What Will it Take to Make Covid-19 Vaccines Variant-Proof?

As emerging mutations threaten the progress made against the pandemic, scientists and regulators are racing to figure out a process for updating shots.
vaccine
Photograph: KENA BETANCUR/Getty Images

Last week, two more pharmaceutical firms backed by the US federal government’s Operation Warp Speed program announced preliminary results from large-scale clinical trials of their Covid-19 vaccines. And both had very welcome results to report. Mostly.

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According to Johnson & Johnson’s press release, the company’s single shot was 85 percent effective in preventing severe forms of the disease across the 44,000 people enrolled in each of three trials in the United States, Latin America, and South Africa. But when it came to fending off more mild cases of coronavirus infection, the vaccine worked best in the US, where it was 72 percent protective compared to just 57 percent in South Africa. (The shot’s efficacy in Latin America was 66 percent.)

It was the same story with Novavax, a much smaller, Maryland-based company. In its 15,000-person United Kingdom trial, the vaccine demonstrated 89 percent efficacy against mild, moderate, and severe cases of Covid-19; in the company’s smaller study in South Africa, the efficacy rate fell to about 50 percent.

The dramatic difference likely comes down to the particular versions of the coronavirus circulating in different locationss. Late last year, around the time that both Novavax and Johnson & Johnson were launching their South African trials, scientists in Durban uncovered a new cluster of cases, all united by a unique constellation of mutations in the gene for the virus’s spike protein. That variant, known as B.1.351, quickly expanded across the country, becoming the dominant strain in just a few weeks’ time and fueling a massive surge in new infections.

Since B.1.351’s initial discovery, scientists around the world have been sprinting to better understand its mutations. A series of non-peer-reviewed studies posted as preprints in recent weeks found that one in particular, called E484K, made it much harder for antibodies found in the blood of recovered Covid-19 patients and immunized people to recognize version B.1.351 of the virus. Based on those lab experiments, scientists had a strong suspicion that the current class of authorized vaccines would still work against that strain—but maybe just not as well. Data gathered from the Novavax and Johnson & Johnson trials now seems to be bolstering that hunch.

“This is a wake-up call to all of us,” Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, said at a White House press briefing on Friday. He acknowledged that the virus is changing more quickly than once thought, and that the variants now spreading around the world won’t be the end of its evolution. “That means that we as a government, companies, all of us in this together, will have to be nimble to be able to adjust readily, to make versions of the vaccine that are specifically directed toward whatever mutation is prevalsent at any given time,” he continued.

B.1.351 is one of at least three variants—including one first found in the UK and another in Brazil—thought to spread more easily than earlier forms of the coronavirus, though it’s not yet clear how much more transmissible each one is, and to what extent they can cause reinfections. What is apparent to scientists and public health experts is that the US, and indeed the world, is now in a race to vaccinate as many people as possible before these problematic mutations gain a foothold. But at the same time, parallel efforts to develop and distribute multi-variant vaccines to tackle all the existing strains must also begin. How will that actually work?

Executives from both Pfizer and Moderna, the first companies to have Covid-19 vaccines authorized by the US Food and Drug Administration, have said they are retooling their shots to boost protection against these new mutations, just as a precaution. Moderna has gone so far to begin preparing for a Phase I study of a B.1.351-specific booster dose that would be given as a follow-up to people who already received the original vaccine.

But FDA regulators haven’t yet decided what sorts of experiments and data will be required to allow for the rollout of a second generation of Covid-19 vaccines before the first one has been fully approved. (Moderna and Pfizer’s vaccines have received emergency use authorization, which only lasts until the Covid-19 public health emergency ends.) And some scientists are skeptical that the updated immunizations will be as straightforward to make as the originals. How easy the reinvention-regulation cycle turns out to be will have a big effect on just how nimble the US response to vaccine resistance is, with possible implications for how quickly the pandemic can be brought to an end.

“This is the virus’s gambit, and we don’t need to panic, but we need to pay attention, and we need to up our game,” says Larry Corey, a prominent virologist at the Vaccine and Infectious Disease Division of the Fred Hutchinson Cancer Research Center. Early on in the pandemic, Fauci tapped Corey and the Hutch to serve as the operational command center for a federally funded network of clinical trials testing Covid-19 treatments and vaccines—including the Moderna, Novavax, and Johnson & Johnson shots.

