Worrisome New Coronavirus Strains Are Emerging. Why Now?

[mood]

Worrisome New Coronavirus Strains Are Emerging. Why Now?

Across the globe, SARS-CoV-2 is evolving ways to evade the immune system and become more infectious. Blown pandemic response plans are to blame.

 

PHOTOGRAPH: GETTY IMAGES

 

TOWARD THE END of last year, doctors in Nelson Mandela Bay, a city of about 1 million people in the Eastern Cape of South Africa, started to see something alarming. The city had been hit by a tsunami of Covid-19 cases in June and July, swamping hospitals and leading to thousands of deaths. That wave began to subside as winter turned to spring in the southern hemisphere. But starting in November, hospitals in the city and its surrounding province began to fill up with Covid-19 patients again—this time twice as fast they had during the first surge.

 

To figure out what was going on with the steep uptick in new cases, doctors at those hospitals enlisted the help of Tulio de Oliveira, a geneticist and bioinformatician at the University of KwaZulu-Natal in Durban who leads a national network of sequencing labs. His team began piecing together the genomes of the coronavirus that had caused each person’s infection. For months, these researchers had been periodically doing similar genomic surveillance work to keep tabs on the dozens of strains of SARS-CoV-2 that were circulating around the country, looking for any problematic mutations in the virus’s spike protein. Eight months into the pandemic, in 99 percent of the more than 1,500 genomes they’d sequenced, they’d only found one such mutation. De Oliveira was in the process of submitting those findings to a journal.

 

Then, on December 1, the first results came back from Nelson Mandela Bay.

 

In each of the 16 samples gathered from 15 clinics around the city, the viruses all possessed a near identical constellation of mutations unlike any that had ever before been seen in South Africa. And eight of those mutations were in the spike protein. “Literally the day before I had written, ‘The spike genome in South Africa is very stable,’” de Oliveira told WIRED in an interview. “Then I saw this new cluster and I thought, ‘Wow, that has changed.’”

 

He walked upstairs, to the office of South Africa’s corollary to Anthony Fauci, an epidemiologist named Salim Abdool Karim, to tell him the news. Days later, they alerted the World Health Organization. Now on the lookout, scientists in the United Kingdom soon discovered one of those mutations spreading in the southeast part of Britain. A few weeks later, an eerily similar cluster of genetic changes surfaced among travelers from Brazil. But neither was a case of jet-setters seeding a single new strain around the world. Analyses of global coronavirus genome databases showed that these were in fact three distinct versions of the virus—three distantly related branches of the SARS-CoV-2 family tree that had independently acquired some of the same mutations despite emerging on three different continents.

 

That pattern is what scientists refer to as “convergent evolution,” and it’s a sign of trouble ahead.

 

All viruses mutate. They are, after all, just autonomous bits of protein-encased, self-replicating strings of code equipped with imperfect internal spell-checkers. Make enough copies and there are bound to be mistakes. Coronaviruses actually make fewer mistakes than most. This one, SARS-CoV-2, evolves at a rate of about 1,100 changes per location in the genome annually—or about one substitution every 11 days.

 

The predictable pace at which the coronavirus’s genetic building blocks shift around can be detected by genomic sequencing, which allows scientists to identify new strains and follow them as they spread through a population or fade away. For most of 2020, those random changes didn’t have much of an effect on the way the virus behaves. But recently, three notable mutations have begun to show up alone or in combination with each other. And everywhere they do, these versions of the virus tend to quickly outcompete other circulating strains.

“That suggests there’s an advantage to these mutations,” says Stephen Golstein, an evolutionary virologist who studies coronaviruses at the University of Utah. “Every SARS-CoV-2 variant ‘wants to be more transmissible,’ in a sense. So the fact that so many of them are landing on these mutations suggest there could be a real benefit for doing so. These different lineages are essentially arriving at the same solution for how to interact more efficiently with the human receptor, ACE2.”

 

Like any virologist, Goldstein is hesitant to anthropomorphize his subjects. Viruses don’t have dreams and desires. They’re intelligent micromachines programmed to make as many copies of themselves as possible. But one way to do that is to increase their odds of invading new hosts. SARS-CoV-2 does that by guiding the array of spike proteins that coat its exterior toward a protein called ACE2 that sits on the outside of some human cells. The spike is encrusted in sugars which camouflage the virus from the human immune system, except for the very tip, known as the receptor binding domain, or RBD for short. This exposed section is the part that latches onto ACE2, changing the receptor’s shape—like a key rearranging the tumblers inside a lock—and allowing the virus to enter the cell and start replicating.

