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As the Delta Variant Family Grows, the Ancestor Continues To Dominate

As the Delta Variant Family Grows, the Ancestor Continues To Dominate

A colorised scanning electron micrograph of a cell (teal and green) infected with SARS-CoV-2 virus particles (purple and pink). Photo: NIAID/Flickr, CC BY 2.0

During the first few months of the COVID-19 pandemic, the evolution of the causative novel coronavirus was relatively predictable, with substitutions accumulating at a fixed pace of about one every second week. In contrast, the second year of the pandemic has been punctuated by the emergence of several variants, signalling more and faster changes.

In the last few months, our focus has been on the delta variant (B.1.617.2), first detected in India last year but which has since emerged in almost every country. At present, the delta variant seems to be displacing all other variants. As of August 10, 2021, 378,405 sequences of the delta variant had been detected since the lineage was first identified. Its current global cumulative prevalence is 15%.

Alpha and delta

We know that the alpha variant does not have substitutions associated with immune evasion (except for one amino-acid deletion at the N-terminal domain, or NTD, of the spike protein). These substitutions are abundant in all other key variants.

This is in line with the timeline in which the alpha began to spread, around the last quarter of 2020 – when the global population hadn’t been vaccinated and less than a large fraction of the same population had been infected and recovered. So antibody-evasion substitutions bore no selective advantage in infections of naïve individuals.

The delta variant is currently spreading in a different scenario, with more immunised and recovered individuals in the population. So antibody-evasion substitutions could confer a significant advantage on the virus’s survival.

The variants of concern

At the genomic level, variants are characterised by phylogenetic clade – i.e. having a common ancestor – and classified based on the available evidence for increased transmissibility, virulence, or immune escape. WHO classifies the variants that have these characteristics as variants of concern (VOC), variants of interest (VOI) or variants under monitoring/investigation (VUM).

Thus far, the WHO has defined four VOCs:

  1. B.1.1.7 (alpha)
  2. B.1.351 (beta)
  3. P.1 (gamma)
  4. B.1.617.2 (delta)

… and four VOIs:

  1. B.1.525 (eta)
  2. B.1.526 (iota)
  3. B.1.617.1 (kappa)
  4. C.37 (lambda)

An additional 12 variants previously classified as VOIs, such as the B.1.427/9 that originated in California, have now been reclassified as VUMs.

At the genome level, all the VOCs have three key features:

  1. More non-synonymous (NS) substitutions (or point mutations) compared to non-VOCs
  2. NS substitutions predominantly in the spike protein
  3. NS substitutions in the spike are located mostly in the NTD and receptor binding domain

The one exception to these characteristics is the alpha variant, which has only one mutation associated with immune evasion.

Mutations in the virus’s genome alter the amino-acid sequences of the proteins that the genome encodes. (Think of the genome as an instruction manual that each cell ‘reads’ to produce the proteins needed for the virus’s function.)

All VOCs have an amino-acid replacement at position 203, 204 or 205 of the N protein. More recent evidence suggests that N has a crucial role in evading the cell’s innate immune response, and amino-acid replacements in this region may increase the virus’s replication capacity.

The delta variant’s genome has 13 mutations, including significant ones in the gene encoding the spike protein, known to affect the virus’s transmissibility and whether it can be neutralised by antibodies for previously circulating variants of the virus.

In particular, the L452R substitution increases the spike protein’s affinity for the ACE2 receptor and affects the immune system’s ability to recognise the invader. The P681R substitution may boost the variant’s cell-level infectivity.

Curiously, the delta doesn’t have the N501Y substitution, which is an integral part of the alpha, beta and gamma variants, and is known to enhance the virus’s transmission capability.

The delta variant belongs to clade 21A, under the NextStrain phylogenetic classification system, and is designated B.1.617.2 under the Pangolin lineages nomenclature.

Why is delta different?

The delta variant with all its characteristic mutations and deletions in the spike protein. The N417K mutation in the RBD of the spike is associated with its two sub-lineages, AY.1 and AY.2. Delta and AY.3 do not contain the N417K mutation. Source: Author provided

The delta variant is different from the other VOCs in its ability to transmit more vigorously, and – as we have seen – it has also evolved somewhat differently. Most variants are characterised by long branches on the evolutionary tree leading up to their emergence, with an excess of NS substitutions occurring particularly in the spike and N proteins. But the delta lacks the signature long branch and is characterised by an ongoing step-wise evolutionary process.