Corey points to some data from the Novavax trial in South Africa that wasn’t included in the press release but was discussed in a webinar presentation by one of the study’s lead scientists, Shabir Madh. It showed that in the placebo group—which included people who had been previously infected and people who hadn’t—volunteers of both types ended up contracting SARS-CoV-2 at the same rate. In other words, said Madh, the bad news the researchers gleaned from that result is that past infection with the strains that had been circulating earlier in South Africa didn’t protect those people against getting Covid-19 again. But there was also good news: The people in the vaccine arm of the trial fared much better, regardless of a previous infection.

“That shows you have an escape resistance variant, and a very effective escape resistance variant at that,” says Corey. But the vaccines seem to do better than natural immunity against the new mutations. “That means the data is still telling us ‘vaccinate, vaccinate, vaccinate,’” he continues. “But no one wants to see a 30 percent drop in efficacy, so we do need to pretty urgently also start thinking about how we’re going to construct a better countermeasure.”

As of Tuesday, about 32.2 million people have received at least one dose of a Covid-19 vaccine, and about 5.9 million of those people have been fully immunized with both doses, according to data from the US Centers for Disease Control and Prevention. That is well short of the outgoing Trump administration’s aims of vaccinating 20 million Americans by the end of 2020. Plans put forward by President Joe Biden last month are even more ambitious: Get shots in the arms of 100 million people in his first 100 days in office.

The arrival of new working vaccines from Novavax and Johnson & Johnson will aid that drive, and evalsuating them will keep the FDA busy in the coming weeks. But the agency is simultaneously sorting out a regulatory process for variant-targeted vaccines and boosters, should they be needed in the future. “We are assessing the impact of the new strains on authorized products and are working with medical product sponsors to provide information on evalsuating any potential impact that these or other variants may have on effectiveness of their products,” an FDA spokeswoman told WIRED via email. At this time, she continued, the agency has confidence that the currently authorized vaccines remain effective in protecting the American public against the current Covid-19 strains.

However, she wrote, agency scientists have begun to think about developing a potential pathway for authorizing changes needed to update Covid-19 vaccines, should information on emerging variants make them necessary. “The agency has experience with other situations where such changes are needed, for example, as is the case with influenza virus vaccines,” she wrote.

After all, the US already has a model for quick-turn vaccine updates: flu shots. The influenza virus mutates much faster than SARS-CoV-2, so variants capable of escaping existing vaccines arise all the time. That’s why there’s a global flu surveillance system to monitor which strains are circulating and which ones are wreaking the most havoc. It’s also why shot makers have to constantly rewrite the recipes for their flu vaccines in order to keep up.

The FDA approved its first widely available flu vaccine in 1945, and since then it has approved dozens more. But ensuring that the US has a shot that works each flu season is a constant process. Twice a year, the World Health Organization convenes scientists, including from the FDA and the CDC, to look at the thousands of virus strains circulating. They identify the four most likely to cause serious illness, as well as the best-performing vaccines against them. The WHO then makes recommendations on the composition of vaccines for the upcoming flu season—in February for the northern hemisphere and in September for the southern hemisphere. A few weeks after the February meeting, an FDA advisory panel meets to make its own determination about what the coming crop of vaccines should look like for the US. These decisions have to be made months in advance to allow time for vaccine makers to reformulate, test, manufacture, and distribute their updated shots.

Because of the time crunch, the FDA doesn’t require large-scale clinical trials of the latest versions of each vaccine. The agency makes its licensing decisions based on much smaller tests that prove the shots are safe and spur potent antibody production. Since the coronavirus mutates more slowly than the flu, and it’s still unknown how long immunity to it will last—either via vaccines or natural infection—it’s not yet clear if a similar process will make the most sense for Covid-19.

According to the FDA spokeswoman, the agency is considering many potential regulatory paths for future variant-specific vaccines or booster shots, and she wouldn’t comment on which one the agency is most likely to pursue. In guidance posted last summer, FDA officials left the door open for emergency authorization or accelerated approval by biomarker alone—meaning a booster could get approved based on whether vaccine recipients have changes in antibody levels “reasonably likely to predict” protection against SARS-CoV-2. In that situation, these surrogate measures would replace a full Phase III trial designed to determine if vaccinated folks are less likely to contract Covid than a placebo group.

At the time, the move alarmed critics—including Jerry Avorn, a drug epidemiologist and professor of medicine at Harvard Medical School. But now, six months and a few successful Phase III clinical trials later, he says scientists know a lot more about how an antibody response corresponds to protection against the virus. Given the threat of new variants, he believes the move could be very much justified. “I’d be fine with it in this instance,” he told WIRED via email, especially because doing full clinical trials for boosters or multivalent vaccines could get morally murky very quickly.