 

The mutations that have scientists so worried all occur in that little exposed bit of spike. And now researchers are racing to figure out how each of them might be giving SARS-CoV-2 some new tricks.

 

There’s N501Y, a mutation that occurs in all three variants, which replaces the coronavirus’s 501st amino acid, asparagine, with tyrosine. Studies in cells and animal models suggest that the change makes it easier for SARS-CoV-2 to grab onto ACE2, which is one hypothesis for why the variant has been, at this point, pretty convincingly associated with increased transmission. The best evidence for that so far has come out of the UK, which is doing more genomic sequencing than any other country in the world. Scientists there estimate that the UK variant, alternatively known as B.1.1.7, is between 30 and 50 percent more infectious than other circulating strains.

 

In Ireland, it became the dominant version of the virus in just a few weeks, and it has since spread to more than 60 countries, including the US. As of Tuesday, the US had detected 293 cases of the UK variant, according to data from the US Centers for Disease Control and Prevention. The agency estimates it will become dominant in the US by March.

 

A Brazilian variant, also called P1, and the South African one, sometimes called B.1.351, also have a second and third mutation in common: K417T and E484K. At this moment, scientists know more about the latter. It changes an amino acid that was negatively charged to one that’s positively charged. In variants without this mutation, that section of the RBD sits across from a negatively charged stretch of ACE2, so they repel away from each other. But the E484K mutation reverses that charge, making them snap tightly together instead.

 

On Monday, Minnesota reported the US’ first case of the Brazil variant, but so far no cases of the South African variant have yet been confirmed in the US.

 

Scientists at the Fred Hutchinson Cancer Research Center found that E484K might be the most important alteration when it comes to enhancing the virus’s ability to evade immune defenses. In lab experiments, they observed that antibodies in the blood of recovered Covid-19 patients were 10 times less effective at neutralizing variants possessing the E484K mutation. In a separate study, some of De Oliveira’s colleagues tested the blood from Covid-19 patients who fell ill in South Africa’s first wave, and they found that 90 percent of them had some reduced immunity to the new E484K-containing variant. In nearly half of the samples, the new variant escaped the preexisting antibodies completely. Another study by another South African colleague, this time using live virus, found similar results. (All are being shared as preprints—neither has yet been peer-reviewed, as has become common in the age of Covid.)

“All the evidence is starting to point in the same direction,” says de Oliveira. “We have a virus that is much less neutralized by convalescent plasma.” It’s still too soon to tell what that means in the real world. True reinfections are notoriously difficult to pin down. Scientists have to sequence samples taken from the first bout of illness and the second, and then compare the genetic signatures to determine if a different viral variant is responsible for each infection. De Oliveira says his group is in the process of doing that right now, and they’re finding many instances of what appear to be real reinfections with the South African variant. That data is not yet published. And until they sequence more samples, they can’t say whether B.1.351 is causing more reinfections than previous versions of the virus, which would be a sign that herd immunity might be much farther off than previously thought.

 

Researchers in Brazil have also found evidence of at least one reinfection with the new P1 lineage, but data there is even sparser. Some reinfections are to be expected, says William Hanage, an infectious disease epidemiologist at the Harvard T. H. Chan School of Public Health. The important thing is whether there are more reinfections with the new variant than the models would expect.

 

Still, that these worrying mutations are all cropping up in the same region of the spike protein is not a coincidence, says Goldstein. Of all the places in the coronavirus’s genome, the RBD is the least stable. “That’s because, historically, it’s been under the most evolutionary pressure to change,” he says. It may feel like the Covid-19 pandemic has been happening forever. But in evolutionary terms, it’s been but a blink.

 

Before SARS-CoV-2 crossed into humans, it had been circulating inside bats for millions of years. And when scientists began taking a closer look at the bat version of ACE2, they found a staggering diversity of the gene that codes for that protein. What they were seeing were the genetic scars of an evolutionary arms race. Bat populations had lived with SARS-CoV-2 for long enough that their ACE2 receptors had started changing—morphing in shape so that they became harder for the virus to grab onto. And in turn, SARS-CoV-2 had evolved to try to fit into those new shapes. Eventually, one of those descendants looked enough like the human ACE2 receptor that it could make the cross-species leap (with perhaps an intermediary host in there somewhere).

