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By Roger Highfield on

COVID-19: Rise of the Delta variant

Delta infections are surging in highly vaccinated countries, like the UK, that once seemed to have made progress in curbing COVID-19. Roger Highfield, Science Director, talks to Professor Ravindra "Ravi" Gupta of the University of Cambridge, about why Delta is the most concerning variant seen so far.

COVID-19 vaccines are highly effective at preventing severe disease and death.

But they are not 100% effective, and some fully vaccinated people will become infected, experience illness and pass on the disease. They can also develop long term problems, though the vaccine cuts the risk of long COVID  from 11 to 5 per cent.

Delta and other genetic variations of the SARS-CoV-2 virus that can slip past the immune defences raised by vaccination are called “escape mutants.”

I discussed Delta with Professor Ravindra “Ravi” Gupta, professor of clinical microbiology at the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the University of Cambridge. His edited responses are shown in italics.

How is the delta variant spreading?

In all the places where we are studying the genetic sequence of the virus, Delta is taking over, except for South America, where the Lambda variant is responsible for a significant proportion. You can see the spread using GISAID, which shares COVID-19 data.

But it is hard to interpret what’s happening right now because there is a delay in gathering these genetic data about the virus. And when it comes to getting a global view, the surveillance representativeness is very poor, with much of the work in the UK, Denmark, and the United States, so it’s geographically biased.  

All viruses, including SARS-CoV-2, the virus that causes COVID-19, mutate, and change over time. Most changes have little to no impact on the virus’ properties. Some are detrimental while others may affect how easily it spreads, the associated disease severity, or the performance of vaccines, therapeutic medicines, diagnostic tests and so on.

There are vast numbers of different strains of SARS-CoV-2 but in late 2020, the emergence of variants that posed an increased risk to global public health prompted the search for ‘Variants of Interest’, such as Eta, Iota, Kappa and Lambda, and the more worrying ‘Variants of Concern’, notably Alpha, Beta, Gamma and, of course, Delta.

The Alpha strain first appeared in the UK, the Beta strain surfaced in South Africa, and the Gamma strain was identified in Brazil. Delta, also known as B.1.617.2, belongs to a viral lineage traced to the state of Maharashtra, India, in late 2020 and has rapidly taken hold in the UK, as it becomes more efficient, passing through and between people more quickly. (The new naming conventions for the variants were established by the World Health Organisation to avoid baffling numerical names, or demonising innocent geographical areas.)

The Delta variant is now the most common SARS-CoV-2 lineage in several higher-income and lower-income countries on all continents, currently accounting for more than 99% of new cases in England

Delta is at least 40% more transmissible than the Alpha variant identified in the United Kingdom in late 2020: when people are unprotected, the average person infected with the original coronavirus strain will infect 2.5 other people, while Delta would spread from one person to 4 other people.

Researchers at Public Health England and the MRC Biostatistics Unit, University of Cambridge, studied 40,000 people and found the risk of hospital admission was two times higher for individuals diagnosed with the Delta variant (after adjusting for differences in age, sex, ethnicity, deprivation, region of residence, date of positive test and vaccination status).

When broadening the scope to look at the risk of either hospital admission or emergency care attendance, the risk was 1.45 times higher for Delta than Alpha.

You carried out some of the earliest work on delta, can you Tell me about it?

In our preprint about breakthrough infections  in June, which is now being published in Nature, we had the first data on vaccine breakthrough infections in the world. We recorded the data in India, where Delta emerged, and where they had vaccinated health care workers. We identified that Delta had increased infectivity and its immune escape, which we quantified in terms of the degree of escape from the workers’ protective antibodies, so called neutralising antibodies.

These were among the very first data on vaccine breakthrough. The US Centers for Disease Control changed guidance on mask wearing as a result – they said this is why we need to start wearing masks, even if you’re vaccinated, since you can still pass on the virus if infected.  

We did a comprehensive study in vitro (in the laboratory) with the virus, grew it and tested how it replicates in human tissues and organoid systems (mini-organs) that mimic the lungs and airways. We then tested how well antibodies from people who were vaccinated can stop that virus causing infections in cells.

You can also study animal models, but these experiments are trickier to do and interpret (the moment you go into a mouse or hamster, it is all different), so we used three different model systems, based on human cells.

