Yet Another Curveball in the COVID Mutation Nightmare

Authors: David Axe September 6, 2022 The Daily Beast

When the pharmaceutical industry scrambled to develop the first COVID vaccines back in 2020, it made sense that developers focused on the part of the virus that allows it to grab onto and infect our cells: the spike proteins.

The best vaccines contain a piece of the spike, or genetic data about the spike, either of which can spur an immune response. Not to be outdone, the virus has been mutating—with many of the changes occurring on that same spike.

But other parts of the virus are changing, too. Now, for the first time, a team of scientists has scrutinized these changes—and voiced a warning.

“With each major variant that has been identified, we are seeing mutations outside of [the] spike that we are trying to figure out,” Matthew Frieman, a University of Maryland School of Medicine immunologist and microbiologist and lead author of the new study, told The Daily Beast.

It’s possible the virus is accumulating non-spike mutations in an attempt to gain some advantage over our collective immunity as the COVID pandemic grinds toward its fourth year. These new mutations might not make the virus more infectious the way spike mutations do, but they could be associated with longer infections.

If this trend continues—and there’s no reason to believe it won’t—we might eventually need new antiviral drugs and new vaccine formulations that aren’t so specifically focused on the spike.

It’s possible the virus is accumulating non-spike mutations in an attempt to gain some advantage over our collective immunity as the COVID pandemic grinds toward its fourth year. These new mutations might not make the virus more infectious the way spike mutations do, but they could be associated with longer infections.

If this trend continues—and there’s no reason to believe it won’t—we might eventually need new antiviral drugs and new vaccine formulations that aren’t so specifically focused on the spike.

Vaccine developers weren’t wrong to focus their initial efforts on the spike protein, Frieman and his co-authors explained in their peer-reviewed study, which was published in Proceedings of the National Academy of Sciences and appeared online on Tuesday. “The spike protein is the immunodominant antigen,” they wrote. In other words, it’s the part of the virus most likely to produce a strong immune response.

Moreover, the major variants and subvariants of SARS-CoV-2—Delta then the various forms of Omicron including BA.4 and BA.5—have piled up mutations on the spike. As the spike evolves, the virus gets better and better at grabbing onto our cells despite the presence of antibodies.

That’s one reason why the vaccines have been getting somewhat less effective, and we’re seeing more and more breakthrough cases in vaccinated people. And it should come as no surprise that one of the leading contenders for the next dominant subvariant, a spinoff of Omicron called BA.4.6, features a particularly worrying mutation on the spike called R346T.

But there have been hints that non-spike mutations are becoming a bigger factor, too. Geneticists noted that BA.5, currently the dominant subvariant, doesn’t just have mutations along its spike—it features changes all across its structure.

There had to be a reason for those mutations, Frieman explained. “Viruses don’t do things by accident.” Instead, they try out small changes, over and over, until some combination of changes helps it survive and spread. The resulting variant or subvariant then outcompetes other forms of the pathogen until it becomes dominant—and the likely basis for the next set of mutations.

To understand the reason for, and effects of, the non-spike mutations, Frieman’s team cloned SARS-CoV-2 then started deleting the spike proteins and testing the resulting “deletion viruses” on mice, assessing how contagious the viruses were and how severe the infections were.

Their conclusion? “Mutations outside of [the] spike may be driving critical phenotypes of SARS-CoV-2 infection and disease.” That is to say, changes beyond the spike are beginning to define the virus.

For now, it seems the spike and non-spike mutations are working together. The spike mutations make the virus steadily more contagious. “Mutations in [the] spike have been identified in every major variant that then out-competes the previous variant,” Frieman explained.

Meanwhile, the non-spike mutations appear to prolong infection. This in turn gives the pathogen more time to mutate inside a particular person, and also spread to other people. “We hypothesize that this balance is critical for further evolution of SARS-CoV-2,” Frieman’s team wrote.

As the virus continues trying out mutations in order to stay ahead of our spike-focused immunity, it might further emphasize changes beyond the spike. BA.5, with its wide breadth of mutations, is a sign that’s already happening.

Take this as an urgent call for further study of non-spike mutations. “As more variants emerge, we will identify additional mutations outside of [the] spike that contribute significantly to viral replication, transmission and pathogenesis,” Frieman and his coauthors wrote.

Frieman said his goal is to scrutinize these non-spike mutations in order to “figure out what they do, how they do it [and] why they make the virus better at being a virus.” “Then we can use that information to make drugs,” including new antiviral therapies and vaccine formulations.

