Delta: a deep dive

This strain has flipped the script on the original SARS-CoV-2 and foreshadows many more acts to this drama.

At the start of this year, the covid situation in India was looking relatively good.

As the pandemic raged in other parts of the world, India was reporting around 10,000 new cases each day¹ – nothing like the hundreds of thousands being diagnosed in the United States.

A new variant of the virus – labelled B.1.617 – had cropped up in October in India, but with infection rates dropping, it didn’t appear to be cause for concern.

Perhaps buoyed with a little too much confidence, India eased its public health restrictions. Festivals and political rallies went ahead with vast numbers of attendees², but all the while, B.1.617 was quietly circulating. And as numbers of covid cases started to increase in the freely mingling population, the variant mutated.

On 5 February, a SARS-CoV-2 viral sample was taken from a young man in the Indian state of Tamil Nadu. Its genome was closely related to B.1.617, so it was given the designation of B.1.617.2³. Then, that variant exploded, increasing from just 3% of cases in India in mid-March to 21% by the end of March and 96% two months after that.

On 11 May, the World Health Organisation designated viruses within the B.1.617 lineage as variants of concern, based on clear evidence that the variant was transmitting much more quickly and effectively than previous variants, and was spreading rapidly around the world.

Studies of its genome found mutations that could potential increase the ability of the spike protein to bind to the human ACE2 receptor – which enables SARS-CoV-2 to gain access to cells – as well as mutations that may have increased its transmissibility and even helped it avoid being neutralised by some antibodies.

The Delta variant, as it is now known, is now threatening many hard-won public health gains around the world, including the much-sought-after herd immunity. It has been likened to chicken pox in terms of its transmissibility, and emerging evidence suggests even the fully vaccinated transmit the Delta variant at the same rate as the unvaccinated.

In India, infection rates skyrocketed, reaching above 400,000 new cases a day by early May. Hospitals were swamped, lifesaving supplies ran out and the news was dominated by heartbreaking stories of people searching for help for themselves or their dying family and friends.

It was only a matter of time before Delta found its way elsewhere.

The variant started circulating widely in the United Kingdom in early April and the United States in mid-April, and now makes up the vast majority of samples taken in those countries⁴.

Australia recorded its first cases of Delta in late May. The source of the infection was unknown but fortunately those first cases were contained. Then a single case of the Delta variant in an airport limousine driver⁵, diagnosed on 16 June, led to Australia’s third life-or-death battle with SARS-CoV-2.

“It’s a bigger threat, and we should have seen this coming because England gave us plenty of warning,” says Professor Mary Louise McLaws, an epidemiologist with expertise in infectious disease control at UNSW Sydney and member of a WHO advisory panel on covid-19.

England has become an unwitting study in how the Delta variant behaves, particularly in a population that is largely vaccinated.

In early May, the UK was recording just a couple of thousand new infections a day. The nation has since plunged into its third major wave which reached a peak of over 50,000 new infections a day in mid-July. And they’re almost entirely caused by the Delta variant⁶.

The first thing that became obvious with Delta was that it was spreading much faster than previous variants.

“The numbers that I think most people agree on at the moment is it’s perhaps twice as infectious as Alpha, which was perhaps 1.5-2 times more infectious than the original strain,” says Associate Professor Paul Griffin, an infectious diseases physician and microbiologist at the University of Queensland.

An outbreak in Guandong province in China, which began with a single case in an elderly woman on 21 May, led to 167 cases across four cities in one month⁷. A preprint study of that outbreak estimated that the Delta variant had a mean incubation period of 4.4 days, compared to around six days for the original SARS-CoV-2⁸; a mean generation time –the time from one generation of virus to the next – of just 2.9 days, compared to 5.7 days for the original virus; and significantly more transmission was occurring in the presymptomatic phase of infection.

Another study of 28 primary and secondary infection pairs within households in Singapore – all infected with the Delta strain – concluded the virus wasn’t necessarily infecting people any faster: it was that each index case infected a greater number of people than previous strains of SARS-CoV-2⁹.

The increased transmissibility has shocked even those who know how viruses evolve and adapt. Dr Katrina Lythgoe is an expert in evolutionary epidemiology, studying the evolutionary dynamics of infectious disease, at the University of Oxford, and she says Delta has “scarily fast” doubling times.