One of them was a human cell line, Calu-3 which is lung cancer cell line. They’re quite hard to use, but we managed to get them to work, along with airway epithelial organoids, where stem cells from our colleagues in Cambridge are embedded in matrix gel where they grow into clumps of cells, or organoids. The third uses human airway epithelial cells, which is a layer of cells at the interface between air and wet tissue, mimicking what’s happening in the airways. In all three systems, the Delta was very very much ‘hotter’ and made more virus particles.

We could also show breakthrough infections in healthcare workers who have been vaccinated that the Delta variant is preferentially more transmissible than the older variants – Alpha, Beta and so on – so it will have an advantage in vaccinated people.

Although the Delta virus didn’t evolve in a vaccinated person, it seems as though it is adapted for vaccinated people because it is much more transmissible, it makes a lot more virus in each infected human cell and makes more copies of itself. The viruses that do emerge from infected cells are much more mature (in terms of their spike protein, which is in a state that enables higher infectiousness per viral particle). This encapsulates why we have a problem with Delta.

How do these variants of concern emerge?

We believe these variants arise in chronically ill people, who are infected with COVID-19 for weeks and months. Many are immune suppressed, so they don’t quite clear the virus and the virus basically learns to adapt to the human immune system. Earlier this year, in the journal Nature, we gave the blueprint for how that’s happening in a single person. We followed one of these patients for a long period – 101 days – and saw many, many mutations. Some we subsequently saw circulating in the Alpha and other variants.

We also made artificial viruses to show what those mutations were doing, and we found this immune escape mutation and infectivity enhancing mutations – that’s so important because it was shown in real time how variants of concern emerge within one person, rather than just popping up somewhere. The fact that those mutations are seen in other variants of concern was basically, you know, for me proof that this is how it happens. You can’t imagine 20 odd mutations turning up from out of nowhere, so viral evolution must be happening within individuals.

Could delta further evolve to evade vaccines?

Yes, that is the concern. Potentially Delta is the starting point for viruses that do escape more and more bits of the immune system over time.

We are also seeing some data that says if you get infected despite vaccination you have the same viral load as someone who is unvaccinated. In the days following infection the viral load comes down much quicker if you are vaccinated because the immune system kicks in eventually and controls the amount of virus and you are not as infectious for as long.

But I can imagine that the virus would like to reverse this too and so might select for mutations that keep its viral load high even in vaccinated people and that will involve escape from T-cell receptors – which activate another arm of the immune response – or further mutations.

If the virus continues to spread and mutate rapidly, such escape mutants could be around the corner -we’re not necessarily that far away from them.

Vaccine protection against infections that cause symptoms has already been seen to wane when it comes to Delta for both the Pfizer mRNA vaccine and the Oxford-AstraZeneca — falling to 84% for Pfizer and 71% for AstraZeneca – and these breakthroughs were linked with higher viral loads in the nose or throat, suggesting they are more likely to spread the virus to others. Using data from the Office for National Statistics COVID-19 Infection Survey, which regularly tests more than 300,000 randomly selected people across the UK, the effect emerged in a recent study that compared the numbers of fully vaccinated and unvaccinated survey participants who tested positive for SARS-CoV-2 in the spring, when the Alpha variant dominated, and the summer, when Delta was dominant.

Is there concern that immunity against delta will fade more quickly in vaccinated people?

Yes, it will because the vaccine is less effective to start with, so you’ll probably experience a faster decline in terms of loss of protection against Delta or severe disease or infection.

As one example, a study of the University of California San Diego Health workforce reported that RNA vaccine effectiveness against symptomatic disease is considerably lower against the Delta variant, and may wane over time since vaccination. A decline was also seen in Qatar, though protection ‘persists at a robust level against hospitalization and death for at least six months following the second dose.’

How does delta differ from other covid variants?

The Delta spike has a number of mutations, many of which are in a part of the protein that is relatively poorly understood, called the NTD, the N terminal domain.

There are also mutations in the RBD (the receptor-binding domain, located on the spike, which allows it to stick to human cells) though the precise contributions of each mutation are yet to be fully elucidated.

The overall effect appears to be enhanced infectiousness and reduced sensitivity to antibodies made after a vaccine or infection with older variant.  A key mutation appears to be P681R. 

The Delta virus is a scrap of genetic code wrapped in protein, which pirates human cells to reproduce. When a mutation takes place in the genetic code of the virus, it can cause changes in the building blocks (amino acids) that make up the protein.

