How dangerous is the new Delta Plus variant? Here’s what we know.

A new variant of the coronavirus has emerged, and scientists are working to figure out if it is more dangerous than its infamous cousin, the Delta variant, which has killed hundreds of thousands of people in India and is fast becoming the dominant variant around the world.

The state of Maharashtra, India, which was hit hard by the devastating second wave of COVID-19, has now reimposed lockdowns due to rising fears about this new variant, dubbed Delta Plus (which is not an official designation).

Delta Plus differs just slightly from Delta—the predominant strain in India and the United Kingdom—which is more infectious and is thought to cause more hospitalizations than previous strains. Existing vaccines are effective against Delta, but only when people are fully vaccinated.

Out of an abundance of caution, the World Health Organization has urged fully vaccinated people to continue wearing masks. “Once you’ve been fully vaccinated, continue to play it safe because you could end up as part of a transmission chain. You may not actually be fully protected. Sometimes the vaccines don’t work,” Bruce Aylward, WHO senior adviser, said at a news conference last week.

The Delta Plus variant began appearing in global databases after mid-March, and by April 26 cases were found in England, prompting the United Kingdom to ban international travel on June 4. However, several patients with no history of travel or contact with travelers got infected with Delta Plus, which suggests the variant had begun to circulate in the U.K. through community spread. While the variant isn’t yet common, the Indian Health Ministry designated Delta Plus a Variant of Concern (VOC) on June 22, citing its perceived increased transmissibility, ability to bind more strongly to receptors on lung cells, and potential to evade an antibody response.

But whether Delta Plus meets the threshold for VOC designation is unclear. “India called it a VOC out of caution rather than any hard data,” says Ravindra Gupta, an immunologist and infectious diseases specialist at University of Cambridge.

Is Delta Plus a variant of concern?

When a variant becomes frequent and displays worrying traits, public health authorities initiate a formal investigation, designating it as a Variant Under Investigation (VUI). If it is found to be more transmissive, more resistant to antibodies, or to cause more severe disease, the variant is designated a VOC.

The Indian SARS-CoV-2 Genomic Consortium (INSACOG), a country wide network of laboratories and government agencies that monitors variations in the genetic code of coronavirus, actually described Delta Plus as a Variant of Interest, not a VOC, says virologist Shahid Jameel, who until recently led INSACOG’s scientific advisory group. But, argues Jameel, the new mutation would not have made the Delta Plus less transmissible than Delta, or reduced the virus’s ability to escape the immune response. “Hence there is nothing wrong with designating Delta Plus also a Variant of Concern,” he says.

Now at least two versions of the Delta Plus variant are slowly spreading around the world. The variant has been detected in Canada, Germany, Russia, Switzerland, Poland, Portugal, Nepal, Japan, the U.K., and the U.S. The more Internationally prevalent version is designated “AY.1”, while “AY.2” is confined mostly to the U.S. Delta Plus has already been detected 150 times in the U.S.

Existing vaccines still work against the original Delta variant but are less effective, especially among people who might not mount an effective immune response after vaccination, are older, or whose protection may wane faster. A single dose of the Pfizer or the AstraZeneca vaccine was only 33 percent effective against symptomatic disease caused by Delta variant. After both doses, the AstraZeneca vaccine was 60 percent effective, and the effectiveness of the Pfizer jab rose to 88 percent. New early research suggests that Moderna’s vaccine is less efficacious against the Delta variant and Johnson & Johnson is only about 60 percent effective.

But in Israel, where 57.1 percent population is fully vaccinated, about half of Delta variant infections occurred among those fully vaccinated with the Pfizer shots. This prompted Israel to reinstate wearing masks indoors.

“In terms of variants … we know vaccines work; we know that masking and social distancing work. As scary as it looks, we still have measures to counter it,” says Priyamvada Acharya, an immunologist at Duke Human Vaccine Institute.

What do we know so far?