Speed matters. The Omicron variant and its rapid-fire subvariants, each coming just a couple months after the last, was a warning that our pharmaceutical research-and-development processes might be too slow. Note that the U.S. Food and Drug Administration just last week green-lit Omicron-specific vaccine boosters—a full 10 months after the initial Omicron variant first became dominant. “Omicron and its lineages”—another term for subvariants—“taught us a lesson for the need to be more agile in modifying the vaccine,” Ali Mokdad, a professor of health metrics sciences at the University of Washington Institute for Health, told The Daily Beast.

That problem could get worse if the rate of non-spike mutations accelerates. Our vaccine R&D is too slow even when it’s narrowly focused on the spike. What happens when it needs to broaden its scope to combat a virus that’s learning to mutate across its structure?

There’s another wrinkle. These accumulating mutations across the novel-coronavirus—on the spike and not on the spike—could start to mess with the polymerase chain-reaction tests we use to detect and track the virus.

PCR tests and sequencing use primers tailored for a certain range of viral characteristics. Too many mutations “can mess with the PCR test,” Niema Moshiri, a geneticist at the University of California-San Diego, told The Daily Beast.

Pay attention, but don’t panic. It’s really no surprise that SARS-CoV-2 is trying out mutations on different parts of the virus. That’s what viruses do—adapt. The trick for us, the novel-coronavirus’s host, is to adapt at least as quickly.

We did it before by rapidly developing vaccines and therapies targeting the most dangerous part of the virus. We can do it again as the virus finds new ways to evolve. It just takes political will… and money.

Omicron’s Mutations Impaired Vaccine Effectiveness, CDC Says

Authors: Madison Muller  August 25, 2022 Bloomberg

Almost 40% of people hospitalized in the US with the Covid subvariant that circulated this spring were vaccinated and boosted, highlighting how new strains have mutated to more readily escape the immunity offered by current shots.

The findings from scientists at the US Centers for Disease Control and Prevention underscore the importance of having Covid shots that are better at targeting omicron subvariants. 

From the end of March through May, when the omicron BA.2 and BA.2.12.1 subvariants were dominant in the US, weekly hospitalization rates increased for all adults — with those over 65 hit the hardest. Even so, the total number of hospitalizations remained much lower than when the delta variant was rampant last fall. 

The overall number of hospitalizations is an important point, said Abraar Karan, an infectious disease doctor at Stanford University.

“When you look at who’s hospitalized, it’s much more likely that they will have been vaccinated because so many people are vaccinated now,” Karan said. “The real comparison is how many hospitalizations do we have now versus in the past when people were not vaccinated or not up-to-date with boosters.”

CDC scientists found that vaccines and boosters did a better job of keeping people with delta infections out of the hospital than those with later variants. Effectiveness decreased slightly with the BA.1 variant, then changed significantly with BA.2 — with a much greater share of hospitalized adults who had been vaccinated with at least one booster. 

Read more: Retiring Fauci expected Covid to be ‘behind us’

Immunity from vaccines starts to wane within six months, so staying up-to-date with shots is key to being fully protected. Fewer than half of Americans have gotten a booster shot.

Adults with at least two booster shots fared better than other people when BA.2 was dominant. The majority of those admitted to the hospital also had at least one underlying condition. Unvaccinated adults were more than three times as likely to be hospitalized, but breakthrough infections still represented a significant number of the severe Covid cases, the data show.

US regulators have pushed Moderna Inc., Pfizer Inc. and BioNTech SE to expedite development of omicron-specific boosters for a September rollout. The drugmakers this week submitted early data to the US Food and Drug Administration seeking emergency clearance for updated shots that target the BA.4 and BA.5 virus strains. Scientists and vaccinemakers are already beginning to look toward next-generation shots that may provide longer-lasting protection against more variants. 

The new report’s findings also indicate that along with vaccination, other pharmaceutical and non-pharmaceutical measures should be used by those at highest risk of getting Covid. That includes easy access to therapeutics such as Pfizer’s antiviral drug Paxlovid and Gilead Sciences’ remdesivir, as well as AstraZeneca’s Evusheld for immunocompromised people. Scientists also note that wearing a mask can help guard the wearer from getting sick.  

Though the number of Covid deaths is the lowest it has been since last July, the US continues to see hundreds of deaths each day from Covid, CDC data show.

The summer of subvariants

Authors: Tina Reed, July 9, 2022 Axios Vitals

As this summer heats up, so has the spread of the hot new version of COVID-19.

Why it matters: This subvariant of Omicron called BA.5 — the most transmissible subvariant yet — quickly overtook previous strains to become the dominant version circulating the U.S. and much of the world.

BA.5 is so transmissible — and different enough from previous versions — that even those with immunity from prior Omicron infections may not have to wait long before falling ill again.