 

There are two major evolutionary forces driving diversification of the spike protein: interacting with ACE2, and getting clobbered by neutralizing antibodies. In the human population, a year isn’t long enough for new versions of ACE2 to crop up and be passed on to a new generation of people. And ACE2 plays a key role in regulating blood pressure, wound healing, and other essential functions, so any genetic changes that impair its ability to do those things would likely not get very far, even if they made it more difficult for the coronavirus to start an infection.

So if the evolution of the ACE2 receptor can’t rescue us in the short term, that leaves the body’s immune system, and the armies of cells that orchestrate ejecting any unwanted visitors from it. Many pathogens mutate their proteins toward new shapes to avoid being recognized by the antibodies that would normally adhere to them, blocking their entry into cells. That’s called antigenic drift. And that’s what some scientists think drove the emergence of the Brazil and South African variants.

 

 

In a study recently posted as a preprint and not yet formally reviewed, Theodora Hatziioannou, a virologist at Rockefeller University in New York, and her colleagues described creating a pseudo-coronavirus carrying a nonvariant version of the spike protein. They grew it in the presence of individual antibodies they had extracted from the blood of people who had received one of the two FDA-authorized Covid-19 vaccines, one from Pfizer/BioNTech and one from Moderna. Some antibodies spurred the pseudo-SARS-CoV-2 to acquire the E484K mutation. Others nudged it toward K17T or N501Y.

 

They tried the experiment again with no antibodies present, and none of these three mutations—the ones in the triple-variant threat—evolved the same evasive maneuvers. “This data shows that these mutations accumulating in the spike protein are antibody escape mutations,” says Hatziioannou. “As soon as you add a specific antibody, you see specific mutations.”

 

Her group used blood donated by immunized people. But the vaccines have not been rolled out widely enough to be exerting significant evolutionary pressure on the general population. So the obvious question is: Where did the virus encounter these antibodies?

 

Hatziioannou and others think there are clues to be found in the genomes of viruses that took up long-term residence in the bodies of immunocompromised Covid patients. Up until a few weeks ago, the prevailing theory was that escape mutations could have emerged in people with chronic infections, who might be receiving monoclonal antibody treatments or convalescent plasma, and therefore supercharging the selective pressures the virus has to contend with.

 

Goldstein has a simpler explanation, one that’s beginning to get more traction in the scientific community. The convergent evolution of wilier versions of the virus might just be a consequence of so many poorly managed government pandemic responses, which didn’t marshal sufficient resources or inspire the kind of collective action required to not just crush the initial curve, but keep it crushed. “The fact that we lost control in so many places in the fall allowed for the ballooning of this incredibly huge viral population size,” says Goldstein. That created the opportunity for that many more mutations to happen, and in some places, the right circumstances for some particularly insidious ones to get selected.

 

Hanage put it this way to reporters last week: “The strategy here and elsewhere has been to try and control the level of transmission that doesn’t require very severe restrictions, but also doesn’t allow the virus to go exponential and overload health care systems.” But the problem with that approach is that it still gives the virus plenty of opportunities to mutate, and in so doing, change its behavior. If those changes make it spread faster or give it an edge against treatments and vaccines, that balancing act falls apart. “It tips you from a point where you’re capable of dealing with it to a point where you’re not,” he continued.

 

Hannage pointed to what’s going on right now in Manaus, a city in the Brazilian Amazon where a devastating surge in May left up to 70 percent of its residents infected with SARS-CoV-2, according to an analysis published this month in Science. Doctors and researchers there assumed the city was safe for a while—that herd immunity, or close to it, had been reached. But this month, the Manaus public health system collapsed again under a new Covid crush, leaving hospitals scrambling to get enough oxygen for its mass of patients. “I’m not yet aware of any evidence to suggest that the P1 variant is more likely to infect or reinfect people,” said Hanage. “But the fact that this is happening in a place that had previously been exposed to such high amounts of transmission is extremely worrying, very worrying indeed.”

 

Scientists may never get a clear answer to exactly where and under what conditions these new variants emerged. But de Oliveira isn’t so sure it matters. “The one thing we know for sure is that if you keep the virus circulating long enough, it will develop escape mutations,” he says.

 

The much more pressing question, then, is to what degree will such mutations affect efforts to vaccinate our way out of the pandemic?

 

A spate of recent studies, released as preprints have mostly good—and some mixed—news on that front. Lab tests conducted by scientists at BioNTech showed that their vaccine should still work just as well against B.1.1.7, the UK variant.