Delta Plus differs from Delta because of an extra mutation—K417N—located in the spike protein, which covers the surface of the SARS-CoV-2 virus. This same location is mutated in other VOCs: Beta (first identified in South Africa) and Gamma (first identified in Brazil). The K417 mutation has also been detected in some samples of Alpha (first identified in UK).

The K417 position is within the region of the spike protein that interacts with the ACE2 receptor protein and enables the virus to infect cells—including those in the lung, heart, kidney, and intestine. When the spike protein encounters ACE2, it transforms from a “closed” to an “open” state to bind to the receptor and infect the cell. Based on studies of the Beta variant, which carries this same mutation, K417N can help the spike reach the fully “open” state, which likely increases its ability to infect. Increased ACE2 receptor binding and a more open state are traits of other highly transmissive and antibody resistant variants.

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Studies show that mutations at the K417 location help the Beta variant evade antibodies, so that could mean Delta Plus may dodge vaccines and antibodies even better than Delta.

“In the Delta variant lineage, the presence of the K417N mutation detected in some cases is a strong indicator that the variant may evolve to be more resistant to neutralizing antibodies,” speculated Olivier Schwartz, head of the Virus and Immunity Unit at Institut Pasteur in France. Schwartz’s early research has shown (in studies that have not yet been peer reviewed) that Delta is less vulnerable to antibodies extracted from the blood of convalescent and vaccinated individuals.

But the incremental effect of K417N on the viral spike protein that distinguishes Delta Plus from Delta is not easy to predict, because impact of individual mutations on proteins cannot simply be added together.

“Mutations have a way of working [together] across the spike, to have more of an effect than any one of them would do individually,” explains Acharya. Besides K417N, Delta Plus also inherits a collection of mutations from its Delta parent.

“The important part here is not only a single mutation, but how all of these mutations together change the spike,” says Sophie Gobeil, a biochemist at Duke Human Vaccine Institute.

For example, a more open spike protein may have an easier time binding to the ACE2 receptor and infecting a cell, but it also makes it more susceptible to neutralizing antibodies. 

So the two effects of this mutation may just cancel each other out, says Thomas Peacock, a postdoctoral scientist at Imperial College London. “This is very speculative though and will require empirical data to prove one way or the other.”

Acharya, who studies emerging variants in her lab, says, “The data that is out there right now is that we do not see any effect, or an increase in ACE2 binding, due to the K417N mutation. We don't see any significant effect on immune evasion based on the antibodies we have tested, and even others have tested. So, my general feeling is the K417N mutation on its own, probably will not do anything to make the Delta variant any more scary.”

What precautions should we take?

Some scientists speculate that K417N mutation may weaken Delta Plus and make it less of a threat than Delta.

“Mutation at 417 has been seen frequently on B.1.1.7, and it didn’t take off at all, so I would suggest we watch for expansion of this variant,” says Ravindra Gupta.

It’s not clear how prevalent the Delta Plus variant is in India and beyond. “It is thus premature to conclude that this so-called Delta Plus variant will be problematic,” Schwartz reiterates.

The existing vaccines are still effective against Delta Plus since half of the cases in the U.K. occurred among people who were not vaccinated, and only a few occurred among those who were fully vaccinated. None of the Delta Plus patients died.

Only 400 out of 97,374 Delta variants sequenced to date have been identified as Delta Plus. But, because of limited sequencing in India, Nepal, and other countries where Delta Plus might be more prevalent, “there aren’t enough sequences [yet] to make a determination on transmissibility, lethality, and vaccine escape in the population,” says Jameel, who is the director of Ashoka University's Trivedi School of Biosciences.

Typically, scientists grow the variant in the lab and test a known quantity of the virus with varying quantities of antibodies from vaccinated people. This allows scientists to determine if the antibodies can neutralize the new variant as efficiently as other variants.

The preliminary results from studies reveal that antibodies from vaccinated individuals can neutralize some Delta Plus variants are reassuring. But scientists are just beginning to study these new mutations.