We know the delta variant has shorter incubation as well as latent periods than the ‘original’ B.1 strain. This means: People infected by the delta test positive more quickly after exposure than if they had been infected by the B.1. Individuals infected by the delta shed more virus particles, while the delta also binds and replicates faster, producing a higher viral load.

Recent studies show that the viral loads in people with delta infections were about 1,000-times higher than in those with B.1 strain infections, on the day the persons test positive. Overall, the time difference was similar but with a higher viral load among those with the delta variant. This could be one reason why the second COVID-19 outbreak in India earlier this year spread so fast.

On the flip side, if individuals show symptoms of an infection sooner, they (ought to) isolate themselves, preventing the virus from spreading to more people through them. This could be why the number of cases during the delta-variant outbreak in India both rose and fell steeply.

Importantly, for vaccines, the symptoms of an infection by the ‘original’ viral strain took around a week to show, whereas symptoms of an infection with the delta appear to show up in around four days. This is a big difference for our immune system. In April 2020, we held one of the fundamental aspects of COVID-19 to be six to seven days for a viral infection and around two weeks for severe pneumonia. These windows are consistent with the immune system having enough time to deal with the infection at the two different stages. The delta variant makes this more difficult.

Immunological impact

For the immune system, every day counts. T cells and B cells multiply fast. In fact, they are among the fastest replicating human cells. You can go from just one of these cells to 1,000 more in less than three days.

This was one reason we assumed that vaccines would likely be successful against COVID-19 – and they have been. Vaccines have done their job incredibly well, against infections of the B.1 strain in particular. But the delta variant infects faster and is more transmissible, so we will need to be on guard. Thankfully, for now, the mRNA vaccines, and also two doses of the AstraZeneca vaccine, seem to still work well against the delta.

As a reminder, our immune system has multiple ways to protect us: antibodies, T cells and B cells. Antibodies are the first line of defence and work to prevent an infection from taking root. But if you do get infected, T cells and B cells get activated, multiply for several days and then ‘fight’ the virus. If the viral population crosses an important threshold two or three days sooner, the T cells and B cells will have a harder challenge on their hands. Put another way, the delta variant imposes a greater burden on the neutralising antibodies to stop its invasion upfront.

This said, there is a lot more time to prevent severe disease. It still looks like a good mix of antibodies, CD4 T cells and CD8 T cells likely suffices to prevent severe COVID-19. And if a vaccine elicits such a mix, of CD4 T cells, CD8 T cells and/or memory B cells, it will also probably provide significant protection against severe COVID-19.

The T cells and B cells can jump in to help and probably have an effect in six or seven days, but probably not in four days. This is one reason why even the most potent vaccines are struggling against the delta variant, particularly to protect against infection and symptomatic disease. However, it would have been a different story if we had a mucosal vaccine that provided the T cells and B cells in the nose and the mouth, instead of in the blood.

Also read: COVID-19: Herd Immunity Is Not Going To Happen, so What Next?

The sub-lineages

Based on genomic characteristics, the delta variant has been divided further into three important sub-lineages: AY.1, AY.2 and AY.3, according to the Pangolin nomenclature.


The AY.1 variant is also known as the ‘delta plus’, and is characterised by B.1.617.2 plus one more mutation (K417N – also found in the beta variant).

The earliest sequence of this genome was reported from Europe in late March 2021. Some countries where AY.1 has been isolated from samples include the US (33% of samples), Portugal (12%), Japan (12%), the UK (9%,) and Switzerland (9%). It has also been reported from India and South Korea, and overall in 33 countries. However, its global prevalence is limited to less than 0.5%.

As of August 10, 2021, 519 sequences of the AY.1 lineage had been processed since the sub-lineage was first identified.


In the Pangolin nomenclature, AY.2 is also called B.1.617.2.2. It was first identified in May 2021. Around 99% of all AY.2 sequences have been isolated from the US, although many infections have also been reported from Mexico and Spain.

As of August 10, 2021, 1,056 sequences of the AY.2 strain had been detected in at least seven countries (and 36 US states). However, worldwide, its cumulative prevalence is lower than 0.5%, as with the AY.1.