 

In their recent preprint, Hatziioannou’s group also took a closer look at B.1.351, the South African variant. They found that antibodies taken from people vaccinated with either Pfizer/BioNTech or Moderna’s shots were up to three times less effective at neutralizing the pseudoviruses carrying the mutations found in B.1.351, compared to ones without those genetic changes in the spike protein. But since those vaccines have such a high starting efficacy—over 90 percent—there’s still a lot of wiggle room.

 

On Monday, Moderna scientists and their partners at the National Institutes of Health released the not-yet-peer-reviewed results of their own lab experiments using blood from people who had received the company’s vaccine. Although antibodies from immunized people fended off the UK variant just fine, they found, the South African variant caused some issues. Against that strain, the neutralizing power of the antibodies induced by Moderna’s vaccine was reduced six-fold, though they still functioned at levels believed to be effective.

 

In a statement, Moderna CEO Stéphane Bancel said that he is confident the company’s vaccine should still be protective against the newly detected variants, but that “it is imperative to be proactive as the virus evolves.” To that end, Moderna’s scientists are retooling the company’s mRNA sequence to more closely mimic the most significant mutations and plan to test it as an additional booster shot in clinical studies later this year.

“We shouldn’t panic yet, but we should be careful. This is a warning,” says Hatziioannou. “If the virus continues to accumulate mutations in its spike protein, we run the risk of the efficacy of vaccines diminishing further.”

 

Vaccines target the whole spike protein, and they have been shown to make lots of different antibodies that bind to different parts of it. So losing the ones that block the RBD isn’t game over. There are plenty of built-in redundancies. But it leaves more work for the rest of the immune system. It’s like trying to kick out a home invader after you’ve left the front door unlocked. It gives the virus a little leg up. “The most important antibody targets do happen to be the most variable parts of the spike protein,” says Goldstein. “That’s why we’re locked in this evolutionary battle with the virus.”

 

With these new variants showing signs of being better at spreading and eluding both natural immune defenses and treatments like monoclonal antibodies and convalescent serum, the race is on to vaccinate as many people as possible in the shortest time frame. At least in the US, the last mile challenges with getting ultra-cold, two-shot vaccines into people’s arms are proving so problematic that the Biden administration has proposed creating 100 new mass vaccination sites across the country.

 

That’s good. But scientists like Hanage are still worried that if governments and societies don’t do enough to slow the speed of infections soon, more dangerous mutations will almost certainly emerge. “The fact that it’s happened three times already means we can expect it to continue happening,” he said during last week’s press briefing.

 

If you ask de Oliveira, he’ll tell you that it is already happening, and much faster than anyone realizes. “I am quite convinced that there are dozens, if not hundreds, of variants with similar mutations emerging around the world right now,” he says. He believes that the only reason that South Africa and the UK picked them up first is because their governments invested in comprehensive surveillance networks. That’s why he thinks nations need to stop useless travel bans and start ramping up testing, sequencing, contact tracing, and vaccination efforts. It may take years to inoculate enough people to curb the coronavirus’s evolution. Buying time until then means doing everything that has so far proven effective at limiting its chances of finding new hosts, and new opportunities to mutate: social distancing, mask-wearing, avoiding crowds, and increasing ventilation. “The important thing,” says de Oliveira, “is to realize we have to drive transmission to almost zero if we are to avoid new variants emerging in the future.”

 

 

Source: Worrisome New Coronavirus Strains Are Emerging. Why Now?

[Karlston]

Coronavirus variants: What they do and how worried you should be

The Ars guide to the coronavirus variants

Enlarge / Coronaviruses

Getty | BSIP

37 with 30 posters participating

Ever since the novel coronavirus, SARS-CoV-2, began jumping from human to human, it’s been mutating. The molecular machinery the virus uses to read and make copies of its genetic code isn’t great at proofreading; minor typos made in the copying process can go uncorrected. Each time the virus lands in a new human victim, it infects a cell and makes an army of clones, some carrying genetic errors. Those error-bearing clones then continue on, infecting more cells, more people. Each cycle, each infection offers more opportunity for errors. And, over time, those errors, those mutations, accumulate.

