Viruses live – if you can call it that – to replicate themselves. They hijack cells, including our own, and use them to make copies of themselves.
But every time a virus like the one that causes COVID-19 copies itself, as it does millions of times inside each infected person, mistakes can happen. Instead of perfectly copying its 29,811 bases, the four-letter alphabet used to describe its genetic code, a wrong letter sneaks in.
These changes are random and most are unimportant, but each infection increases the risk of a mutation that could make the virus more infectious, deadlier, or just different enough to render vaccines and natural infections less protective, or treatments ineffective, said Dr. Robert Bollinger, a professor of infectious diseases at Johns Hopkins School of Medicine.
“Eventually, you’d expect some of these mutations to result in advantage for the virus,” he said.
Lately, variations of the SARS-CoV-2 virus that causes COVID-19 have popped up all over the world – including ones first seen in the U.K., South Africa, Brazil, and most recently, California.
British Prime Minister Boris Johnson announced Friday that the British variant, believed to be more infectious, is also killing a higher percentage of its victims.
For 1,000 people age 60, approximately 10 people would be expected to die, he said. With the new variant, called B.1.1.7, roughly 13 or 14 are dying, he said, citing data from the New and Emerging Respiratory Virus Threats Advisory Group, which advises the United Kingdom Government.
“I want to stress there’s a lot of uncertainty around these numbers and we need more work to get a precise handle on it, but it obviously is a concern that this (variant) has an increase in mortality as well as an increase in transmissibility,” said Sir Patrick Vallance, Johnson’s chief scientific adviser.
Even if the variant isn’t deadlier, more infectious variants will kill more people, Dr. Anthony Fauci, the nation’s top disease expert, said Thursday.
“If you have a virus that’s more transmissible, you’re going to get more cases,” . “When you get more cases, you’re going to get more hospitalizations, and when you get more hospitalizations, you ultimately are going to get more deaths.”
Bollinger said that the United States, which has a worse outbreak than anywhere else at the moment, “is now the world’s largest breeding ground for new mutations.”
That’s why, he and others say, more must be done to track the virus and rein in its spread.
“The longer the virus has to circulate, the longer it has to mutate,” said Dr. Monica Gandhi, a professor of medicine at the University of California, San Francisco.
So far, as far as scientists know, vaccines still work against the variants, as do diagnostic tests.
And the protective measures we all know so well – masks, social distancing, washing hands, avoiding crowds – are still the best defense, though people may have to be even more vigilant in using them.
What’s less clear is whether targeted drugs developed to help the immune system fight the SARS-CoV-2 virus will continue to work, and whether natural infections will provide as much protection.
As long as there is virus circulating widely, it can mutate and cause more trouble.
Barry Bloom, an immunologist at the Harvard T.H. Chan School of Public Health, said studies published this week have made him anxious about several of the variants.
“It’s the first time I’ve been concerned,” he said. “I’m now quite worried about them.”
COVID, one year later:The first US case. The first death. The first outbreak at a nursing home.
Not deadlier, but more infectious
So far, none of the new variants appears to make people sicker or cause more death.
Generally, it doesn’t make sense for a virus to become deadlier because viruses that kill their hosts too quickly can’t continue reproducing.
Middle East Respiratory Virus, for instance, which is similar to SARS-CoV-2, kills about one-third of its victims. But after a few scares when it first appeared in 2012-2013, it hasn’t spread much beyond Saudi Arabia, where it was first seen.
Virologists were relieved COVID-19 wasn’t as deadly but from the start its rapid rate of spread made it dangerous. And the newvariants appear to be even more contagious.
The B 1.1.7 variant first seen in the U.K. is estimated to be about 56% more infectious, and the 501Y.V2 identified in South Africa about 50% more, meaning both do a better job than the original virus at getting into human cells.
Gandhi thinks that may have to do with where the different variants spend most of their time. If the newer ones mostly inhabit the nose and throat, they may be passed more readily to other people via talking, sneezing, or coughing.
Those variants may not produce higher viral loads deeper in the lungs, where they could potentially result in more severe illness, she said.
The original virus also has a negative charge where it attaches to the human cell. The cell also is negatively charged so the two repel each other, slowing infection down somewhat, said Salim Abdool Karim, a clinical infectious diseases epidemiologist at the Mailman School of Public Health at Columbia University and apro-vice-chancellor at the University of KwaZulu-Natal in Durban, South Africa.
