Over a year after the US authorized its first vaccines, COVID cases continue to pile up, leaving many vaccinated people wondering: “Do I need a vaccine upgrade?” People who are fully vaccinated and boosted have been testing positive in huge numbers, particularly since the omicron-triggered wave started its relentless burn across the United States in December. Vaccines that once caused experts to declare COVID-19 a “pandemic of the unvaccinated” don’t protect as well against illness, even as they continued to protect against the most severe disease. Breakthrough infections are so common that the near-miraculous protection the vaccine promised a year ago feels very far away.

Part of the problem is that the virus that the vaccines target — the first version of the coronavirus that started spreading in early 2020 — doesn’t exist anymore. Now, regulators, researchers, and vaccine companies are turning to the next phase of the vaccine development process: finding a way to protect against the virus that’s spreading now and finding a way to protect people against future variations of the virus.

On June 28th, an FDA committee will meet to discuss whether and how future booster doses of vaccines might specifically target emerging variants of the virus. Like the seasonal flu shot, the next vaccines may at some point protect against whatever version of the virus is going to be circulating in a particular year. At the same time, other scientists are looking into ways of making the protection from any booster shot last longer. Longer-term, COVID-19 vaccines might be very different from current shots, using different technology and protecting against viruses that don’t even exist yet. Some might not be shots but nasal sprays, which might be able to prevent even mild infections.

“Preventing severe disease was the original goal, and I understand that. At the beginning of the pandemic, that made sense,” said Akiko Iwasaki, a professor of immunobiology at Yale University School of Medicine. “But now we understand the virus better and the fact that the variants are here — I think we need to shift our thinking.”

The next virus

The first step for the future of COVID-19 vaccines is to play catch-up with the recent past. After over two years, the version of the virus that was first detected in Wuhan, China, has been replaced by its more contagious and immune-evading variants. Several vaccine manufacturers have already started testing vaccines tailored to the omicron variant. An early analysis of Moderna’s omicron-specific shot showed that it generated more antibodies against the omicron virus than the original vaccine, the company announced earlier this month. The vaccine is bivalent — it’s made to protect against both the “original flavor” coronavirus and omicron.

Moderna says its booster may be “available by late summer in some markets,” wrote Elise Meyer, senior director of communications at Moderna, in an email to The Verge.

Pfizer and BioNTech are also running a clinical trial to update their shots against omicron, examining standard booster shots of the original vaccine, a version targeting only omicron, and a bivalent shot like Moderna’s. At a press briefing in April, Pfizer CEO Albert Bourla said an omicron shot might be available in the fall.

Novavax, whose vaccine might be approved soon in the US, is working on its own omicron booster. Its clinical trial testing both omicron-targeted shot and a bivalent vaccine started on May 31st. The vaccine, which has been under review by the FDA since January, seems to have less severe side effects than the other vaccines, making it potentially ideal to use as a non-disruptive booster.

But it’s still unclear if the omicron shots will work much better than the original vaccine against omicron and other variants. In one study on mice, the original vaccine “actually worked quite well, at least in the short-term,” said Larissa Thackray, an associate professor of infectious disease at the Washington University School of Medicine in St. Louis.

If omicron-specific vaccines don’t have a major benefit over the existing vaccines, they could be a hard sell to be authorized by the FDA. Yet despite the uncertainty, Thackray said she thinks an omicron booster is overdue. A vaccine targeting a current or at least recent variant makes more sense than one targeting a much different virus — the original strain of SARS-CoV-2, which doesn’t exist anymore.

At some point, omicron might not be circulating anymore either. It’s already evolved into several sublineages, and the virus will only keep evolving. Figuring out a way to continuously update the shots is one way to keep on top of it. But other researchers are working on “universal” vaccines — which could theoretically protect against any new form of the virus.

Vaccines like this take advantage of the immune system’s ability to respond to the parts of viruses that stay the same as they evolve, said David Martinez, an immunologist at the University of North Carolina at Chapel Hill and an author of a 2021 study examining a proposed universal coronavirus vaccine.

Martinez and other researchers made their vaccine by combining genetic material from a handful of different coronaviruses. Their goal was to make a shot that could generate an immune response against current and future variants, as well as other coronaviruses that could cause another pandemic. It’s still preliminary — that particular universal vaccine has only been tested in animals — but it’s a first step toward broad protection.

This kind of vaccine might still work even if the virus substantially changes, said Martinez. But it will be a long time before we know if this is true — it’s likely that this kind of vaccine will take years for scientists to develop, test, and get approved, he said.

Shot-less shots

Universal vaccines aren’t the only next-gen products in development. Researchers are also working on vaccines that aren’t shots at all — they’re nasal sprays.

Intranasal vaccines could protect against the virus right where it enters the body, said Iwasaki, the immunobiologist at Yale University School of Medicine.

“It makes sense to establish immune defense right at these mucosal sites,” she said, referring to the inside of the nose. “It can prevent the infection of these tissues altogether.” Without infection, people wouldn’t transmit the virus, and they’d be protected from long COVID.

There is one intranasal vaccine given now — FluMist — but it uses a weak version of the live flu virus, which is not safe for immunocompromised people. Iwasaki and her colleagues are working on a strategy to get around that issue: using a nasal spray containing a version of the COVID-19 virus’ spike protein as a booster after an initial mRNA shot. Because it’s used as a booster, the spray doesn’t need to contain a live virus to trigger a strong enough immune response — immunity from the initial shot is enough to drive a strong response to the protein in the spray.

So far, the technique is experimental and only has been tested in mice. But Iwasaki co-founded a company, Xanadu Bio, to make these vaccines, though she says they are still raising money to start clinical trials and working on testing the vaccine in nonhuman primates. And Xanadu is far from the only one looking at nasal spray vaccines. There are more than a dozen clinical trials of intranasal vaccines already in progress in the US and globally.

There are still a lot of challenges ahead before the next set of COVID-19 vaccines are available to the public. There’s still a lot experts don’t know about the current vaccines — like why they lose their efficacy over time, regardless of new variants, says Deepta Bhattacharya, a professor of immunobiology at the University of Arizona College of Medicine. He says it can be hard to know exactly what it is about a vaccine that makes it work well for a long time.

“When you’re comparing one vaccine to another, there’s a lot of things that are different,” he said. “And so trying to extract which of those differences are really important is almost as much guesswork as it is science.”

There are also practical limitations. The FDA meeting next week to discuss vaccinating against COVID-19 variants could have a big impact on the direction that future vaccine development will take. Funding, both for new research and to make shots available to people for free, will also probably be an issue. Unless Congress can agree on more pandemic funding, free future vaccines might be limited to only the most vulnerable people.

Despite everything, Bhattacharya is optimistic about the future of COVID-19 vaccines. Research seems to show that combining and refining the next-generation vaccine techniques like intranasal, vaccine-targeted, and universal vaccines could have great success, he said.

“I think the science is there for sure to have better vaccines in the coming years,” he said.