What they’re saying: “I had plenty of friends and family who said: ‘I didn’t want to get it but I’m sort of glad I got it because it’s out of the way and I won’t get it again’,” Bob Wachter, chairman of the University of California, San Francisco Department of Medicine told Axios. “Unfortunately that doesn’t hold the way it once did.”

  • “Even this one bit of good news people found in the gloom, it’s like, ‘Sorry’,” Wachter said.

State of play: This week, the CDC reported BA.5 became the dominant variant in the U.S., accounting for nearly 54% of total COVID cases. Studies show extra mutations in the spike protein make the strain three or four times more resistant to antibodies, though it doesn’t appear to cause more serious illness.

  • Hospital admissions are starting to trend upward again, CDC data shows, though they’re still well below what was seen during the initial spread of Omicron.
  • It’s unclear whether that could be indicating an increase in patients in for COVID, or patients who happen to have COVID, Wachter said. “We’re up in hospitalizations around 20% but with a relatively small number of ICU patients,” Wachter said about COVID cases at UCSF.
  • In South Africa, the variant had no impact on hospitalizations while Portugal saw hospitalizations rise dramatically, Megan Ranney, academic dean at the Brown University School of Public Health told Axios.
  • “So the big unknown is what effect it’s going to have on the health care system and the numbers of folks living with long COVID,” she said.

Yes, but: “I’m certainly hearing about more reinfections and more fairly quick reinfections than at any other time in the last two and a half years,” Wachter said.

Zoom in: That is also largely the experience of the surge seen firsthand in New York City by Henry Chen, president of SOMOS Community Care, who serves as a primary care physician across three boroughs of the city.

  • With this particular variant, he said: “The symptoms are pretty much the same but a little bit more severe than the last wave. It’s more high fever, body ache, sore throat and coughing,” Chen said, adding his patient roster is mostly vaccinated.
  • But it is occurring among patients who’d gotten the virus only three or four months ago, he said.

The big picture: Another summertime wave of cases could prolong the pandemic, coming after many public health precautions were lifted and with available vaccines losing their efficacy against the ever-evolving virus.

The bottom line: The messaging isn’t to panic, but to understand the virus is likely spreading in local communities much more than individuals realize due to shrinking testing programs  and without the level of protection they might assume they have.

  • “If you don’t want to get sick, you still need to be taking at least some precautions,” Ranney said. “[COVID] is still very much among us.”

This New ‘Ninja’ COVID Variant Is the Most Dangerous One Yet, Says Who?

Authors: David Axe Fri, July 8, 2022 Yahoo News

When Will People Realize That COVID is Here To Stay? Live With It!

The latest subvariant of the novel coronavirus to become dominant in Europe, the United States, and other places is also, in many ways, the worst so far.

The BA.5 subvariant of the basic Omicron variant appears to be more contagious than any previous form of the virus. It’s apparently better at dodging our antibodies, too—meaning it might be more likely to cause breakthrough and repeat infections.

Vaccines and boosters are still the best defense. There are even Omicron-specific booster jabs in development that, in coming months, could make the best vaccines more effective against BA.5 and its genetic cousins.

Still, BA.5’s ongoing romp across half the planet is a strong reminder that the COVID pandemic isn’t over. “We’re not done yet, by any stretch,” Eric Topol, founder and director of the Scripps Research Translational Institute in California, wrote on his Substack.

High levels of at least partial immunity from vaccines and past infection continue to prevent the worst outcomes—mass hospitalization and death. But globally, raw case numbers are surging, with serious implications for potentially millions of people who face a growing risk of long-term illness.

Equally worrying, the latest wave of infections is giving the coronavirus the time and space it needs to mutate into even more dangerous variants and subvariants. “The development of variants now is a freight train,” Irwin Redlener, the founding director of Columbia University’s National Center for Disaster Preparedness, told The Daily Beast.

In other words, unstoppable.

BA.5 first turned up in viral samples in South Africa in February. By May it was dominant in Europe and Israel, displacing earlier forms of the basic Omicron variant while also driving an increase in global daily COVID cases from around 477,000 a day in early June to 820,000 a day this week.

In late June, BA.5 became dominant in the United States. Cases haven’t increased yet—the daily average has hovered around 100,000 since May. But that could change in coming weeks as BA.5 continues to outcompete less transmissible subvariants.

Topol offered a concise explanation for BA.5’s ascendancy. Where the mutations that produced many earlier variants mostly affected the spike protein—the part of the virus that helps it to grab onto and infect our cells—BA.5 has mutations across its structure. “BA.5 is quite distinct and very fit, representing marked difference from all prior variants,” Topol wrote.

BA.5’s widespread mutations made the subvariant less recognizable to all those antibodies we’ve built up from vaccines, boosters and past infection. BA.5 has been able to slip past our immune systems, ninja-style, contributing to the rising rate of breakthrough cases and reinfections.

