.617.2): The fastest spreading variant which also caused a sharp spike in cases during the second wave in India, Deltait is a sublineage of the B.1.617 variant, which was known as the “double mutant” strain.
First detected in India, the Delta variant according to WHO has displayed “significantly increased transmissibility”. It is twice as transmissible as the original Covid-19 strain and 60 per cent more transmissible than the Alpha variant. The strain has several key mutations, with L452R and D6146 allowing it to attach more firmly to receptor cells and others such as P681R allowing it to evade immunity more easily.
PHE has said that Delta causes an “increased risk of hospitalisation compared to contemporaneous Alpha cases”. The variant has now spread to at least 104 countries.
Variants of Interest (VOI)
The CDC defines a VOI as a “variant with specific genetic markers that have been associated with changes to receptor binding, reduced neutralization by antibodies generated against previous infection or vaccination, reduced efficacy of treatments, potential diagnostic impact, or predicted increase in transmissibility or disease severity”.
The WHO says that a variant of interest can become a variant of concern if it demonstrates an “increase in transmissibility or detrimental change in COVID-19 epidemiology, increase in virulence or change in clinical disease presentation or a decrease in effectiveness of public health and social measures or available diagnostics, vaccines, therapeutics”.
However, they are classified as VOI as long as there is no conclusive evidence to suggest that they are deadly enough to be classified as VOC. For instance, the Kappa variant (B.1.617.1) came from the same lineage as Delta but the latter has proved to be far more dangerous and widespread.
By contrast, the Lambda variant (C.37), which was first detected in Peru, is seen as an emerging threat, with research in Chile showing that it has greater infectivity than Alpha and Gamma. Though scientists continue to closely monitor Lambda, there is not enough conclusive evidence now for it to be classified as a VOC. This is a common factor for other mutant strains which have been classified as VOI — either they are not understood well enough or preliminary research suggests suggest that they cannot be linked to increased risk of infections on a significant level.
But significant spike protein mutations and the risk of evading immunity more easily is common to all of them, as in the Eta variant (B.1.525) identified in UK and Nigeria, Iota variant (B.1.526) first detected in New York City, Epsilon variant (B.1.427/B.1.429) first found in California, Zeta variant (P.2) first detected in Brazil, or the B.1.617.3 (unnamed variant) found in India which shares the same parental lineage (B.1.617) as Delta and Kappa.
R-naught value and high infectiveness of mutant variants
A recently published study, conducted through May and June in Guangzhou, China, found that from the samples it analysed that the viral load of patients infected with the Delta variant was about 1,000 times higher than that in the 9A/19B strains from 2020. This suggested a potentially faster viral replication rate and more infectiousness of the Delta variant at an early stage of the infection. The variant also had a much better immune escape mechanism.
Comparing the R-naught (R0) values gives us a fair idea of how the variants of concern are now more infectious than the original Covid-19 strain. The R-naught, or the basic reproduction number, represents, on average, the number of people that a single infected person can be expected to transmit that disease to and hence the “spreadability” of an infectious disease.
Most studies arrived at an R-nought value of 2.4-2.6 for the original Covid-19 strain found in Wuhan. Subsequent studies found that the R-nought value is 4-5 for the Alpha variant and 5-8 for the Delta strain. It means that the Delta is more infectious than smallpox which in the 1970s had an R-nought of 3.5 to 4.5.
The Guangzhou study also found that in case of the Delta variant, there is an extremely high level of infectiousness in patients even in the pre-symptomatic phase. This means people are in danger of spreading the virus even before suspecting that they may be infected.
A good example in this regard, which also underlines the infectiveness of the Delta variant, is a case of a fleeting, non-contact transmission as reported recently from a mall near Sydney’s Bondi Beach. As caught on CCTV camera, a limousine driver, who was infected with the Delta variant but did not know it at that time, ended by infecting another man who just passed close to him and stood near him for a brief instance. Australian officials took serious note of the footage and only days later a lockdown was announced in Sydney.
Spike protein mutations
Viruses are enveloped with fatty membrane proteins (or glycoproteins as they are frequently covered in slippery sugar molecules) which help them to fuse to the body’s cell membrane.
The spike protein of coronaviruses is one of these viral glycoproteins in the form of a linear chain of 1,273 amino acids, neatly folded into a structure, studded with up to 23 sugar molecules.
In case of SARS-CoV-2, the spike protein is stuck on the roughly spherical viral particle, embedded within the envelope and projecting out into space. Each Covid virus has about 26 spike trimers which help it to cling onto human cells — one of these binds to a protein on the surface of human cells called ACE2, which allows the virus to enter the body.
Mutations which involve significant changes in the spike protein can be of concern because they trigger transformations in the structure and the biochemical property of the virus. This can happen through mutations which make the spikes easier to stick to cells or prevents antibodies from binding to it.
A recent research published in Cell found that a single spike protein mutation may have played a significant role in helping coronavirus jump from animals to people. During the course of the study led by James Weger-Lucarelli, a virologist at Virginia Tech in Blacksburg, scientists found that the amino acid threonine found in the coronaviruses that infected bats or pangolins had been replaced with the amino acid alanine that is found in the coronavirus that causes Covid-19. The researchers found that the swap was made possible by one mutation, named T372A, which removed some sugars coating the spike protein and gave the virus better access to ACE2 to break into human cells.
Since many anti-Covid drugs and vaccines target the viral glycoproteins, changes in the spike protein can make them less effective. For instance, the D614G mutation achieves this by alerting the genetic code for the Covid spike protein by changing a single amino acid “letter”. The mutation also renders the spikes more stable, making it easier for the virus to bind to ACE2 receptors.
Another case in point is the Epsilon variant, which has two distinct lineages, B.1.427 and B.1.429, and was once considered to be a VOC by the CDC but was later downgraded to a VOI. The Epsilon variant decreases the neutralising potency of antibodies induced by vaccines or past Covid infections due to mutations that led to significant rearrangements in critical areas of the spike protein of the virus, a research project led by University of Washington in Seattle and Vir Biotechnology has found.
Electron cryomicroscopy studies on the Epsilon variant showed that a mutation on the receptor binding domain on the spike protein reduced the activity of 14 out of 34 neutralising antibodies. Two other mutations led to total loss of neutralisation by all 10 antibodies specific to the N-terminal domain on the spike protein.
Mutant strains and reduced vaccine efficiency
Most studies have concluded that vaccines are less effective against Covid variants than against the original strain of the virus.
For instance, a study by PHE has found that the effectiveness of the Oxford-AstraZeneca vaccine comes down to 74% against the Alpha variant and 64% against the Delta variant. Earlier, a phase 1b-2 clinical trial published in the New England Journal of Medicine had found that the AstraZeneca vaccine was only a 10.4% efficacy against mild-to-moderate infections caused by the Beta variant.
Bharat Biotech has said that Covaxin offers 65.2% protection against the Delta variant.
Recent data from the Israel Health Ministry shows that two shots of Pfizer offer 64% protection against Covid, with the observation coming at a time when over 90 per cent of the cases being reported in the Middle-Eastern country in recent times being caused by the Delta variant.
Moreover, a study in The Lancet has found that one dose of the Pfizer vaccine offers only 32% protection against Delta, and the level of neutralising antibodies even after two shots is over five times lower against the Delta variant than against the original Covid-19 strain.
Apart from vaccines, most variants are less susceptible to therapeutic interventions and monoclonal antibody treatment.
However, most studies have shown that almost all vaccines are highly effective against preventing hospitalisation.
With some reports stating that booster shots can offer better protection against the variants, many countries are now rolling out a third vaccine dose for the elderly and immunocompromised people.
