SARS-CoV-2 is fitter than ever. Its latest incarnation, the Delta (or B.1.617.2) variant, is the fastest-spreading form of the virus yet. First identified in India, which it swept through killing hundreds of thousands this spring, Delta has swiftly become the most dominant coronavirus variant worldwide. While it’s already driving rapid increases in hospitalizations and deaths—overwhelmingly in unvaccinated populations—simply by virtue of being more transmissible, it may also cause more severe disease than some previously dominating SARS-CoV-2 variants.

Meanwhile, emerging data suggest that when vaccinated people become infected with the Delta variant and develop symptoms—which, although increasing in frequency, remains exceedingly rare, officials report—they might be as contagious as unvaccinated infected people. Those findings motivated the Centers for Disease Control and Prevention (CDC) to recommend in late July that in places with high transmission of the virus, even fully vaccinated people should wear masks indoors.

The Delta variant’s emergence isn’t a shock to many researchers; spreading throughout the globe for a year and a half, SARS-CoV-2 was destined to adapt to humans and become better at infecting them. The mystery remains, however, exactly how Delta affects the human body differently than other variants. A flurry of recent research, little of which has undergone peer review, is yielding some clues—on how the Delta variant might produce greater amounts of virus in people’s airways, for instance, which could make it more transmissible, and how it could cause more severe disease.

Scientists are also uncovering cause for hope. Although the antibodies induced by vaccines available in the US are slightly less effective against the Delta variant, the shots are largely still powerful protectors against severe cases of COVID-19. And according to preliminary data, “breakthrough” infections in vaccinated people resolve faster than in unvaccinated people.

“We’ve already seen a variety of other variants that have some—but maybe not all—of the same characteristics that Delta has,” such as increased transmission and a slight reduction in the effectiveness of vaccine-induced antibodies, says Richard Kennedy, an immunologist at the Mayo Clinic in Rochester, Minnesota. “None of those are really a surprise. This [variant] just seems to have more of all of those.”

What makes Delta more transmissible

Measuring SARS-CoV-2’s transmissibility in the real world is notoriously difficult as human behavior is continuously changing, notes virologist Paul Bieniasz of Rockefeller University, but the fact that the Delta variant has so quickly displaced its dominating predecessor Alpha (B.1.1.7) is convincing evidence that it’s able to spread more rapidly in incompletely vaccinated populations. The UK government’s Scientific Pandemic Influenza Group on Modelling, Operational sub-group (SPI-M-O) estimates that Delta is between 40 and 60 percent more transmissible than the Alpha variant and nearly twice as transmissible as the original virus first identified in China.

In explaining this heightened transmissibility, scientists point to not-yet-peer-reviewed data suggesting that infection with the Delta variant results in greater levels of virus accumulating more rapidly in human airways. In China, researchers tracked 62 people exposed to the virus who developed infections with the variant. They took daily measurements of the concentrations of viral RNA in swabs from the backs of the participants’ throats. Compared to 63 people infected with other variants, people with Delta infections tested positive sooner: four days after viral exposure compared to six. And when patients infected with Delta first tested positive, they carried around 1000 times more viral RNA. Although virologist Angela Rasmussen of the University of Saskatchewan’s Vaccine and Infectious Disease Organization cautions that viral RNA isn’t necessarily a proxy for the amount of virus that is actually infectious, “it’s probably a safe assumption that people are making more virus and shedding more virus” when infected with the Delta variant, she says.

Perhaps the variant replicates faster inside cells or binds more tightly to human cells’ ACE2 receptor, which the virus’s spike protein uses to enter cells, Kennedy speculates. But much attention has surrounded a particular mutation on the Delta variant called P681R, which suggests another potential mechanism. The mutation lies at the junction between two subunits of SARS-CoV-2’s spike protein, at a site that allows the human cellular enzyme furin to cleave the spike into two parts. This cleavage, some experiments suggest, primes spike proteins in a way that allows them to fuse more readily with a host cell’s membrane, according to a detailed description in Nature  

The Delta variant’s P681R mutation seems to allow that cleavage to occur more efficiently than in the original SARS-CoV-2 strain. This could help the variant infect more cells in a given amount of time, and therefore, make more copies of itself overall. “Having a more efficient furin cleavage site could lead to increased amounts of virus in the respiratory tract,” Bieniasz says. The Alpha variant—also more transmissible than other versions of SARS-CoV-2 when it first emerged—has a similar mutation.