This comes as no surprise to epidemiologists who’ve warned for many months now that persistently high case-rates—which they largely attribute in part to a stubborn anti-vax minority in many countries—would facilitate ever more infectious and evasive variants and subvariant. The more infections, the more chances for significant mutations.

In that sense, BA5 might be a preview of the months and years to come. A year ago, we had a chance to block SARS-CoV-2’s main transmission vectors through vaccines and social distancing.

But we didn’t. Restrictions on businesses, schools and crowds have become politically toxic all over the world. Vaccination rates remained stubbornly low, even in many countries with easy access to jabs. In the U.S., for example, the percentage of fully vaccinated has stalled at around 67 percent.

The Massive Screwup That Could Let COVID Bypass Our Vaccines

So COVID lingers, 31 months after the first case was diagnosed in Wuhan, China. The longer the virus circulates, the more variants it produces. BA.5 is the all but inevitable result of that tragic dynamic.

The situation isn’t entirely hopeless. Yes, BA.5 seems to reduce the effectiveness of the best messenger-RNA vaccines. Vaccine-maker Moderna published data indicating that a booster shot it’s developing specifically for Omicron and its offspring works only a third as well against BA.5 compared to earlier subvariants.

But vaccines, boosters and past infection still offer meaningful, if reduced, protection against BA.5. “Even a boost of the original genome, or a recent infection, will [produce] some cross-protective antibodies to lessen the severity of a new Omicron subvariant infection,” Eric Bortz, a University of Alaska-Anchorage virologist and public-health expert, told The Daily Beast.

The more additional jabs you get on top of your prime course, the better protected you are. Arguably the best protection results from two prime jabs of the mRNA vaccines from Pfizer or Moderna plus a couple boosters. “Get your damn fourth shot!” Redlener said.

The problem, in the United States, is that only people 50 years old or older or with certain immune disorders qualify for a second booster. And the U.S. Food and Drug Administration won’t say whether, or when, it might authorize second boosters for younger people. “I have nothing to share at this time,” an FDA spokesperson told The Daily Beast when asked about boosters for under-50s.

It’s an obvious bureaucratic screw-up. As many as a million booster doses are about to expire in the U.S., all for a want of takers. “A profound waste, which should be made available to all people, age under-50 who seek added protection,” Topol wrote.

To be fair, Pfizer and Moderna are both working on new boosters that they’ve tailored specifically for Omicron subvariants. On June 30, an FDA advisory board endorsed these variant-specific boosters. The FDA announced it might approve them for emergency use for some Americans as early as this fall.

But there’s a risk these jabs will show up too late, especially if they’re highly optimized for just one recent subvariant and thus ineffective against future subvariants. “Variant-chasing is a flawed approach,” Topol wrote. “By the time a BA.5 vaccine booster is potentially available, who knows what will be the predominant strain?”

Fortunately, there are fallbacks. Masks and voluntary social-distancing, of course. Post-infection therapies including the antiviral drug paxlovid also help. “This is not a time to abandon non-pharmaceutical intervention,” Redlener stressed.

But voluntary mask-wearing and paxlovid are bandaids on a festering global wound. The surge in BA.5 infections creates the conditions for the next major subvariant—BA.6, if you will. It might be even worse.

It’s looking more and more likely that COVID will be with us, well, forever. “COVID is becoming like the flu,” Ali Mokdad, a professor of health metrics sciences at the University of Washington Institute for Health, told The Daily Beast.

That is, endemic. An ever-present threat to public health. The big difference, of course, is that COVID is much more dangerous than today’s flu. And it keeps mutating in ways that make it even worse.

Why Are So Many People Getting COVID a Second and Third Time?

Doctors say if you got infected with the Omicron BA.1 or BA.2 variants, your antibodies might not fully protect you against the newer BA.4 and BA.5 subvariants now spreading through Southern California

Authors: Joel Grover and Josh Davis  June 16, 2022 NBC News

A sign encouraging mask use hangs on a fence before the local school council and the Chicago Teachers Union held a press conference Tuesday, Sept. 28, 2021 outside Jensen Elementary School in Chicago’s North Lawndale neighborhood. (Brian Cassella/Chicago Tribune/Tribune News Service via Getty Images)

Just days after Congresswoman Maxine Waters attended the Summit of the Americas in downtown LA last week, she tested positive for COVID-19. It was the second time in less than two months Waters has tested positive.

Until recently, many people who got COVID-19 thought they had months or years of protection from getting it again. But researchers tell the NBC4 I-Team that’s not the case.

“I’m not surprised to see people testing positive a second and third time,” says Dr. Saahir Khan, an infectious disease expert at USC’s Keck School of Medicine.

