We knew it was going to be a long, dark winter. But unfortunately, it’s now looking even more grim. Just as the first coronavirus vaccines began rolling out in the US and countries around the world in December — offering hope for the end of the Covid-19 pandemic — two fast-spreading variants of the SARS-CoV-2 virus were discovered in the United Kingdom and South Africa.
Within a matter of weeks, the new mutations replaced other versions of the virus in some regions. Scientists say they now may be driving some of the stunning case growth in the UK and South Africa, forcing new and tough control measures.
They’re also proliferating around the world. As of January 5, the UK variant had been found in 40 other countries and the South Africa variant in six, according to the World Health Organization. On Thursday, the WHO’s Europe director called on countries to urgently enhance their coronavirus controls and “flatten the steep vertical line” of rising cases.
“It’s scary, isn’t it?” said Richard Lessells, a University of KwaZulu-Natal infectious disease specialist in Durban, South Africa, who co-discovered the South Africa mutation. “I’m a Scotsman so talking about my emotions doesn’t come to me naturally but I have a lot of anxiety at the moment.”
All viruses mutate as they move through populations, and until recently, the mutations in SARS-CoV-2 weren’t cause for much concern. But B.1.1.7 in the UK and 501Y.V2 in South Africa each have a startling number of changes in the virus’s spike protein, the part that fits into the receptor in human cells, allowing it to infect people.
These changes may be why the new variants are seemingly more contagious than earlier versions of the already contagious virus. While there’s no evidence they cause more severe disease, more cases mean further stress on hospitals and, after that, a rising death rate.
Some researchers have another, pressing worry: The mutation could evade the currently available vaccines. That’s why doctors, virologists, and other health researchers are calling on officials to “vaccinate 24/7 like it’s an emergency,” as Scripps Research scientist Eric Topol said on Twitter. “Because it is.
If we wanted to get serious vs B.1.1.7
—get N95/K95 masks to all and enforce their use
—get rapid home testing big supply to each household for daily use
—amp up digital, mobility, genomic and wastewater surveillance 100X
—vaccinate 24/7 like it’s an emergency. Because it is.
— Eric Topol (@EricTopol) January 5, 2021
While vaccine manufacturers like Pfizer and BioNTech say their technologies can readily adapt to changes in the virus, we don’t yet know how exactly they’ll work against the new mutations. And as the virus continues to spread and more people get infected, the likelihood of even more dangerous mutations happening rises. So the new variants — and future mutations — may pose a threat to our vaccines and herald a new, potentially even more difficult, chapter in the pandemic.
Why the new Covid-19 variants are different — and more worrisome — when it comes to the vaccines
Scientists have warned that it was always possible the coronavirus could evolve to evade the Covid-19 vaccines that have been approved so far. The arrival of the UK and South Africa variants may be a step in that direction, increasing the odds of the vaccines becoming less effective over time.
In SARS-CoV-2, the main mutations scientists care about are on the spike protein of the virus — the part that allows it to enter human cells. This is also the protein that Covid-19 vaccines currently available in the US (from Moderna and Pfizer/BioNTech) are designed to imitate. About 4,000 mutations in the SARS-CoV-2 spike protein have been detected at various points in the pandemic. Most haven’t altered the function of the virus and haven’t stirred worry.
In rare cases, a mutation, or several at the same time, could lead to changes that give the virus a greater advantage. And that appears to be what’s happening with the UK and South Africa mutation.
The UK variant, B.1.1.7, contains 23 mutations in the genome of the virus while the South Africa variant, 501Y.V2, has at least 21 mutations, with some overlap between the two. In both cases, the changes seem to have increased the fitness of the virus, or its ability to propagate.
“[With genomic sequencing in South Africa] we can show quite clearly there were lots of different lineages circulating prior to October,” Lessells said. “Within the course of just a few weeks, this new lineage — 501Y.V2 — became almost the only lineage you’re detecting.” The story is similar in England, where a stunning one in 50 people were infected with Covid-19 as of last week.
The fact that these mutations have become so dominant so quickly hints that they may be more contagious. It’s not clear how much more contagious the South Africa variant is, but one estimate suggested the UK variant is up to 70 percent more transmissible.
