How the new Covid-19 variants could pose a threat to vaccination

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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 variants replaced other versions of the virus in some regions. Scientists say these variants help explain the recent peak in cases in the UK and South Africa that have forced new and tough social distancing measures. They’re also proliferating around the world. As of January 17, the UK variant had been found in 60 countries, and the South Africa variant in 23, according to the World Health Organization.

“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 variant. “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. (A mutation is a change in the genetic makeup of a virus while a variant is a virus that has a suite of mutations that alter how it behaves.)

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 — and these changes may be why the new variants are seemingly more contagious than earlier versions of the already contagious virus. (There’s already increasing alarm over variants that have emerged in California and Brazil — and these are just the ones we know about right now.)

While there’s no evidence they cause more severe disease, more cases mean further stress on hospitals and, after that, a rising death rate.

And some researchers have another, pressing worry: These mutations could render the current Covid-19 vaccines less effective. Or they could mean the virus eventually “escapes” them all together. 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.

While vaccine manufacturers like Pfizer and BioNTech say their technologies can readily adapt to changes in the virus, we’re still learning about how the shots will work in this new context — and the mutations in South Africa’s 501Y.V2 are causing particular concern.

As the virus continues to spread and more people are infected, the likelihood of even more dangerous mutations happening rises. So too does the threat the mutations pose to the vaccines. So, without drastic countermeasures, the variants could 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, 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 one in 50 people were infected with Covid-19 as of the new year.

The fact that these mutations became so dominant so quickly suggests that they may be more contagious. Scientists in South Africa think the variant that emerged there is about 50 percent more transmissible, and 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. 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.

“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 demonstrated how this might 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 people who had the virus. They also found E484K has antibody evasion capabilities. A third, also in test tubes involving survivor plasma from donors in South Africa, showed that antibodies from a prior infection were totally ineffective against the new variant in about half of the donors.

A couple of caveats here: These studies are in vitro, involving the specimens from Covid-19 survivors, rather than antibodies from someone who received a vaccine. We don’t yet know how people in clinical studies who got a vaccine will respond to the new variants.

Still, Rappuoli said, the findings are cause for concern nonetheless. “If given enough time under immune pressure, this virus has the possibility to escape.”

Another preprint study, from researchers in Brazil, recently provided an alarming example of how this could play out. The paper documents the case of a 45-year-old Covid-19 patient with no co-morbidities: months after her first bout with the illness, she was reinfected with a version of SARS-CoV-2 that had the E484K mutation — and experienced more severe illness the second time around. It’s limited evidence, but it suggests that surviving an earlier SARS-CoV-2 infection isn’t a guarantee of protection against variants with this mutation.

“The finding of the E484K, in an episode of SARS-CoV-2 reinfection might have major implications for public health policies, surveillance and immunization strategies,” the authors wrote.

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?

“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 said even if there’s no evidence yet showing the variants can outsmart the immune response created by vaccines, “we should be prepared that at some point in the future that may happen,” he added. For Fred Hutch Cancer Research Center scientist Trevor Bedford, that point could come as early as autumn this year:

Vineet Menachery, a coronavirus researcher at the University of Texas Medical Branch, said the laboratory experiments on SARS-CoV-2 variants represent “the worst-case scenario.”

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 completely escape the immune response generated by the vaccines. He called the odds of this happening “unlikely but not impossible.”

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.”

The incoming Centers for Disease Control and Prevention director, Rochelle Walensky, also took comfort in the very high rate of protection the vaccines already have. “The efficacy of the vaccine is so good and so high, that we have a little bit of a cushion,” Walensky said in a January 19 interview with JAMA.

And if the vaccines do turn out to be less effective against the new variants, vaccine developers say they’ll be up for the challenge of adapting them. 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.

In a January 19 preprint, BioNTech and Pfizer found the UK’s variant may not pose as much of a threat to their vaccine: Antibodies in blood samples from people who got the shot appeared to work against the B.1.1.7’s mutations, making it “unlikely” the variant will escape the vaccine. If a stronger viral foe comes along, BioNTech’s chief executive Ugur Sahin told the FT, “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,” said Anna Durbin, a vaccine researcher and a professor of international health at the Johns Hopkins School of Public Health.

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. According to Salim Abdool Karim, chief adviser on Covid-19 to the South African government, social distancing measures in the country appeared to be bending the curve. “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.”

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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.”

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