Since the pandemic began, its viral cause—SARS-CoV-2—has been mutating. These genetic changes appeared inconsequential at first. But recently some alterations have produced variants with the unsettling potential to make the new COVID vaccines less effective, just as the shots have begun to make their way into people’s arms. Now, drug makers are responding by developing different follow-up shots against these variants to keep the disease at bay. These efforts mark the next phase in what’s shaping up to be a long battle between an ever-changing virus and the immunizations deployed against it.
The worrisome new variants change the behavior of the virus. One, called B.1.1.7, was detected first in the United Kingdom. It contains several mutations, including one that helps the virus transmit more easily between people, and it also could be more lethal than the original version. Scientists predict it could be the dominant strain in the United States by March. Another disturbing variant, called B.1.351, was noticed first in South Africa. This one contains mutations that make it far more difficult for immune system antibodies to interfere with the coronavirus’ spike protein. Spike is the viral component that latches onto cells to start infection, and thus it is a major target for natural antibodies and those produced by vaccination. In a recent preprint, a research paper that has not yet been peer-reviewed, scientists reported that antibodies taken from the blood of people who got two shots of the new Moderna vaccine were 8.6 times less effective at neutralizing B.1.351 in laboratory samples than they were at neutralizing earlier versions of the virus. That same study indicated that the new vaccine made by Pfizer was 6.5-fold less active against that new variant.
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These reductions may not hamper vaccine effectiveness, however, particularly against the severe levels of disease that put people in the hospital. Antibody levels induced by the vaccines are so elevated to begin with that such drops still leave enough antibodies to offer protection, according to virologist Roberto Burioni from the Vita-Salute San Raffaele University, Milan, who noted his view on Twitter.
Real-world evidence also offers positive news, indicating that the current vaccines protect against the worst forms of COVID. In a clinical trial that included South Africa, where B.1.351 has become widespread, Johnson & Johnson’s vaccine reduced the average person’s risk of getting severe disease by 85 percent and reduced the risk of hospitalizations and death by 100 percent. Overall, it reduced risk of symptomatic infections by 57 percent. Lance Baldo, chief medical officer at Seattle–based Adaptive Biotechnologies, which makes tests to evaluate immune responses to viral infection, says protection against severe disease likely is because the vaccines produce broad antivirus activity that extends beyond antibodies, and probably involves T cells, which recognize and kill infected cells. [Editor's note, 2/19/21: This sentence was changed to say the company is based in Seattle, not in San Francisco as the original article stated.]
Paul Offit, a pediatrician and director of the Vaccine Education Center at the Children’s Hospital of Philadelphia agrees. It “is good news” that vaccines in general protect against severe COVID, he says, and keeping people out of the hospital is a top priority. “If fully vaccinated people start winding up hospitalized with one of these variants, then we need to worry more. So far that line hasn't been crossed,” he says.
To boost protection against even mild disease, vaccine makers think they can adapt the existing shots to the variants without too much trouble. Vaccines based on genetic material, such as the Moderna and Pfizer immunizations, are especially well suited to these modifications, since scientists can easily swap in new genetic sequences as needed. Moderna plans on tackling variants with a two-pronged strategy. The company intends to test a booster shot of its existing vaccine to see if bumping up antibody levels even higher can protect against emerging variants. Moderna has also begun manufacturing a new vaccine targeted specifically at mutations contained in the B.1.351 variant. The company president, Stephen Hoge, says that booster could be used with people who were immunized with the first Moderna vaccine, or a vaccine from a different company. He also says the shot could be used on people who already had a natural infection from the earlier virus but may be vulnerable to reinfection from one of the new variants. In a January 25 press release, the company announced that it was advancing the booster into preclinical studies and an early-stage clinical trial in the United States.
Hoge would not comment on when the new booster might be publicly available. He emphasized that “our current vaccine appears to have generated neutralizing antibodies that we think are protective against” the most concerning variants, shown in a preprint released in late January and based on research by scientists at the U.S. National Institutes of Health and Moderna. Hoge said that “if two or three months from now the variants really start take over in terms of infection, and we’re getting clinical data that say ‘OK you can boost,’ then we'll have to figure out when we switch and how.”
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Other companies are moving in a similar direction. Pfizer has posted preprint results indicating that its vaccine protects people against B.1.1.7 and B.1.351. But in an e-mail to Scientific American, a Pfizer spokesperson said the company is also “laying the groundwork to respond quickly if a variant of SARS-CoV-2 shows evidence of escaping the vaccine.” An updated vaccine would be administered as a booster, the spokesperson said.
AztraZeneca, which uses a common cold virus to deliver spike protein DNA into human cells, plans to release a new vaccine against B.1.351 in the fall. Johnson & Johnson, which also uses a harmless virus as a delivery vehicle for its DNA vaccine, has just applied for emergency authorization from the U.S. Food and Drug Administration. The company is “thinking about whether a revised booster or other modified vaccine [for addressing variants] may be necessary,” said the vaccine’s co-developer Dan Barouch, director of virology and vaccine research at Beth Israel Deaconess Medical Center in Boston.
Finally, the vaccine maker Novavax, now in late-stage clinical trials with a shot made from an early-version SARS-CoV-2 spike protein, is working on an updated booster that the company expects to test in April or the months thereafter. In an e-mail to Scientific American, a Novovax spokesperson said company officials are looking into targeting the South African variant, although a decision has not been made yet.
Even as vaccine researchers strategize ways to produce new shots, it is not yet clear what kind of tests will be needed to secure government authorization to use them. Norman Baylor, former director of the FDA’s Office of Vaccines Research and Review, and currently the president of Biologics Consulting, in Alexandria, Va., emphasizes that for simple changes to gene-based vaccines, most questions about safety and effectiveness can be answered with small, rapid studies; these could enroll at most a few hundred people, rather than the tens of thousands needed for the original vaccine clinical trials. The aim, he says, is to show that the neutralizing antibody levels induced by a booster are “comparable to those seen in the clinical trial with the original vaccine.” If that turns out to be the case, and the manufacturing platform itself remains unchanged, he says, then it is likely a booster will quickly get a green light.
But approval still leaves major questions about how to deploy a booster and against which mutations. “Who should get it and when? Do companies have the capacity to switch gears and start generating millions of doses of a new vaccine targeting the mutations?” Baylor asks.
Experts anticipate that in the future, COVID vaccine programs could mirror plans for immunizing against yearly influenza. For that disease, the World Health Organization and other collaborating agencies track circulating strains and tailor vaccines as part of an internationally synchronized strategy. If SARS-CoV-2 continues to circulate for years, or becomes a background virus that never completely goes away, decisions about which variants to vaccinate against could be made in a similar way, proposes Nikolai Petrovsky, an immunologist at Flinders University, in Bedford Park, South Australia. As it currently stands, “vaccine manufacturers are each deciding on their own strategy,” Petrovksy says. The better approach, he says, would be for companies and international groups to coordinate their efforts around a consensus set of mutations deemed most likely to escape vaccine immunity.
Until that happens, Petrovsky stresses that the best way to stop dangerous new variants from emerging is to vaccinate globally as fast as possible while encouraging mask wearing, social distancing and other basic public health measures. These steps will deprive the virus of new hosts in which it can evolve new versions. “We will always be vulnerable until everyone is protected,” he says.