There could also be other more familiar variables that are driving the spread of these new variants, like holiday travel.
“When you are seeing such huge transmission everywhere in the world in November and December, I just don’t know how you can say that it’s because this particular virus [variant] is more transmissible or it’s because we’re seeing great increases in transmissibility everywhere for a variety of factors,” said Anna Durbin, a vaccine researcher and a professor of international health at the Johns Hopkins School of Public Health.
Scientists still have to complete experiments in animals to pinpoint differences in transmissibility between these mutations and earlier versions of the virus — and to what extent shifts in peoples’ behavior might also explain the growth in cases.
But they’ve already zeroed in on concerning changes in the virus that are relevant to vaccine effectiveness. With the South Africa variant, for example, one change of particular interest is the E484K mutation in the receptor-binding domain of the virus where it latches on to human cells.
So currently when we’re thinking antibody response and protection from infection, E484K is the more concerning mutation of those we’re seeing currently. Found in SA but it will pop up elsewhere as well and in combination with different other mutations. So what we need now are: /4
— Dr. Tara C. Smith (@aetiology) January 5, 2021
“The E484K mutation has been shown to reduce antibody recognition,” said Francois Balloux, a professor of computational systems biology at the University College London, in a statement. This means it can help the virus “bypass immune protection provided by prior infection or vaccination.”
Researchers have shown exactly how this can happen in cell culture and small human experiments. One, described in a pre-print paper (and therefore not yet peer reviewed) on Biorxiv, looked at several generations of SARS-CoV-2 challenged with antibody-rich plasma from a Covid-19 convalescent patient and watched to see what happened. At first, the antibodies seemed to beat back the virus. But as the virus mutated, eventually making the E484K substitution, it started to proliferate in spite of the presence of the antibodies.
The senior author on the study, Rino Rappuoli, a professor of vaccines research at Imperial College and chief scientist at GSK, told Vox that when he and his colleagues first ran the experiment, they didn’t know how relevant their findings would be. “But when the South Africa and UK variants came along, we looked at [our data] and saw that, in real life, the first steps of what we saw in vitro are happening.” (GSK has a Covid-19 vaccine in clinical trials with the drugmaker Sanofi.)
Other scientists are coming to similar conclusions. In a second preprint, researchers tracked how mutations altered the effectiveness of the antibody response in four people who had the virus and they also found E484K has antibody evasion capabilities.
One caveat here is that these studies looked at plasma from people who survived a Covid-19 infection rather than antibodies from someone who received a vaccine. But Rappuoli said the findings are cause for concern nonetheless. “If given enough time under immune pressure, this virus has the possibility to escape.”
Researchers are racing to figure out how vaccines work against the variants
So what does this mean for the vaccine rollout effort? Will pharmaceutical companies have to tweak their existing vaccines to fight the new variants?
We don’t yet know.
“It is one of the key questions that we are trying to find answers to at the moment, and we have groups around the country working around the clock to get a better understanding of this,” said Lessells. “This also involves collaboration with other groups around the world, with groups running the vaccine trials, with vaccine developers.”
Rappuoli pointed out that there’s no evidence in humans yet that the South Africa and UK variants are able to outsmart the immune response created by vaccines, “but we should be prepared that at some point in the future that may happen,” he added. At least 30 countries have begun to administer Covid-19 vaccines, many of which are restricting immunizations to health workers and people at high risk of illness.
For Vineet Menachery, a coronavirus researcher at the University of Texas Medical Branch, the laboratory experiments on SARS-CoV-2 variants represent “the worst-case scenario,” where the mutations render prior immunity much less effective.
The currently available vaccines in the US — from Pfizer/BioNTech and Moderna — help the immune system target multiple areas of the spike protein, so the virus would have to change drastically to totally escape the immune response generated by the vaccines. He called the odds of this happening “unlikely but not impossible” and estimated it would take a couple of years to get there.
“There’s still many steps for the virus to overcome this barrier. We are not even close to that, in my opinion,” Menachery continued. “The variants are kind of going down that road, but we’re not there yet.”