“The virus is mutating very quickly,” Dr. Khan told NBC4.

Doctors like Khan say if you got infected with the Omicron BA.1 or BA.2 variants, your antibodies might not fully protect you against the newer BA.4 and BA.5 subvariants now spreading through Southern California.

“As the virus mutates more and more, the antibodies to the prior variants give less and less protection over time,” Dr. Khan says.

But public health experts say second and third infections are often very “manageable.”

“The thing about these reinfections, is they get increasingly milder. Much less likely to even cause you to call your doctor,” says Dr. Amesh Adalja of Johns Hopkins Bloomberg School of Public Health.

So how soon can you get COVID for a second or third time, after a previous infection?

U.S. Health and Human Services Secretary Xavier Becerra tested positive this past Monday, less than a month after his first positive test.

“I wouldn’t say there’s a hard and fast timeline when you can get reinfected. It’s just that your protection wanes over time, over the course of a few months,” says Dr. Khan at USC.

Public health experts say the vaccines that are now available might not prevent reinfection by newer variants, but a new class of vaccines that could be out by this fall could provide wider protection.

“COVID is spread through the air, particularly in indoor spaces where people share the same air. And so what you can do to prevent reinfection is wear a mask indoors, particularly in a high risk situation where a lot of people congregate, like airports and grocery stores, Dr. Khan told the I-Team.

Coronavirus wave this fall could infect 100 million, administration warns

Authors: Yasmeen Abutaleb, Joel Achenbach May 6, 2022 The Washington Post

The Biden administration is warning the United States could see 100 million coronavirus infections and a potentially significant wave of deaths this fall and winter, driven by new omicron subvariants that have shown a remarkable ability to escape immunity.

The projection, made Friday by a senior administration official during a background briefing as the nation approaches a covid death toll of 1 million, is part of a broader push to boost the nation’s readiness and persuade lawmakers to appropriate billions of dollars to purchase a new tranche of vaccines, tests and therapeutics.

In forecasting 100 million potential infections during a cold-weather wave later this year and early next, the official did not present new data or make a formal projection. Instead, he described the fall and winter wave as a scenario based on a range of outside models of the pandemic. Those projections assume that omicron and its subvariants will continue to dominate community spread, and there will not be a dramatically different strain of the virus, the official said, acknowledging the pandemic’s course could be altered by many factors.

Several experts agreed that a major wave this fall and winter is possible given waning immunity from vaccines and infections, loosened restrictions and the rise of variants better able to escape immune protections.

Many have warned that the return to more relaxed behaviors, from going maskless to participating in crowded indoor social gatherings, would lead to more infections. The seven-day national average of new infections more than doubled from 29,312 on March 30 to nearly 71,000 Friday, a little more than five weeks later.

“What they’re saying seems reasonable — it’s on the pessimistic side of what we projected in the covid-19 scenario modeling run,” said Justin Lessler, an epidemiologist at University of North Carolina Gillings School of Global Public Health. “It’s always hard to predict the future when it comes to covid, but I think we’re at a point now where it’s even harder than normal. Because there’s so much sensitivity, in terms of these long-term trends, to things we don’t understand exactly about the virus and about [human] behavior,” Lessler said.

Another modeler, epidemiologist Ali Mokdad of the University of Washington’s Institute for Health Metrics and Evaluation, said in an email Friday that a winter surge is likely. His organization, which has made long-term forecasts despite the many uncertainties, just produced a new forecast that shows a modest bump in cases through the end of May and then a decline until the arrival of winter.

New Omicron BA.4 and BA.5 Sublineages May Evade Vaccines, Natural Immunity. What Experts Say

Authors: Mint Newsletters April 29, 2022

  • The BA.4 and BA.5 sublineages appear to be more infectious than the earlier BA.2 lineage
  • The sub-lineages have been detected in seven of South Africa’s nine provinces and 20 countries worldwide

New omicron sublineages, discovered by South African scientists this month, are likely able to evade vaccines and natural immunity from prior infections, the head of gene sequencing units that produced a study on the strains said, according to Bloomberg report.

It is important to note that the BA.4 and BA.5 sublineages appear to be more infectious than the earlier BA.2 lineage, which itself was more infectious than the original omicron variant, Tulio de Oliveira, the head of the institutes, said.