 

Some of these changes are meaningless. Some are lost in the frenetic viral manufacturing. But some become permanent fixtures, passed on from virus to virus, human to human. Maybe it happens by chance; maybe it’s because the change helps the virus survive in some small way. But in aggregate, viral strains carrying one notable mutation can start carrying others. Collections of notable mutations start popping up in viral lineages, and sometimes they seem to have an edge over their relatives. That’s when these distinct viruses—these variants—get concerning.

 

Scientists around the world have been closely tracking mutations and variants since the pandemic began, watching some rise and fall without much ado. But in recent months, they have become disquieted by at least three variants. These variants of concern, or VOCs, have raised critical questions—and alarm—over whether they can spread more easily than previous viral varieties, whether they can evade therapies and vaccines, or even whether they’re deadlier.

 

Here, we’ll run down what we know and what we don’t know about these variants. With much research yet to be done, there’s a lot of unanswered questions. But researchers are working quickly to address the most important unknowns. High on the list is whether the vaccines we already have will be effective against the variants. So far, it seems likely that they will be. Still, the virus is sending a clear message: with rampant transmission accelerating viral evolution, more variants will arise and we need to be prepared.

 

With more data becoming available by the day, we’ll update this story with significant findings as they come along. Before we get to the data we have, a quick note on names: it’s problematic to identify diseases or infectious agents—in this case, virus variants—based on where they were identified. Such geographic associations risk creating stigma and may discourage reporting, so there is an active discussion in the scientific community about how best to name the current variants. In the interim, it has become all too common to refer to these by their country of origin. We’ll try to avoid that as much as possible while making clear which variants we’re talking about.

B.1.1.7

Alternate names: 501Y.V1 and VOC 202012/01
Geographic association: United Kingdom
Number of countries reporting cases: 70
Increased transmissibility: Yes
Increased disease severity/mortality: A “realistic possibility”
Vaccine efficacy: Still effective

 

In early December 2020, researchers and officials in the UK began warning of a new variant that seemed to be spreading abnormally fast while carrying an unusually large number of mutations—23. The first record of the variant in the UK stretched back to two samples taken from infected people on September 20 and September 21. In a matter of weeks, the variant began making up a larger and larger proportion of total cases there. Researchers quickly suspected the variant had evolved to become more transmissible—that is, it's able to spread more easily from person to person.

Transmission

Data analyses since December have supported that hypothesis, but researchers are still working out exactly how much more transmissible it is compared to earlier versions. In early January, UK researchers released preliminary results from a series of models that estimated the variant tacks on an additional 0.36 to 0.68 onto SARS-CoV-2’s observed reproduction number. That means, on average, people infected with B.1.1.7 will go on to infect an additional 0.36 to 0.68 people on top of how many they would have infected if they were carrying an earlier version of the virus. More recent estimates have been roughly in this range, suggesting B.1.1.7 has around a 47 percent or 56 percent increase in transmission.

 

B.1.1.7 has now been detected in more than 60 countries beyond the UK, including the United States, where it has been found in at least two dozen states. A modeling study published by the US Centers for Disease Control and Prevention on January 15 estimated that it will become the predominant strain in the US in March.

Mutations

Some of the mutations B.1.1.7 carries seem to help explain the virus’s newfound ability. The variant carries 23 mutations in all: 13 mutations that change the virus’s protein sequences (non-synonymous), four deletions, and six synonymous mutations. Of B.1.1.7’s mutations, eight occur in the virus’s spike protein, the now notorious club-like protein that juts out from the virus’s spherical particle. That spike is what the virus uses to latch onto and infect cells, which the protein accomplishes by binding a receptor on the outside of human cells called ACE2.

 

So far, we know that at least three of B.1.1.7’s eight spike mutations may be relevant to the variant’s boosted transmission. Chief among them is a mutation that changes one of the spike proteins’ critical amino acids—the amino acid at position 501 of spike’s protein sequence. Specifically, the mutation changes the amino acid at 501 from an asparagine (N) to a tyrosine (Y), so the mutation is written as N501Y. The 501 amino acid is critical because it lies within the area of spike that directly binds to ACE2—called the receptor binding domain (RBD)—and it is one of just six key contact residues in the RBD. Lab experiments have suggested that changing from an N to a Y at 501 increases spike’s ability to bind ACE2, and experiments in mice linked the mutation to increased infectiousness and disease.