“We saw a clear step-up in transmissibility from previous variants to the alpha variant, and now we’ve seen a step-up again with the Delta variant,” Lythgoe says. “As soon as it’s got even a little bit of a hold, it’s just going to spread.”

Different and dangerous

What is it about Delta that makes it so much more transmissible than other variants? The biggest clue yet has again come from that same outbreak in Guandong province in China, which started from a single case on 21 May. Another preprint study¹⁰ looked at the outbreak, but this time they looked at the viral load – the quantity of virus in a given volume – reported for each patient in the outbreak.

This revealed that patients’ viral loads at the time of first detection were more than 1000 times greater with the Delta variant than with original strain. The study also found that people tested positive much sooner after exposure to Delta than to other variants; four days, instead of six.

It suggests that the virus is also replicating faster in individuals, and this has big implications for self-isolating practices, says Lythgoe, who was a co-author on the Guandong study. “You’re going to be become infectious very soon after that exposure event,” she says. “As soon as there’s any inkling that you could have been exposed, you really need to be isolating, and you need to isolate until you’re sure you’re not infected.”

There’s also some evidence suggesting that Delta could cause more severe disease. A preprint study from Singapore¹¹ looked at the outcomes of 976 confirmed covid infections – 57 of which were caused by the Alpha variant, and 67 by the Delta variant. They found Delta was associated with a four-fold higher risk of more severe disease, although the authors noted they weren’t able to account for other risk factors such as comorbidities and many of the Delta patients came from an outbreak among older patients in a healthcare facility.

Other studies from Scotland and Canada also point to a higher risk of hospitalisation, severe disease and death with Delta¹².

Another question is whether the Delta variant poses a greater health threat to young people. While children are far less likely than adults to get severe covid or die from it, the higher viral load associated with the Delta variant could change that. Already, the UK and US are seeing the fastest growing infection rates among those in their teens and 20s¹³.

Currently in NSW of the 54 people in ICU, 17 are under 50 and eight are in their 20s, and one woman has died of covid aged just 38 – when the pandemic began, severe disease and death in these age groups were rare.

But these are also the age groups with the lowest levels of vaccine coverage, and it’s not yet clear whether younger people are also experiencing higher rates of severe disease compared to with previous variants¹⁴. The data does suggest that the severe outcomes are mostly happening in unvaccinated young people.

Another key concern with Delta is whether it can evade vaccine-derived or naturally acquired immunity.

An early laboratory preprint study of B.1.617 identified two unique mutations in the section of the spike protein that binds to the ACE2 receptor on human cells, which the authors suggested could reduce the neutralising ability of antibodies against SARS-CoV-2¹⁵.

Another more recent study found that sera collected from individuals vaccinated with one dose of either the Pfizer or AstraZeneca vaccine “barely inhibited” the Delta strain in laboratory tests. Two doses did generate a neutralising antibody response against Delta, but the levels of antibodies were significantly lower than those generated against the Alpha variant¹⁶.

With these concerns, the world has watched closely how the Delta variant has behaved in the highly-vaccinated UK, US and Israel. And here at least, there is some good news: existing vaccines appear to be effective at preventing serious illness, hospitalisation and death from Delta infection.

A UK preprint study¹⁷ of just over 14,000 cases of Delta infection found one dose of vaccine was 75% effective at avoiding hospitalisation with Delta (compared with 78% efficacy against Alpha) and two doses were 94% protective against hospitalisation with Delta, compared with 92% against Alpha.

There were some differences between the two vaccines: a single dose of Pfizer was significantly more effective against Delta than a single dose of AstraZeneca. But after two doses the difference was much smaller: 96% with Pfizer compared with 92% with AstraZeneca.

The protection offered by vaccines against serious illness and death shows up clearly in the contrast between hospitalisation and deaths in England’s latest Delta-driven wave and those in the first and second waves¹⁸.

Deaths in the latest wave of infections only number in the tens, even as infection rates number in the tens of thousands. In contrast, many hundreds of people died each day during the first and second waves of the pandemic, but infection rates were – in the case of the first wave with the original virus – substantially lower¹⁹.