Since the FDA-authorized vaccines are so far clearly effective, new trials in which some people would only get a placebo might not get a greenlight from an ethical review board. “It could be also ethically problematic to randomize someone to the new, improved, optimized vaccine versus the old one if a mutant version of the pandemic is raging,” Avorn wrote.

Other prominent scientists are also in favor of skipping the full Phase III clinical trial route when it comes to vaccine updates. In a recent Wall Street Journal op-ed, former FDA commissioner Scott Gottlieb argued that keeping up with emerging threats to vaccine efficacy will require a lighter regulatory touch than what has been employed so far. “As it becomes clearer that the vaccines mount the desired immune response, and their long-term safety is well understood, we need to be able to license vaccines efficiently that have small tweaks,” he wrote. “The effort will require a new scientific and regulatory framework that allow[s] countermeasures to be adapted and updated quickly as the threat evolves.”

How quickly such countermeasures can be vetted and licensed is one thing. But actually making them will be another. The two currently authorized vaccines are both made with mRNA technology—essentially strings of genetic code that serve up the instructions for how to make parts of the coronavirus’s spike protein. In theory, updating that strand of mRNA to match the mutations found in the most worrying variants should be as simple as swapping a few nucleotides in a few key locationss—maybe adding in a few more lines of code. Then those new recipes can get tested in animals to see which ones provoke production of the right kinds of antibodies. Pfizer and BioNTech officials have said that the development and lab testing process should take about six weeks.

But that depends on the assumption that the mutations of concern, particularly E484K, are causing trouble by acting in a particular way, says Kristian Andersen, an immunologist and director of Infectious Disease Genomics at the Scripps Institute in San Diego. That mutation reverses the polarity of a key part of the spike protein, making it easier to latch onto a receptor that acts as a doorway into human cells. It could be that that structural change also makes it harder for the immune system to recognize the mutated spike protein. In which case, updating the vaccine so the resulting proteins more closely mimic the new shape of the spike should train up an army of effective antibodies. “That’s the part that would be simple,” says Andersen.

But there’s another possible explanation. Instead of directly disrupting the ability of antibodies to bind, E484K could be “shielding” parts of the protein, making it harder for the antibodies to “see” the virus at all, kind of like a cloaking device. Other viruses, like HIV and the one that causes dengue fever, have evolved such a trick. So far, nobody knows if this coronavirus has too. If so, updating the vaccine gets a whole lot more complicated, because even a retooled recipe risks not eliciting a very strong immune response. “We don’t know which of the two are at play here,” says Andersen. “But we need to know rapidly, so we can get a sense of what updated vaccines would look like.”

Pfizer’s confidence in its ability to meet a six-week turnaround time is because of the flexibility of its mRNA technology, which allows for quick alterations to be made to the vaccine sequence, according to a statement emailed to WIRED by a company spokesperson. “We are already laying the groundwork to respond quickly if a variant of SARS-CoV-2 shows evidence of escaping immunity by our vaccine,” the statement read. “However, the studies needed to evalsuate a vaccine that encodes an updated viral antigen have yet to be determined, in agreement with regulators. We will need to generate data that gives confidence that any updated vaccine is safe and effective.”

Neither Moderna nor J&J responded to WIRED’s questions. A spokesperson for Novavax would not say whether or not the company has already begun testing new multivalent versions of its vaccine.

Corey says he’s hopeful that the large inflow of cash to these companies from Operation Warp Speed has enabled them to bulk up the personnel and resources required for this new development sprint. But as to whether they’ll be able to deliver in time to thwart threatening new mutations, he says, “We’ll just have to see.”

In his own work developing an HIV vaccine, Corey says that changing the recipe to better match a new strain of the virus almost never affects the safety of the shot. “Safety is driven almost entirely by the technology platform,” he says. “The thing that changes when you drop in a new gene is really just the immune response.”

“It would have been nice if the virus didn’t do this, but it did,” says Corey of its recent surge in mutations. What’s getting lost in all the worries over new variants though, he says, is the monumental stroke of luck that two large-scale vaccine trials happened to have kicked off in South Africa, exactly where one of the new strains emerged. “We learned about it as quickly as one could, so now we can know we’re OK, but we’re certainly not done.”

In other words, the virus has made its move. Now it’s technology’s turn.


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