Some scientists are skeptical that the P681R mutation is to blame for the heightened viral load in people infected with Delta. Kei Sato, a virologist at the University of Tokyo, says that in his own experiments, he and his colleagues generally didn’t observe much difference in replication or the ability to infect cells when comparing the Delta variant to a previously described form of the virus that lacks the P681R mutation. In any case, Bieniasz says he’d be surprised if the Delta variant’s heightened transmissibility were caused by P681R alone. The variant carries a handful of other mutations on the spike protein, and more scattered around the genome. But “there isn’t really any information at this point that would tell you mechanistically what their contribution is to the increased fitness of Delta,” he says.

The biology behind “breakthrough” infections

The fact that the Delta variant has also triggered increasing numbers of infections in vaccinated people has generated a bevy of headlines, some of which have been criticized for their alarmist nature. The CDC’s revised guidelines on mask-wearing were based in part on data from an outbreak in Massachusetts in the wake of large public gatherings. In July, officials identified 469 people in Barnstable County who tested positive, mostly for the Delta variant (participants had likely asked to be tested, and the majority had developed COVID-19 symptoms). Three-quarters were fully vaccinated, in part reflecting a relatively high vaccination rate in the area. Scientists stress that the vaccines still work as intended; they were designed to prevent severe disease, not infections. The Massachusetts study, for instance, reported only five hospitalizations—four in fully vaccinated people—and no deaths.

Nationwide, robust figures on the frequency of breakthrough cases are elusive—particularly of asymptomatic or mild cases; the CDC only monitors instances that have progressed to hospitalization or death. According to an unpublished internal CDC document obtained by ABC News, breakthrough cases are reported for 0.096 percent—or 153,000—of the 156 million Americans who are fully vaccinated. A recent review of data from 25 states also estimated the rate of breakthrough cases to be “well below 1 percent.” According to that same review, the rates of hospitalizations and deaths with COVID-19 among the fully vaccinated range from “effectively zero” to 0.06 percent and 0.01, respectively.

Surprisingly, the Barnstable County study detected similar amounts of viral RNA in the specimens of vaccinated and unvaccinated participants. While that’s not necessarily reflective of the people’s capacity to infect others, “it is indisputable that in this outbreak, there seems to be transmission between previously vaccinated people,” says Hana Akselrod, an infectious disease physician at George Washington University. The fact that participants had been gathering in bars and other crowed spaces probably created a high-risk setting for viral transmission, she adds.

Kennedy cautions that it’s hard to say how much of the increase in breakthrough infections is because of the Delta variant’s specific biology, rather than simply because it’s dominating a general surge in cases. But recent CDC data from Colorado does suggest vaccines are less effective against the variant; when it sped through Mesa County, the overall effectiveness of the available vaccines against symptomatic infection dropped to 78 percent, while in counties with lower Delta levels, it was 89 percent.

The variant’s fitness advantage could feasibly allow it to build up a high viral load before vaccinated immune systems crank out enough antibodies to quash it, Akselrod says. Anatomically speaking, it’s possible that while antibodies induced by current vaccines form high, protective levels in the lungs—where infection is associated with severe COVID-19 symptoms—they might be less able to access mucosal tissues in the nose and upper respiratory tract, allowing viral replication to occur there, Bieniasz speculates.

Another possible factor in establishing infections in vaccinated people is the Delta variant’s modest ability to evade vaccine-induced antibodies, Akselrod suggests. One yet-to-be-peer-reviewed paper posted to medRxiv in mid-July pitted antibodies isolated from 40 healthcare workers who had received either the Pfizer-BioNTech or Moderna mRNA vaccines against different variants. They found the Delta variant reduces the ability of antibodies to neutralize the virus by around 2.5-fold compared to a previously described isolate—slightly more so than the Alpha variant but not as much as the Beta variant (B.1.351) first discovered in South Africa or the Gamma variant (P.1) first spotted in Brazil.