AY.3 is also known as B.1.617.3. The AY.3 sub-lineage has been reported primarily from the US, with single reclassified cases in the UK and India. There are no known significant properties of this mutation. Until recently, the AY.3 variant accounted for approximately 15% of cases in the US. Worldwide, it has been detected in at least 61 countries.

As of August 10, 2021, 17,792 sequences of the AY.3 strain had been detected.

Both AY.1 and AY.2 have three mutations in common – K417N, L452R and T487K – in the receptor binding domain of the spike protein. The AY.3 sub-lineage, however, does not have the K417N mutation, and has only two substitutions in the domain, like the delta: L452R and T487K.

Further, the AY.1 does not have the characteristic 157-158 deletion in the NTD of the spike protein and AY.2 has two more substitutions in the NTD. However, all sub-lineages of the delta have other key spike protein substitutions, like the D614G, the P681R and the D950N.

However, remember that these mutations, when taken individually, are not unique to the variant. What’s common is their simultaneous occurrence. Also remember that these point mutations are not adequate to exert the effects we have come to associate with different variants. It is the company that these mutations have in the rest of the genome that decide their infectiousness, virulence and immune evasion.

Delta-D, a new sub-clade

Some of the ‘signature mutations’ associated with the delta (e.g. L452R and P681R in the spike protein) were created in a series of independent steps from its parent variant, the kappa (B.1.617). When scientists analysed all globally available delta sequences, they noticed that delta phylogeny could be separated into five distinct clades – from A to E, each characterised by a specific set of substitutions. These clades are in addition to the three recently noted VOIs, AY.1, AY.2 and AY.3.

Researchers have analysed the prevalence of these five newly characterised delta clades in several countries, where the frequency of variant has been rapidly increasing over time, and reported that the D clade is becoming more dominant.

In India, wherefrom the delta variant was first reported, all the delta clades co-occurred at first; the D clade started gaining only around May 2021. The first sequences bearing strains of the delta-D lineage are dated February-March 2021, and are predominantly from India, suggesting this clade first emerged there.

Although the delta-D is characterised by an excess of non-synonymous mutations, scientists noted no notable differences between delta-D and delta-A/B/C/E vis-à-vis viral load, age distribution and immune evasion. The global increase in the delta’s prevalence has happened concurrently with the increasing prevalence of the delta-D clade, suggesting that what we now call ‘delta’ is specifically the delta-D.

Epidemiological impact

Both the CDC and the WHO have classified all three sub-lineages of the delta variant – AY.1, AY.2 and AY.3 – as VOCs. According to the CDC’s COVID Data Tracker, the delta variant has been estimated to account for 83.4% of all COVID-19 infections in the US. While the estimated prevalence for AY.1 (0.1%) and AY.2 (0.8%) remain small, AY.3 currently accounts for around 9.1% of infections.

We know that the delta variant has a significant impact on the efficacy of the current lot of COVID-19 vaccines, against infection and transmission – although its efficacy against severe disease remains high. In a new study by researchers at the Mayo Clinic, the efficacy of the Pfizer-BioNTech vaccine dropped considerably against infection but remained high against hospitalisation and death.

It would seem the AY.1 and AY.2 sub-lineages of the delta variant have traded higher transmissibility for greater immune evasion potential, compared to the delta. In fact, both sub-lineages are unlikely to be more transmissible than the delta itself. There is still a paucity of data on the efficacy of vaccines against infections of these two strains.

According to a recent report by scientists at the Indian Council of Medical Research, people who had received Covaxin developed 23% lower levels of antibodies against delta variant infections (compared to infections of the B.1 strain); 33% lower against AY.1 and nearly 47% lower against AY.3. These results indicate that the AY.3 sub-lineage seems to be less susceptible to neutralisation followed by AY.1 and then the delta variants (compared to B.1).

However, the prevalence of AY.1 and AY.3 is extremely low in India, with only 60-odd cases identified so far. Overall, the delta variant’s sub-lineages don’t ring too many alarm bells. To date, there is no clear evidence one of them will come to dominate their common ancestor, the delta variant.

Dr Vipin Vashishtha, MD, FIAP, is a consultant paediatrician at the Mangla Hospital and Research Centre, Bijnor.

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