In Australia’s outbreak so far, almost none of the individuals currently in intensive care with the Delta strain are fully vaccinated, and no deaths have been reported in fully vaccinated individuals.

That’s the good news. The less-good news is that existing vaccines may not be quite as good at preventing overall infection with Delta.

A study of 19,543 RT-PCR-confirmed SARS-CoV-2 infections in Scotland²⁰ found two doses of Pfizer vaccine offered 92% protection against infection with the Alpha variant but 79% protection against infection with Delta. The AstraZeneca vaccine offered 73% protection against Alpha but just 60% protection against Delta infection.

Population-based data from Israel, where around 64% of the population is fully vaccinated with the Pfizer vaccine²¹, suggests two doses are just over 91% effective at preventing severe covid, but only around 40% effective at preventing infection – including asymptomatic infection²².

However Griffin notes that the risk of infection in those who are fully vaccinated is influenced by the greater freedoms that the fully-vaccinated enjoy in countries such as Israel. “If you’re vaccinated, you can move about freely, go to events, stadiums, cafes, and things like that,” he says, which may mean they are more likely to be exposed to the virus than those who are unvaccinated.

The early evidence suggests breakthrough infections in those who are fully vaccinated are much less severe than infections in the unvaccinated. A study²³ of 39 cases of breakthrough infection in Israeli healthcare workers showed none required hospitalisation, and the two-thirds of people who did experience symptoms only had mild ones such as congestion and muscle aches.

Vaccination may also not prevent transmission of the Delta variant. Two separate clusters of Delta infections in Singapore have started with a fully vaccinated index case. A cluster associated with a cleaner at Changi airport, who tested positive in early May, spread to more than 100 people in less than a month²⁴. A fully-vaccinated nurse was the index case for another cluster at Tan Tock Seng Hospital, which grew to 40 cases in just one week²⁵.

And a leaked slide from the US Centers for Disease Control²⁶ – published by the Washington Post – cited concerning data from two studies in the US. The first found that people with breakthrough infections with Delta had ten-fold higher viral loads than breakthrough infections with Alpha or other variants. The second found no difference in viral load between vaccinated and unvaccinated people with Delta infections.

Dealing with Delta

What does this mean for our ability to get on top of this latest wave of the pandemic?

Firstly, the speed of transmission makes Delta a particular challenge for contact tracing. “Contact tracing is chasing a racehorse on foot,” McLaws says. She argued strongly for an earlier lockdown in Sydney for this very reason. “I think our authorities in NSW were optimistic, but when they didn’t lock down until 54 cases, they basically missed the train.”

Secondly, the available data supports the importance of vaccination, particularly in those most likely to get severe disease, says Lythgoe. “It has to be the most vulnerable people getting vaccinated because they’re the most likely to get severe disease,” she says. “They just have to encourage people to get whatever vaccine they can and not to be choosy about it.”

But it also supports the importance of other infection prevention measures, such as masking and rapid testing in workplaces, alongside vaccination. “The thought that the vaccine is all we need here was perhaps a little bit flawed from the outset,” Griffin says. “I don’t think was ever realistic to suggest that we be able to have enough people vaccinated that those other mitigation strategies no longer apply.”

As well as better adherence to proper mask-wearing, McLaws advocates for daily rapid antigen testing of employees in essential workplaces. “You can then cut the cycle of them causing more infections to their workmates and if they do test positive in the morning, you’ve got more of a chance of catching them and not letting them go home,” she says.

The evolution of the Delta – and previous variants – adds even greater urgency to the need for vaccination and public health measures to control infection rates. Because the more SARS-CoV-2 can circulate, the greater the chance of further mutations.

“I think the most likely scenario is that we will continue to see variants that are more transmissible, whether that be the Delta variant gradually evolving to get more transmissible or a whole new variant on the scene,” Lythgoe says.

And that also means a variant could evolve resistance to existing vaccines. “You’re going to see an increased evolutionary pressure on the virus to escape natural immunity and escape vaccine immunity.”

References

Different and dangerous

Dealing with Delta

Covid still our most lethal respiratory virus

God help America

When you’re far from home, a GP can be a lifeline

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Different and dangerous

Dealing with Delta

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