But the new variant found in South Africa has a mutation making it positively charged at the point where it attaches to the cell. The opposite charges attract, making it more likely to infect the cell, he said during a webinar earlier this week.
Another new variant, B.1.429, is on the rise in California. Doctors there are keeping a close eye on it, though it’s not clear why it’s spreading so fast. Its mutation, dubbed L452R, has been detected on a few occasions dating back to March but appears to have been very rare until November.
Between Nov. 22 and Dec. 13, the variant made up 3% of California cases where the virus was genetically sequenced. But between Dec. 14 and Jan. 3, that rose to 25%, said Dr. Charles Chiu, a professor of medicine and expert in viral genomics at the University of California, San Francisco.
Like the others, this variant appears to be more communicable but there’s no evidence that it makes people any sicker.
“The takeaway is not that we need to start worrying about this,” said Dr. Sara Cody, health officer and director of public health in the County of Santa Clara. “The takeaway is that we need to lean in and learn more about it.”
Although the new variants themselves don’t seem more dangerous, when hospitals are overrun with patients, they can’t take as good care of each one, and people are more likely to have bad results, Karim said.
A study published Tuesday found that deaths from COVID-19 increase when hospital intensive care units are full. That’s in part why the death rate in New York was so high last spring.
So, a more infectious virus can, indirectly, be deadlier.
Immune ‘escape’ may be underway
Virologists describe a virus as having “escaped” when it can no longer be controlled by antibodies built up after infection or vaccination.
The variant discovered in South Africa, 501Y.V2, with a mutation called 484, may be escaping some or all of the antibodies people developed against a natural infection – though it’s too soon to know whether vaccines will be effected.
Looking at blood from 44 South Africans who recovered from COVID-19, more than 90% showed reduced immunity to the new variant, and almost half had no protection at all against it, according to a study published Tuesday though not yet peer-reviewed.
The true test of whether a virus has “escaped” immunity is whether people can be re-infected. In South Africa, “the data at this point do not point in that direction,” Karim said.
In Manaus, Brazil, however, one 29-year-old woman who had COVID-19 back in March caught a different variant in December, according to a study posted this week. The woman had been healthy prior to her first infection with no immune issues.
Both infections were confirmed with molecular tests and she had an antibody test just a week or so before falling ill the second time, showing that she still had antibodies against the virus from her first infection.
It’s far too early to tell whether her case is a fluke, but it raises the specter that the variant may have changed enough to make her natural antibodies useless.
“Obviously this is cause for concern,” said William Hanage, associate professor of epidemiology at the Harvard T.H. Chan School of Public Health. “We need to know if more people are getting re-infected there than we would expect by chance.”
Manaus was among the areas of the world hardest hit by COVID-19, with roughly 76% of the population infected by October, suggesting that as the virus evolves, it will be impossible to reach so-called herd immunity with natural infections.
This kind of escape is more likely to happen in places that have had a lot of infections, like Brazil, South Africa and the United States, said Dr. Larry Corey, a professor of vaccinology at the Fred Hutchinson Cancer Research Center in Seattle.
“We are in a situation where variants are going to occur,” he said. “There’s no way not to see an increasing number …The more we look, the more we’ll see.”
The fact that both the South African variant and the one from Brazil seem to be able to evade natural antibodies suggests the virus is under pressure to mutate its so-called “spike protein.”
That’s concerning, Bloom said, because most of the vaccines developed against SARS-CoV-2 take aim at that protein.
Fauci said Thursday such variants could potentially weaken the effectiveness of current vaccines. “The diminution of what would be vaccine-induced antibodies,” as he put it.
But there’s a “cushion effect,” meaning current vaccines will still offer some protection, and will still be far better than no vaccine at all.
“It is all the more reason why we should be vaccinating as many people as we possibly can,” he said.
Monoclonal antibodies, a type of treatment given to high-risk people shortly after catching COVID-19, also could lose their effectiveness as the virus shifts, suggests a new study led by researchers at The Rockefeller University.
The drugs are very targeted, and mutations in the same area could, metaphorically, mean that the key no longer fits the lock.
The variant seen in South Africa and potentially Brazil, “has much greater chance of obliterating the efficacy of a monoclonal antibody,” Fauci said.
