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The U.S. is now rolling out a new generation of bivalent COVID-19 boosters designed to target the currently dominant BA.5 variant. The updated boosters aim to provide stronger protection against BA.5 and, hopefully, whatever variant emerges next.

The development of variant-specific vaccines is a key step forward as mutations make the virus better at evading immunity. But vaccine development may not always be able to keep up with the virus. To prepare for future mutations, scientists have called for a greater focus on immunization strategies that provide broader or different forms of protection.

“We don’t know what variants are coming down the pipe—that’s why focusing on vaccines that give strong overall immune protection and longer durability may be the approach [we need],” says Dr. Peter Hotez, professor and dean of the National School of Tropical Medicine at Baylor College of Medicine.

Universal coronavirus vaccines: the ultimate goal

By the time a vaccine is modified to address a particular variant and then tested and administered, the COVID-19 virus may have already mutated again. To avoid this pitfall, scientists are working on vaccines that produce immunity broad enough to protect against existing and future variants.

The Walter Reed Army Institute of Research has been developing a variant-proof vaccine that is now being tested in humans. If successful, this vaccine would protect against future COVID-19 strains without the need for updates.

Some scientists are looking further ahead and designing vaccines that protect not only against future COVID-19 variants but also against other types of coronaviruses. Only seven coronaviruses have been found in humans so far, but many more exist in wildlife and have the potential to spill over into the human population. In the last two decades, humans have experienced three coronavirus outbreaks: SARS in 2002, MERS in 2012, and COVID-19 in 2019. The current outbreak will not be our last, Hotez says.

The diversity of coronaviruses makes it challenging to devise a one-size-fits-all vaccine, but several projects seek to target subsets of these viruses that pose the highest risk to humans.

Pamela Bjorkman, a biochemist at the California Institute of Technology, is developing a vaccine that protects against sarbecoviruses, a group of SARS-related coronaviruses. If successful, this vaccine would protect against COVID-19 and its variants, SARS, and other SARS-related coronaviruses that could be transmitted to humans from animals in the future. But human trials for Bjorkman’s pan-sarbecovirus vaccine are not expected to begin until 2024.

“There was a burst of extra funding during SARS, and then nobody cared after that. There was another burst during MERS, and then nobody cared after that. Then there was another burst during SARS-CoV-2, and I just wish people would get the hint here that we need to care about this.”

Pamela Bjorkman, a biochemist at the California Institute of Technology

A pan-betacoronavirus vaccine would offer even broader protection. Betacoronaviruses, one of the four coronavirus genera, encompass sarbecoviruses as well as lineages that include MERS and two common cold viruses. The ultimate goal would be to concoct a pan-coronavirus vaccine that works against all four coronavirus genera.

“The question is, how far can we push it?” Bjorkman says. “If we could make a pan-coronavirus vaccine, we’d be protected against this whole universe of viruses that could spill over.”

Although a universal coronavirus vaccine would be ideal, Florian Krammer, professor of vaccinology at Mount Sinai’s Icahn School of Medicine, questions whether it’s worth aiming so high, especially since viruses in two of the genera have not yet been found in humans.

“Finding a vaccine that would protect against all coronaviruses would be great, but it might take a very long time and a lot of money,” Krammer says. “There’s this huge diversity, and it’s very hard to imagine what type of vaccine would be able to get to that point.”

He notes that multivalent vaccines that protect against the next few variants of concern may be an easier target. Similar to our annual flu vaccines, multivalent COVID-19 vaccines would be designed to protect against multiple viral strains rather than just one or two, as is the case with our original COVID-19 vaccines and our new bivalent boosters, respectively. 

But even these multivalent vaccines are in the early stages of development and could take years to hit the market. In the meantime, chasing variants looks like our best option, Krammer says, though it will be key to establish a method of updating vaccines quickly so that they are ready when needed.

Nasal vaccines: a promising alternative

Developing universal coronavirus vaccines isn’t the only immunization strategy with potential. Mucosal vaccines, specifically nasal vaccines, have been receiving more attention as a possible way to decrease the risk of infection. Since they are delivered through the nose and mouth, mucosal vaccines can stimulate immunity at the initial sites of infection, getting rid of the virus before it spreads beyond our upper airways. 

Krammer views nasal vaccines as a critical tool that could be used in conjunction with our current vaccines, which have become significantly less effective at preventing infection from new variants. Nasal vaccines have the potential to fill this gap. “Hypothetically, these vaccines could cut down on infections quite a bit,” Krammer says. “But they still need to be somewhat matched to circulating strains.”

Nasal vaccines could be particularly beneficial to individuals who are immunocompromised and more vulnerable to severe disease if infected. These vaccines may also be more widely accepted by the general public, since they don’t involve an injection.

However, like universal coronavirus vaccines, nasal vaccines will likely take at least a few more years to be ready, Hotez says. Before then, he stresses the need to consider non-mRNA vaccines as boosters.

Mix-and-match boosting strategies: a short-term solution

Our current mRNA vaccines continue to provide excellent protection against severe disease, but most people, and especially immunocompromised individuals, need a booster every few months to keep immunity up. However, less than half of people have gotten their first booster.

Some research has shown that mixing and matching boosters may produce longer-lasting immune responses. Hotez is especially interested in studying how a recombinant protein booster would work on top of an mRNA primary series. Novavax, a recombinant protein vaccine, is currently authorized in the U.S. as a primary series, though not yet as a booster. Hotez is involved in the development of another recombinant protein vaccine, Corbevax, which is currently in use in India.

“We don’t know what variants are coming down the pipe—that’s why focusing on vaccines that give strong overall immune protection and longer durability may be the approach [we need].”

Dr. Peter Hotez, professor and dean of the National School of Tropical Medicine at Baylor College of Medicine.

But Krammer doesn’t expect mix-and-match boosting strategies to make a huge difference. “I don’t think we’ll end up in a situation where you give an mRNA vaccine twice followed by a recombinant protein vaccine and then all of sudden you have lifelong immunity against all coronaviruses. We’re not talking about phantom leaps in terms of protection.”

All of these immunization strategies—universal coronavirus vaccines, nasal vaccines, and mix-and-match boosters—need to be studied further. But their progress hinges on available funding, which has not been easy to obtain. Hotez notes that many funders no longer feel that coronavirus research is an urgent priority. “People think it’s all one-and-done with mRNA vaccines, which I don’t feel is the case,” he says.

Bjorkman, who struggled to secure funding for her pan-sarbecovirus vaccine in the winter of 2020 after mRNA options entered the market and before major concerns arose around variants, agrees that funding for coronavirus research is fickle and largely focused on urgency rather than preparedness.

“There was a burst of extra funding during SARS, and then nobody cared after that. There was another burst during MERS, and then nobody cared after that,” Bjorkman says. “Then there was another burst during SARS-CoV-2, and I just wish people would get the hint here that we need to care about this.”