 

After N501Y, there’s P681H. The mutation at position 681—changing the amino acid from a proline (P) to a histidine (H)—falls near a unique furin cleavage site on SARS-CoV-2’s spike protein. For SARS-CoV-2 to successfully get into a cell after binding ACE2, the spike protein needs to be cleaved into its two subunits by enzymes. The split changes spike’s conformation and activates it, allowing it to fuse itself to the cell membrane and dump its contents into the now-infected cell. In animal studies, the furin cleavage site seemed to boost the virus’s ability to enter cells. Researchers suspect the new mutation may boost entry further.

 

Enlarge / A patient prepares to receive an injection of the Oxford/AstraZeneca COVID-19 vaccine by Royal Navy medics at a vaccination center set up at Bath racecourse in Bath, southwest England.

Adrian DENNIS / AFP / Getty Images

The third spike mutation known to be significant is a deletion of six nucleotides in its genetic code, which leads to the loss of two amino acids at positions 69 and 70 in the spike protein. It’s unclear what this deletion does for the virus exactly, but it has arisen a number of times in different lineages, suggesting it offers an advantage. For now, there is one clear consequence for researchers: the deletion messes up a diagnostic test for SARS-CoV-2. The test is a three-target RT-PCR test, meaning it works by detecting three snippets of the SARS-CoV-2 genome, including one in the gene that codes for spike. When this 69-70 deletion is present, the test will show up negative for the spike gene but positive for the other two SARS-CoV-2 genetic sequences. This result is referred to as “S gene dropout” and is now used to help identify infections caused by B.1.1.7.

 

These three mutations are the most notable in B.1.1.7 for now. There’s scant data on the other 20, but researchers are working swiftly to assess what each might do on its own or in combination with the others.

Disease severity/mortality

When researchers first raised concerns about B.1.1.7, all of those issues related to increased transmissibility. Preliminary evidence looking at infection outcomes did not suggest that B.1.1.7 was causing more severe disease or more deaths than other virus strains. Still, some saw little comfort in this, given that any increase in the total number of infections still leads to more severe cases and deaths in absolute numbers.

 

The situation took a darker turn January 21, when a UK government advisory group—NERVTAG—found preliminary evidence that “there is a realistic possibility that infection with VOC B.1.1.7 is associated with an increased risk of death compared to infection with non-VOC viruses.”

 

So far, some experts are not yet convinced by the preliminary evidence presented, and they’re calling for much more data before any conclusions are drawn. For one thing, the full data sets behind some of the analyses done so far have not been published, and some of them relied on comparing small numbers of deaths in people infected with B.1.1.7 with larger numbers of deaths in people infected with other strains. Some experts also wonder whether the calculated increase in deaths could simply be explained by overburdened hospitals rather than a deadlier variant.

Vaccine efficacy

With increased infectiousness and the possibility of being deadlier, a critical question raised by B.1.1.7 is whether or not the current vaccines we have—mRNA vaccines from Pfizer/BioNTech and Moderna—will work against the variant. So far, the answer appears to be yes.

 

On January 19, researchers at Pfizer and BioNTech released a non-peer reviewed study where they pitted antibody-laden blood from 16 people given their mRNA vaccine (BNT162b2) against a pseudovirus that carried B.1.1.7’s mutated spike protein. The researchers found that the vaccines’ antibodies were just as good at neutralizing the pseudovirus with B.1.1.7’s mutated spike protein as they were at neutralizing a pseudovirus with the spike protein from a reference SARS-CoV-2 virus.

 

“These data… make it unlikely that the B.1.1.7 lineage will escape BNT162b2-mediated protection,” the researchers concluded.

 

Likewise, on January 25, Moderna released its own non-peer reviewed study, which was similar in design. They tested the antibodies from eight people given their mRNA vaccine against a pseudovirus bearing B.1.1.7’s mutated spike protein. Again, the antibodies neutralized the pseudovirus at levels comparable to those seen with a pseudovirus carrying a reference spike protein.

 

Yet another similar study, led by researchers at Columbia University and released January 26, found the same results. Antibodies from 12 people who received Moderna’s vaccine and 10 people who received Pfizer’s vaccine were able to neutralize a pseudovirus containing B.1.1.7’s mutated spike protein, with only a modest drop in potency compared with neutralization of a pseudovirus carrying a reference spike protein.

 

Enlarge / A mutation so of note, it has its own Getty Images illustrations already.