Omicron sublineages  mutated to evade immunity

  • As almost all South Africans either having been vaccinated against the coronavirus or having had a prior infection the current surge in cases means that the strains are more likely to be capable of evading the body’s defenses rather than simply being more transmissible, de Oliveira said.
  • There are “mutations in the lineages that allow the virus to evade immunity,” he said in a response to queries. “We expect that it can cause reinfections and it can break through some vaccines, because that’s the only way something can grow in South Africa where we estimate that more than 90% of the population has a level of immune protection.”
  • South Africa is seen as a key harbinger of how the omicron variant and its sublineages are likely to play out in the rest of the world. South African and Botswanan scientists discovered omicron in November and South Africa was the first country to experience a major surge of infections as a result of the variant.
  • The new sublineages account for about 70% of new coronavirus cases in South Africa, de Oliveira said in a series of Twitter postings. 
  • “Our main scenario for Omicron BA.4 and BA.5 is that it increases infections but that does not translate into large hospitalizations and deaths,” he said.
  • So far, the sublineages have been detected in seven of South Africa’s nine provinces and 20 countries worldwide. 

Two COVID Variants Just Combined Into a ‘Frankenstein’ Virus

Authors: David Axe Published  Apr. 07, 2022 4:49AM ET 

The first subvariant of Omicron, the latest major variant of the novel coronavirus, was bad. BA.1 drove record cases and hospitalizations in many countries starting last fall.

The second subvariant, BA.2, was worse in some countries—setting new records for daily cases across China and parts of Europe.

Now BA.1 and BA.2 have combined to create a third subvariant. XE, as it’s known, is a “recombinant”—the product of two viruses interacting “Frankenstein”-style in a single host.

With its long list of mutations, XE could be the most contagious form of the coronavirus yet. “From the WHO reports, it does appear to have a bit more of an edge in terms of transmissibility,” Stephanie James, the head of a COVID testing lab at Regis University in Colorado, told The Daily Beast.

But don’t panic just yet. The same mix of subvariants that producedXE might also protectus from it. Coming so quickly after the surge of BA.1 and BA.2 cases, XE is on track to hit a wall of natural immunity—the antibodies left over from past infection in hundreds of millions of people.

Those natural antibodies, plus the additional protection afforded by the various COVID vaccines, could blunt XE’s impact. For that reason, many experts worry less about XE and more about whatever variant or subvariant might come after XE.

And rest assured, that future subvariant is coming. “COVID-19 continues,” Eric Bortz, a University of Alaska-Anchorage virologist and public health expert, told The Daily Beast.

Testers first detected XE in the United Kingdom back in mid-January. Six weeks later U.K. authorities had identified 600 XE infections. Those cases are a proverbial drop in the bucket in light of the millions of BA.1 and BA.2 cases the U.K. has tallied in the past three months. But XE stood out.

According to the World Health Organization, XE is 10 percent more contagious than BA.2, which itself is up to 80 percent more contagious than BA.1, a subvariant epidemiologists described as the most transmissible respiratory virus they’d ever seen when it first appeared in South Africa back in November.

There’s a lot of uncertainty about XE. The WHO stressed that its own finding about the subvariant “requires further confirmation.” But given what we think we know, it seems XE evolved in someone with overlapping BA.1 and BA.2 infections, when two separate but related viruses swapped genetic material.

“We don’t have a roadmap.”

XE isn’t the first COVID recombinant—there have been at least two others, including the so-called “Deltacron” subvariant that sprang from simultaneous Delta and BA.1 infections. But with two highly contagious parent viruses, XE stands a chance of being the fastest-spreading recombinant. Health officials have also detected XE in Thailand.

The subvariant hasn’t shown up in U.S. tests yet. But that doesn’t mean it hasn’t reached U.S. shores. “It might not be detected by the standard analysis pipeline,” Rob Knight, the head of a genetic-computation lab at the University of California, San Diego, told The Daily Beast. Major new forms of SARS-CoV-2 can require tweaks to testing methods.

XE is a nasty bug, owing to potentially dozens of mutations to its spike protein, the part of the virus that helps it grab onto and infect our cells. And it’s a strong reminder that the pandemic isn’t over. Even with widespread natural immunity and highly effective and safe vaccines, SARS-CoV-2 keeps finding pockets of unprotected people—and opportunities to evolve.

But it’s not 2020 anymore. The novel coronavirus has changed, but so have we. Each successive wave of infections—Alpha then Delta then both major forms of Omicron—has seeded the population with natural antibodies that offer strong, albeit temporary, protection against the worst effects of future infection by a related form of the virus.

The leading vaccines, meanwhile, have stood up to each new variant and subvariant, especially when you add one or two booster doses.

Even as more and more countries fully reopen schools, businesses and borders, the peak death rate from a COVID wave keeps dropping in a lot of countries. Cases might go up as some new subvariant outcompetes an earlier subvariant and becomes dominant. But deaths don’t necessarily increase in the same proportion—a phenomenon epidemiologists call “decoupling.”

