When the omicron variant of COVID-19 emerged in South Africa late last year, it took only weeks to overtake delta, the variant that previously dominated. Then the original version of omicron was replaced by one subvariant, and then another. The latest subvariants, BA.4 and BA.5, are now quickly spreading in the U.S.
The virus is evolving so quickly that when Moderna recently announced preliminary results from the trial of its newest COVID-19 vaccine—the first designed to target both the original virus and omicron—the vaccine was already somewhat outdated since it wasn’t designed to stymie the newest subvariants. And when the Food and Drug Administration (FDA) meets at the end of June to discuss whether the vaccine should be modified before the likely rollout of more booster shots in the fall, it will have to make decisions without knowing how the virus will continue to change.
“There’s no guarantee that the virus that we see in the fall or the winter will be an omicron-derived variant,” says Dr. William Moss, executive director of the International Vaccine Access Center at the Johns Hopkins Bloomberg School of Public Health. Because omicron is so transmissible, he says that there’s a good chance it will still be around. But subvariants will look different than they do now. The FDA faces some difficult questions: How critical is it that the vaccine closely matches the virus? And if it is important, how much red tape should there be when new versions of the vaccine are created?
The original omicron variant has 60 mutations that make it possible for the virus to evade the antibodies generated by current vaccines, so it’s easier to get infected despite vaccination. One recent preprint paper suggests that BA.4 and BA.5, each with their own mutations, may be even better at evading antibodies. Current vaccines, though, still do a good job of protecting against severe disease by generating T cells, another key part of immunity.
“For antibodies to block the virus, they have to bind to a very small area called the receptor binding domain,” says Dr. Otto Yang, a professor of medicine in the division of infectious diseases and microbiology, immunology, and molecular genetics at UCLA. “If you look at a map of where these mutations are occurring in omicron and delta, they’re clustered around that area. So to the antibodies, they’re big, big changes. But the way T cells work is that they recognize tiny pieces of proteins that can be from anywhere, not just the receptor binding domain. If you look at omicron versus the original strain, they’re about 97% identical in sequence.”
Even as infections surged this spring in the U.S., vaccines helped keep the rate of hospitalization relatively low. T cells decline over time, which is why another booster shot may be necessary before another potential fall or winter surge; even a booster shot that doesn’t exactly match the current variant will be helpful in protecting against severe cases and hospitalizations. And something more tailored could potentially help even more.
The mRNA vaccine-development platform that both Moderna and Pfizer-BioNTech used for their vaccines can be quickly adapted. BioNTech, for example, developed an early version of its vaccine targeting the delta variant in less than a month last year. (Pfizer and BioNTech will soon announce results for an omicron-specific vaccine they have been testing.) In theory, new vaccines could be developed and produced as new variants emerge. But regulators will have to decide in June whether each new version needs to go through new rounds of testing.
When the FDA meets, it might decide that COVID-19 vaccines should be treated more like flu vaccines, which are updated each year without the need for new approvals each time. The COVID-19 vaccines use a platform “that we already know is very safe, and the changes are fairly small,” Yang says. “So it may be worth just allowing the company to make versions like this much more quickly . . . with this technology, theoretically, you could reengineer a change within a few weeks and have it out.”
The FDA also will have to evaluate how much benefit new vaccines might bring. Moderna’s new vaccine, tested with a relatively small group of people, showed that it could help produce around 1.75 times more antibodies against omicron, though the increase “is not a huge boost,” says Moss. “We don’t know how long that’s going to last. And one big unanswered question in my mind is, what’s the clinical significance of that?” The tests didn’t evaluate the impact on T cells, which are harder to measure. Moderna also hasn’t shared data on how the vaccine performs against the newest subvariants, though the company told the New York Times that when it tested a small sample, levels of antibodies generated in those cases were two to three times lower than against the original version of omicron; the company said that those levels were still “a very comfortable place,” however.
If new versions of the vaccine can help prevent more infections—and not just severe disease—that would also be a good thing. “I think it would make more sense to update [vaccines] in real time,” says Yang. “Because if the vaccine is altered as the new version is starting to take over, you have the chance to actually slow it down. Part of what we want to do is protect vulnerable people in society that can’t get vaccinated, or [in whom] the vaccines don’t work.”
We may need to keep getting regular doses of updated COVID-19 vaccines, the same way flu shots come out each year. But there’s also a chance that we can reach a threshold of protection that’s longer-lasting. “It may be that after three or four vaccinations, the T cells won’t go down as fast,” he says. “Some vaccines require multiple doses—like the hepatitis B vaccine is three doses. Maybe for these vaccines, it’s simply a matter of needing three or four doses to get to a level where things are more stable. That’s not clear yet.”