User: stigalenas / iStock / Getty Images Plus

501Y.V2

Alternate name: B.1.351
Geographic association: South Africa
Number of countries reporting cases: 31
Increased transmissibility: Suggested, but not determined
Increased disease severity/mortality: Not determined
Vaccine efficacy: Still protective, but efficacy reduced

 

In mid-November, health officials in South Africa began noticing that a new variant was quickly overtaking other variants circulating in Eastern Cape, Western Cape, and KwaZulu-Natal provinces. The variant was picked up in routine sequencing, with the earliest samples dating back to October. On December 18, officials announced the variant, which they dubbed 501Y.V2 because the variant—like B.1.1.7—carries the worrisome N501Y mutation. Though this similarity initially caused some confusion between the two variants, genetic analyses have clarified that 501Y.V2 did indeed arise independently, further supporting the evidence that N501Y is advantageous for the virus.

Transmission

With the rapid spread and N501Y mutation, there is clear concern that 501Y.V2 is spreading more easily than past versions of the virus. Preliminary studies also suggested that the variant was linked to higher viral loads—that is, higher relative levels of virus genetic material detected in people’s respiratory tracts via diagnostic PCR tests. This only bolstered fears of increased transmission. However, neither higher viral loads nor increased transmissibility in general have been confirmed for 501Y.V2.

 

When B.1.1.7 was first noticed, there were similar worries and preliminary reports of higher viral loads. However more recent studies have thrown cold water on that idea. The main difficulty with comparing viral loads is that viral loads change over the course of an infection, ramping up after an exposure, peaking within days of symptom onset, and then declining. For the clearest comparison, researchers would want to know when in the course of an infection a person’s viral load was assessed—information that’s often not available. Researchers note that in the rush to track any up-and-coming variant, tests for viral load may be skewed toward happening earlier in infections, when the viral load may be highest, giving the impression that new variants are creating higher viral loads.

 

While researchers scramble to learn more about 501Y.V2, it has continued to spread. 501Y.V2 has been found in over 30 countries so far, including the United States. On January 28, the CDC released a statement saying it was aware of the country’s first cases of 501Y.V2, detected in South Carolina. “CDC is early in its efforts to understand this variant and will continue to provide updates as we learn more,” the agency said in a statement.

Mutations

Though researchers are still collecting epidemiological data on transmissibility, the genetics of 501Y.V2 can offer some insight. The variant has 21 mutations, with nine changes in the spike protein. As mentioned—and as the name indicates—501Y.V2 contains the N501Y mutation in spike’s receptor binding domain (RBD), linked to increased infectiousness and virulence in lab studies.

 

Two other notable mutations in spike’s RBD make experts nervous: K417N and E484K. The former mutation, K417N—changing a lysine (K) at position 417 to an asparagine (N)—has been shown to modestly throw off some antibodies that target the RBD.

 

With the RBD playing such a critical role in initiating infection, some of the most potent antibodies that disarm and knock back the virus—neutralizing antibodies—target spike’s RBD. As such, any changes in SARS-CoV-2’s spike RBD risk making antibodies less effective at preventing a future infection. This seems to be the case—at least to a modest extent—with K417N. But it’s not nearly as worrisome as the other mutation, E484K.

 

In a non-peer reviewed study released earlier this month, researchers in Washington state surveyed which spike RBD mutations might be able to evade neutralizing antibodies—so called “escape mutants.” Some of the mutations best at escaping were at position E484. When spike proteins with a 484 mutation were pitted against the antibody-loaded blood from 35 people who had recovered from a SARS-CoV-2 infection, virus neutralization often—but not always—dropped significantly. In some cases, E484K reduced neutralization tenfold.

 

This immediately raised fears that immune responses—either from past infections or vaccines—would not protect against future infections with 501Y.V2 or any of its ilk. But the authors of the study were cautious to note that even reduced neutralization can still be protective. Additionally, with such protective mRNA vaccines—each showing around 95 percent efficacy against COVID-19—there’s reason to be optimistic that vaccines will still be protective, the authors point out. And so far, they appear to be correct.

Disease severity/mortality

So far, there is no evidence that 501Y.V2 causes more severe disease or more deaths.

Vaccine efficacy

With the data on E484K, researchers anxiously worked to assess if the current vaccines will still be effective against 501Y.V2. According to preliminary studies, the vaccines still appear protective. But their efficacy has taken a hit, and vaccine makers are preparing to tweak their vaccines so that booster shots can better protect against the new variant.

 

(The mRNA vaccine platforms luckily lend themselves to easy tweaking like this, and new vaccines could be up and running in a matter of weeks. However, the regulatory approval pathways for this type of tinkering are still fuzzy.)