In the case of Delta, the mutation alters a single amino acid in the spike protein which, as the name suggests, makes up the spikes that are responsible for recognising and invading human cells. The COG-UK group monitors variants of concern and they have visualised the effects of spike protein mutations (scroll to the end of this webpage).

The Delta change, which is called P681R, falls within a region of the spike, called the furin cleavage site, a change previously been associated with heightened infectivity in other viruses such as influenza.

Rather like cocking an old-fashioned gun, P681R change ‘pre activates’ the Delta virus, making it more infectious.

To penetrate cells, the SARS-CoV-2 spike protein must be cut twice by human proteins that are present in the body. But with SARS-CoV-2, the presence of the furin cleavage site means that host enzymes can make the first cut as soon as freshly made viral particles emerge from an infected cell. In effect, Delta is pre-activated so that viral particles can then go on to infect cells more efficiently.

There is evidence supporting this: the spike protein is cut much more efficiently in Delta-variant particles than in Alpha particles, according to a study published in May by Wendy Barclay and colleagues at Imperial College London.

There might be other effects.  Spike proteins with the P681R change fuse with uninfected cells — a key step in infection — some three times quicker than those without the change.

However, the P681R change has been seen in some strains that have not taken off, and the Delta variant has other mutations that make a difference.

Can this insight into delta help us develop drugs?

Yes, it does have implications for therapeutics. One of the drugs that might work is camostat because that blocks this mature form of the virus. At the cellular level, an enzyme (trans-membrane protease serine 2, TMPRSS2) primes the spike protein of human coronaviruses and facilitates cell entry and infection. Camostat mesilate is an inhibitor of TMPRSS2 and has been shown to be a potent antiviral agent against SARS-CoV-2 in laboratory studies. So, we could design therapeutics to target that process. I’m not sure we’re there yet, and I’m not sure how safe it is in terms of use – some of these receptors have other uses in the body, so targeting the virus, the human protein could have unintended consequences. We are better off targeting virus proteins because they’re unlikely to cause us problems.  

Does delta look the same under the microscope?

There is a paper out on Delta where electron microscopy has shown a difference in the N terminal domain on the virus, a major binding site for monoclonal antibodies and other antiviral treatments This form of microscopy – cryo-em – suggests that it’s reshaped the N terminal domain and we don’t know how this contributes to antibody escape or even infectivity. But it does seem to have an effect. We have done some experiments where we revert some of these mutations and it does change the phenotype – behaviour and so on – of the virus.

Can we predict delta’s potential to evolve to outwit vaccines?

No, you can’t predict this, and you must do that empirically, with experiments to test which mutations might escape. But the problem is of course, it is risky, and we’re not really supposed to be selecting for more escape mutants in experiments. You don’t want those viruses escaping from the lab for example.  

Do we have to rethink what a successful vaccine looks like?

We might have to rethink what correlates of protection are. (Vaccine developers and regulators seek ‘correlates of protection, such as the levels of antibody that are sufficient to protect against coronavirus infection). Because neutralization is compromised and antibody neutralisation has been shown to be very highly correlated with correlates of infection, and protection from infection, Delta will cause a rethink.

We believe, and I think the data showed, that the infectivity aspect is very important for why Delta can escape vaccines. The virus is so infectious and there’s so much of it that even if you have some antibodies hanging around your nose, it’s not enough to stop those viruses getting in and then setting up an infection.

Why did the exponential rise in delta seen this summer peter out?

Perhaps the surge did not continue because of the school holidays, which put a brake on what was going to be a very very steep surge. However, there are a number of variables which explains why that massive peak didn’t happen.  

Moreover, COVID-19 is a much more complex disease now because there are so many immune people – whether because of vaccination or infection – that you can’t model this anymore and, moreover, the models don’t take into account any of this new work on transmissibility and viral loads of Delta and, of course, human movements are complex too.

Since that spike in cases, we are now seeing a sustained rise in COVID cases and hospitalisations.


The latest picture of how far the pandemic has spread can be seen on the Johns Hopkins Coronavirus Resource Center or Robert Koch-Institute.

You can check the number of UK COVID-19 lab-confirmed cases and deaths along with figures from the Office of National Statistics.

There is more information in my earlier blog posts (including some in German by focusTerra, ETH Zürich, with additional information on Switzerland), from the UK Research and Innovation, UKRI, the EUUS Centers for Disease ControlWHO, on this COVID-19 portal and Our World in Data.