The diversity of immune responses at the population level gives University of Utah evolutionary virologist Stephen Goldstein some comfort, too. “Our immune systems have evolved to deal with antigenic drift — or the selection of different variants of circulating viruses,” he said. “I’m not worried vaccine efficacy is going to fall off a cliff and go from 95 percent to zero.”
And if the vaccines do turn out to be less effective against the new variants, vaccine developers say they’ll be ready: They can quickly adapt the vaccines to fend off mutations of the virus. That’s because the new platforms they’re using can be modified easily to counter new threats.
Vaccine developers say they can adapt their technologies fast
The Pfizer/BioNTech vaccine and the Moderna vaccine both use a molecule called mRNA as their platform to deliver instructions for making the spike protein of SARS-CoV-2. Meanwhile, the vaccine developed by the University of Oxford and AstraZeneca that recently received approval in the UK (but not yet in the US) uses a reprogrammed version of another virus, an adenovirus, to shuttle DNA that codes for the SARS-CoV-2 spike protein.
Human cells then read that DNA or mRNA genetic information and manufacture the spike protein themselves, allowing the immune system to use it for target practice. An advantage of using this approach is that vaccine developers only need to modify DNA or mRNA to tweak the vaccine, something they can do quickly and easily if necessary.
“We’re currently looking into it and will know soon if the [current] vaccine immunizes against the variants,” a spokesperson for BioNTech told Vox in an email. If not, BioNTech’s chief executive Ugur Sahin told the FT, “the beauty of the messenger mRNA technology is we can directly start to engineer a vaccine that completely mimics this new mutation and we could manufacture a new vaccine within six weeks.”
These new vaccines would not necessarily require developers to go through every regulatory hurdle again, former FDA chief scientist Jesse Goodman told Vox in December. Instead, new versions of Covid-19 vaccines could end up going through an approval process similar to vaccines for seasonal influenza — with some initial testing but stopping short of massive clinical trials. That means revised Covid-19 vaccines could potentially roll out quickly.
Lessells was cautiously optimistic for another reason: Even if the current vaccines stop working as well as earlier clinical trials suggested, he said, “There are many vaccines in development. So as we learn more about this virus, the vaccine developers also learn from that, and different vaccines may be developed.”
But while it may be possible to alter the vaccine to adapt to new mutations, it’s not ideal: It would require expensive changes in the vaccine production process and eat up valuable time that could be used to inoculate more people during a devastating pandemic.
“From a cost and manufacturing perspective, it would put us far, far behind,” Durbin said.
Now’s the time to drive down case numbers and vaccinate
That’s why researchers and health officials are hoping to drive down case numbers and rapidly build up herd immunity with the existing vaccines while also getting ready for changes to the virus that may lay ahead.
To track mutations and understand how they may impact vaccine effectiveness, governments also need to invest more in genomic sequencing, Lessells said. And right now, “there’s a lot of variability around the world in how much sequencing is being done and how people are using sequencing.”
Inadequate sequencing of SARS-CoV-2 genomes may create blind spots where new mutations could be lurking. Infectious disease experts told Stat’s Helen Branswell that the US doesn’t sequence enough and may be unaware of how widespread the UK variant is because of that. According to Lessells, the UK sequences about 10 percent of its cases — on the high end of sequencing volume globally — while the number in South Africa is closer to 1 percent.
Of course, there’s another way to prevent dangerous mutations from arising: preventing cases from happening at all through mask-wearing, social distancing, rapid testing, and treating and isolating infected people. The virus can’t mutate if it’s not replicating inside lots of people.
“The bottom line hasn’t changed: We need to suppress the amount of viral transmission as much as we can,” Goldstein said. Vaccines are a part of that suppression effort, but social distancing and masks are too. “Outbreaks grow exponentially and you’re not going to vaccinate at an exponential rate,” he added. “But you can bring outbreaks down to a rate where they are not growing exponentially.”
For now, the emergence of the worrisome mutations is a reminder that, despite our collective fatigue, there’s still a long road ahead, Lessells said.
“We keep passing these milestones — going into a new year, having Christmas — and thinking that the virus is going to suddenly do something different because we are celebrating or whatever. Of course, that’s not the case. We are still in the early days. We are still learning about this virus.”