 

In Moderna’s January 25 non-peer reviewed study, the company pitted antibodies from eight people given their mRNA vaccine against a pseudovirus bearing 501Y.V2 mutated-spike protein. The vaccinees’ antibodies neutralized the pseudovirus with the mutated spike, but it required six times the level of antibodies needed to neutralize a pseudovirus with a standard spike.

 

“Despite this reduction, neutralizing titer levels with [501Y.V2] remain above levels that are expected to be protective,” Moderna said in a statement. Still, “out of an abundance of caution,” the company outlined how it will move forward with developing a booster shot targeted to 501Y.V2.

 

Similarly, in a non-peer reviewed study released January 27, Pfizer and BioNTech looked at how well antibodies from 20 people who received their vaccines neutralized a pseudovirus carrying key mutations from 501Y.V2. They also saw a drop in neutralization from the vaccinees’ antibodies. “However, the Companies believe the small differences in viral neutralization observed in these studies are unlikely to lead to a significant reduction in the effectiveness of the vaccine,” they said in a statement.

 

Pfizer and BioNTech added that they are “are prepared to respond if a variant of SARS-CoV-2 demonstrates evidence of escaping immunity by the COVID-19 vaccine,” and they “believe that the flexibility of BioNTech’s proprietary mRNA vaccine platform is well suited to develop new vaccine variants if required.”

Enlarge / The Centers for Disease Control and Prevention has been tracking COVID-19 variants; thus far (as of January 28, 2021) two of three discussed here are confirmed within the US.

Jason Armond / Los Angeles Times via Getty Images

P.1

Alternate name: 501Y.V3
Geographic association: Brazil
Number of countries reporting cases: 8
Increased transmissibility: Suggested, but not determined
Increased disease severity/mortality: Not determined
Vaccine efficacy: Not determined

 

In December, COVID-19 cases began rising in Manaus, Brazil. This puzzled researchers. The city had already been hard hit by the pandemic, with an estimated 75 percent of the population already thought to have been infected by October. Somehow, cases were surging again in December, leading researchers to dig into why. One possible explanation is the emergence of a new variant, dubbed P.1.

Transmission and Mutations

With the spread in Manaus, researchers immediately became concerned that P.1 has increased transmissibility and/or is able to escape immune responses in people who have recovered from COVID-19. For now, firm data on both of these points is lacking. In the meantime, researchers have looked to P.1’s genetics, which offer grim news.

 

The genome has 17 unique amino acid changes, three deletions, four synonymous mutations, and one insertion. In particular, there are 10 mutations in the spike, including some usual suspects: N501Y, E484K, and K417T. As before, these spike RBD mutations hint at increased transmissibility, virulence, and possible immune escape.

 

While researchers work to understand P.1 and what’s going on in Manaus, the variant is spreading. By late December, 42 percent of SARS-CoV-2 specimens sequenced in Manaus were of the P.1 lineage. It has now been detected in seven other countries, including the United States.

Disease severity/mortality

So far, there is no evidence that P.1 causes more severe disease or more deaths.

Vaccine efficacy

So far, there is no direct data on how well current vaccines protect against P.1.

New variants, old routine

One bright spot in the rise of new variants is that the old-school, low-tech mitigation efforts still seem to work. On the flip side, ignoring those critical mitigation efforts—hand hygiene, mask wearing, physical distancing—comes with a hefty toll. We’ve already seen surges upon surges of cases and brutal death counts without the help of any craftier variants.

 

In a January 22 press briefing, Maria Van Kerkhove—the World Health Organizations’ technical lead on the COVID-19 pandemic—emphasized the need to keep up health precautions. She said:

No matter what virus is circulating—virus variants or not —we have to do everything we can to reduce transmission, everything we can to reduce transmission. We are encouraged by the signs of decreased transmission across the United Kingdom and also in Denmark, in Ireland and also in South Africa, which has a different virus variant, the 501Y.V2, that they identified recently. We see decreasing trends in incidence and this is a good sign and it tells us that the public health measures that are in place work against these viruses… The interventions that are in place that we've seen across so many countries reduce transmission, they break chains of transmission; everything from finding cases, isolating cases, good clinical care, supported quarantining of contacts, individual levels of mask-wearing, physical distancing, hand hygiene, avoiding crowds, opening windows; all of that. We need to stay the course.

 

Coronavirus variants: What they do and how worried you should be