Combinations or cocktails of monoclonals should continue to be effective, Corey said,though drug companies may need to collaborate to combine their individual therapies.
Virus variants need more scrutiny
More research is essential to track the virus and understand how to fight it, said Corey, who also co-leads vaccine testing for the federally established COVID-19 Prevention Trials Network.
The U.S. hasn’t been sequencing enough virus from COVID-19 patients to understand how it might be changing, several scientists said.
The United Kingdom, for example, with just 66 million residents, has sequenced far more virus than the U.S. with a population of 328 million, which is why it discovered the new variant sooner.
At least 144 cases of that variant have been tracked across the U.S., and the Centers for Disease Control and Prevention predicts it may become the predominant variant in the country by March.
Some of the lack of testing is a cost issue. “We haven’t been sequencing all the cases we have because it’s expensive, it’s at least $100 per test,” Gandhi said. “That’s just not cost-effective.”
But now, there’s so much virus, it doesn’t take a lot of sequencing to see changes.
“We’re having such big surges that even if we sequence only a few cases, we start to see the variants,” she said. “If we’d been sequencing all along, we would have been seeing these variants all along.”
Researchers think some variants likely arise from patients whose immune systems can’t quite conquer the virus, allowing it to mutate.
If someone with a mutated virus infects someone else, they may pass it on, said Susan Weiss, a professor of microbiology at the University of Pennsylvania School of Medicine and co-director of the school’s Center for Research on Coronaviruses and Other Emerging Pathogens.
Other variants may spread rapidly, like the one that emerged in Britain, because it replicates faster or is more easily transmitted.
Getting only one dose of a two-dose vaccine, might eventually drive the virus to mutate away from the vaccine, rendering it less protective, warned Dr. Paul Offit, director of the Vaccine Education Center and professor of pediatrics at Children’s Hospital of Philadelphia.
It is certainly possible that over the next months or years, the virus will mutate so much that the vaccines that took nearly a year to make against it will no longer be effective.
“That’s going to be a nightmare,” Offit said in a recent discussion sponsored by the Journal of the American Medical Association.
Retrofitting vaccines if needed
But all won’t be lost.
The new vaccine technology should allow scientists to quickly swap out the current genetic sequence for another. Or even to address several variants at once, Offit said.
The two vaccines authorized for use in the United States are based on so-called mRNA technology, which directs the body to make a protein found on the surface of the SARS-CoV-2 virus.
These were the first two to reach the public because they can be made quickly – which means they can also be altered quickly, if the need arises, said Dr. Kathryn Edwards, a fellow of the Infectious Diseases Society of America and scientific director of the Vanderbilt Vaccine Research Program in Nashville, Tennessee.
With the seasonal flu, the vaccine is changed every year to respond to the strains believed to be circulating that year, she said in a Thursday call with media.
The flu vaccine, which includes three to four different strains, is tested in ferrets and then a few people to make sure it is safe and effective. It’s then quickly rolled out to the broader public, she said, noting that something similar could eventually be done with a COVID-19 vaccine.
Fauci said the government is now looking for variants, and will take quick action if any seem to be evading vaccines.
“Bottom line: We’re paying very close attention to it,” Fauci said. “There are alternative plans if we ever have to modify the vaccine. That’s not something that is a very onerous thing, we can do that given the platforms we have.”
Norman Baylor, president and CEO of Biologics Consulting, which advises companies on the regulatory process, was less optimistic.
Different from the flu, SARS-CoV-2 is a new virus, the vaccine technology has never been used at large scale before, and it’s not clear how the safety and effectiveness of a new vaccine would be shown, said Baylor, a former director of the Office of Vaccines Research and Review at the Food and Drug Administration.
Plus, while the vaccine still works and new variants are still popping up, it’s unclear how a vaccine could or should be redesigned.
In the meantime, in a country like the U.S., with more than 100,000 new COVID-19 cases per day, Corey said mutations will happen. The only way to stop them is to stop the virus from spreading.
“We have to do everything we can to decrease the risk of transmission and acquisition,” he said.
Keep wearing masks. Avoid crowds. Get as many people vaccinated as possible.
“Where there’s a will, there’s a way,” he said.
Contributing from London: Kim Hjelmgaard
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