Decoupling is partially a function of the time between waves. Natural antibodies from past infection can begin fading after three months. But if two variants or subvariants strike within a few months of each other, the second strain collides with the immunity left over from the firs strain—especially if the strains are related. Meanwhile, the second strain produces antibodies that could mitigate the worst outcomes of the next strain, assuming it arrives fast enough.

That’s why Omicron has infected more people than the previous variant, Delta, but has killed fewer. And why many experts consider XE less frightening than BA.2 or BA.1. “Immune responses to XE should be similar to that of Omicron,” Bortz said. “Those with prior Omicron infection and vaccination are going to be mostly immune.”

By the same token, a big gap between separate variants—that is, a long reprieve from COVID—might actually be more dangerous to a population than back-to-back-to-back waves of related strains.

There’s another risk. We were lucky with the major variants and subvariants before XE, in that the leading vaccines worked really well against all of them. Experts are cautiously optimistic that the jabs hold up against XE, too. “XE is, as you say, supposed to be more contagious than BA.2 [or] BA.1,” Edwin Michael, an epidemiologist at the Center for Global Health Infectious Disease Research at the University of South Florida, told The Daily Beast, “but it seems not to be more severe or immune-evasive.”

But if some new variant, perhaps even a recombinant of XE and some other strain, eventually mutates in a way that helps it evade the vaccines and arrives three months or longer after the previous surge in cases, we could be in trouble.

“While thus far mutants that are more transmissible have emerged and spread, there is also the possibility of one that is both more transmissible and immune-evasive to emerge,” Michael said. In that case, neither of our approaches to building population-level immunity–vaccines and natural antibodies—would be able to prevent a devastating spike in deaths.

New Mutant “XE” Omicron Variant May Be The Most Transmissible Version Of Covid Yet, According To WHO

Authors:  Tom Tapp March 31, 2022 4:46pm Deadline Breaking News Alerts

The CDC announced this week that the BA.2 Omicron variant, which is reportedly 30% more transmissible than the original BA.1 Omicron strain — has become dominant among new cases sequenced in the United States. That’s a startling rise for a variant that was less than 1% of all sequences as recently as January. But, just as Americans are hearing about BA.2, there’s already a newer, even more transmissible variant on the rise.

There are actually three new variants that have been given designations. According to a recently-released report from the UK Health Services Agency, the two being called XD and XF are combinations of Delta and BA.1, or so-called “Deltacron” strains, which have been talked about for months but made no significant inroads in any country.

XD is present in several European countries, but has not been detected in the UK, according to the report. XF caused a small cluster in the UK but has not been detected there since February 15. The variant of greater concern, it seems, is the one dubbed XE.

Like the other two new arrivals, XE is a recombinant strain, meaning it is made up of two previously-distinct variants. But it is not a Deltacron mix. XE is actually made up of the original Omicron (BA.1) and the newer Omicron (BA.2) which has taken over in the U.S.

Omicron BA.2 Variant Now Dominant In U.S.; Hitting Northeast Hard

The World Health Organization issued a report yesterday with some preliminary findings about XE.

“The XE recombinant was first detected in the United Kingdom on 19 January and >600 sequences have been reported and confirmed since,” reads the WHO document. “Early-day estimates indicate a community growth rate advantage of ~10% as compared to BA.2, however this finding requires further confirmation.”

Further confirmation is getting more difficult by the day, according to WHO, which registered concern this week at what it calls “the recent significant reduction in SARS-CoV-2 testing by several Member States. Data are becoming progressively less representative, less timely, and less robust. This inhibits our collective ability to track where the virus is, how it is spreading and how it is evolving: information and analyses that remain critical to effectively end the acute phase of the pandemic.”

Covid BA.2 Omicron Variant Likely Now Accounts For Majority Of New Cases In Los Angeles

Last week’s briefing from the UK Health Services Agency reinforces some of the WHO report’s assertions and urges caution about jumping to conclusions. One difference between the two documents is that the WHO data and analysis seems to be more recent.

From the UK HSA briefing:

XE shows evidence of community transmission within England, although it is currently less >1% of total sequenced cases. Early growth rates for XE were not significantly different from BA.2, but using the most recent data up to 16 March 2022, XE has a growth rate 9.8% above that of BA.2. As this estimate has not remained consistent as new data have been added, it cannot yet be interpreted as an estimate of growth advantage for the recombinant. Numbers were too small for the XE recombinant to be analysed by region.

To be clear, XE only accounts for a tiny fraction of cases worldwide. That may change, given that XE is thought to be about 10% more transmissible than the already more-transmissible BA.2. That means it may be roughly 43% more transmissible than the original Omicron that savaged the globe last winter.

But a new wave of infections from the now-dominant BA.2 has not materialized, even as restrictions have been eased. So hopefully the trend with XE, should it out-compete BA.2, will be similar. Only time — and good surveillance — will tell.