This is likely due to mutations to the Delta variant’s receptor binding domain—the patch on the spike protein that latches onto host cells’ ACE2 receptors and is targeted by vaccines, Kennedy says. “What happens is the antibody either doesn’t bind or doesn’t bind as well,” he explains. But the human immune system typically produces many different antibodies against individual viral proteins—not to mention other kinds of immune machinery—preventing a complete reduction in vaccine effectiveness.

To wit: data from the Sisonke clinical trial in South Africa, reported in a news conference on Friday, suggest that even when it comes to Delta, the Johnson & Johnson vaccine is 71 percent effective against hospitalization and 95 percent effective against death. Rasmussen says she expects future variants to arise for which current vaccines are less protective, but for now, “the vaccines are actually holding up very, very well against Delta.”

In line with that idea is unpublished data from Singapore posted to medRxiv on July 31 that tracked Delta infections in 88 vaccinated—and mostly symptomatic—people. Although their viral RNA loads for the first week of illness were similar to those recorded in a group of 130 infected unvaccinated people, they decreased much more quickly in the vaccinated group. “And it showed that they had a huge spike in neutralizing antibodies immediately on testing positive,” adds Rasmussen, who wasn’t involved in the research.

Even so, several experts, including Rasmussen, Sato, and Bieniasz, agree with the CDC’s recommendation that vaccinated people should wear masks in high-risk settings. “No one wanted to be spending the summer sweating under masks, but this is the situation we have now, and we have to protect each other,” Akselrod says. “The primary use of masks is to prevent infections among unvaccinated people” who are more contagious for longer and are most at risk for developing severe COVID-19 with Delta.

More severe COVID-19 symptoms and long COVID?

It’s not clear if the elevated risk of hospitalization and death that some epidemiological studies have linked to Delta has more to do with characteristics of the populations in which Delta is circulating, or with the biology of the variant, Akselrod says. But some researchers have explored possible biological explanations. In a recent preprint, the University of Tokyo’s Sato and his colleagues report that when they allowed a SARS-CoV-2 isolate to infect modified monkey cells in vitro, the cells would stick together, forming connected structures known as syncytia, which have been spotted in the lungs of people with COVID-19. The team suspected that SARS-CoV-2’s furin cleavage site might be facilitating the observed clumping.

In addition to helping the viruses fuse with cells, it’s plausible that cleavage of the spike protein could also somehow cause infected cells to fuse with other cells close by. Notably, the team saw that syncytia induced by the Delta variant—whose P681R mutation may allow for more efficient cleavage—were much larger than those induced by a different form of SARS-CoV-2 that lacks the mutation. Interestingly, hamsters infected with SARS-CoV-2 viruses engineered to express the P681R mutation showed more signs of obstructed airways, and lost weight more quickly, than those infected with the other version of SARS-CoV-2—suggesting the variant caused more severe disease. Sato hypothesizes that by causing larger syncytia to form, the Delta variant could be causing more severe tissue damage in the lung. “I think that is the reason why the P681R-bearing virus is more pathogenic,” he says.

Rasmussen isn’t fully persuaded that the Delta variant is inherently more pathogenic. After all, hamsters are imperfect models of human COVID-19. But the P681R-driven syncytia formation might somehow explain why the virus is more transmissible, she says. Some other viruses are known to use such fused structures to spread from cell to cell, sometimes allowing more rapid spread across tissues.

Meanwhile, Akselrod says she’s worried about a Delta-driven surge of mostly young, unvaccinated people who’ll develop long-term symptoms known as “long COVID.” Amid a depleted healthcare workforce, the COVID-19 recovery clinic she directs is still struggling to care for long COVID patients who were infected with the Alpha variant in late 2020 or early 2021. “To think of getting another giant wave of Delta on top of that is just very, very sad,” she says. It’s still unclear, though, whether long COVID may be proportionally more frequent with Delta, and whether even vaccinated people could develop long COVID. “That’s a big scientific unknown right now,” she says.

As researchers continue to chip away at questions about Delta, they’re also keeping in mind the new variants that are likely on the horizon. “I think we’ll see more variants that have increased transmissibility. We may or may not see variants that cause more severe disease. . . . We’ll undoubtedly see variants that have an increased ability to evade immune responses,” Kennedy says. “We’ll run out of letters in the Greek alphabet before we run out of variants.”