Study evaluates mutation-induced SARS-CoV-2 spike protein fold stability

Authors: Tarun Sai Lomte Mar 24 2022 BioRxiv

In a recent study posted to the bioRxiv* preprint server, researchers evaluated the stability and expression of mutations in the spike (S) protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).

Study: Stability and expression of SARS-CoV-2 spike-protein mutations. Image Credit: Design_Cells/Shutterstock
Study: Stability and expression of SARS-CoV-2 spike-protein mutations. Image Credit: Design_Cells/Shutterstock

Background

The coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has resulted in extensive research into S protein. Its evolution introduces several variations in the protein surface that negatively affect the efficiency of antibodies elicited by vaccines. The virus requires the S protein for host cell entry, and vaccines against SARS-CoV-2 are designed with S protein as the target. The prominent presence of anti-S antibodies in a population might induce selection pressure in the virus to modify its S protein structure to evade vaccine- or infection-induced antibodies. Such antigenic drifts drive the emergence of novel variants with persistent challenges. Moreover, understanding the effects of evolution requires knowledge of the protein’s structure.

The study

The present study assessed whether protein expression levels might serve as a proxy for fold stability. The principal objective was to examine whether expression and ACE2- receptor-binding domain (RBD) binding measured experimentally could relate to the thermodynamic stability of the RBD mutants.

Expression data on the effect of RBD point mutations on ACE2 binding and yeast expression were previously reported. The impact of mutations on expression levels was calculated as the log mean fluorescence intensity difference relative to wildtype. The effect on ACE2 binding was determined from the apparent dissociation constants difference relative to the wildtype.

The free energy change of protein folding (ΔΔG­) was computed using three in silico methods: Deep DDG, SimBa-IB, and mutation cutoff scanning matrix (mCSM) protein stability. In its apostate determined by cryo-electron microscopy, eight experimental structures of S protein were obtained from the protein data bank (PDB). SimBa-IB program calculated the mutated sites’ relative solvent accessible surface area (RSA), and the ΔΔG­ and RSA values were reported as average values.

Results

The authors observed that the effect of mutations on ACE2 binding and expression was strongly correlated. Moreover, the expression levels could affect binding constants even at the same level of ACE2 affinity. The free energy or stability changes were predicted and later compared with binding and expression changes observed experimentally using the three computational methods. The stability effects, as computed, observed that mutations in the 388 – 390 stretch had an impact on the stability of the protein.

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The effect of the mutation at each site was calculated as the mean absolute effect of 19 mutations as a surrogate of tolerance at each mutant site. Expression-affecting mutations were mainly inside the core RBD subdomain, particularly the central beta-sheet with the alpha-helices flanking it. The mutations affecting ACE2 binding were primarily observed in the ACE2 binding subdomain or the central beta-sheet.

The mutations affecting the stability of the protein were observed in the structured core of the RBD. RBD mutations affected its expression, binding, and stability differentially, although some overlap between protein expression and stability was observed. Next, the authors quantified the relationship by plotting predicted ΔΔG­ values against the changes observed in the expression and ACE2 binding of RBD for all mutations and each experimental structure with three methods.

RBD expression and ΔΔG­ for individual structures were correlated with varying magnitudes based on the type of prediction. Similarly, ACE2 binding and ΔΔG­ were associated to varying degrees based on the prediction method; nonetheless, the correlations (for binding) were weaker than that for expression, and the observed correlations were statistically significant.

The effects of mutations on protein stability correlated well with ACE2 binding and protein expression, better with the Deep DDG prediction. The expression and binding results were skewed, over-representing data points between 0 and -1. Therefore, the data were grouped into bins; each bin’s mean binding and expression effect and predicted stability energy values were calculated. The research team noted an increase of correlations upon binning, and it is noteworthy that the computational data correlated well with the binned experimental data.

Lastly, the study reported that mutations deeply buried in the protein core have a more significant effect on protein stability. Similar was the case observed for RBD, in which mutations in the core were less tolerated than those on or near the surface. A moderate correlation was observed when the effect of mutations on the binding and expression was studied regarding the surface exposure of RBD residues with a noticeable tolerance overall at sites with increased solvent exposure.

Conclusions

The current study’s findings demonstrated that the computed protein stability effects were significantly correlated with expression levels for all 48 comparative investigations, but to a certain extent with ACE2 binding. Further, there was a correlation between predicted stability changes and surface exposure.

Therefore, experimental mutational properties could be predicted, at least partly, and the phenotypes might correlate because of underlying correlators such as amino acid properties, site solvent exposure, and codon usage. Such correlations impact the S protein’s mutability, affecting phenotype tradeoffs and viral evolution.