Could a single vaccine work against all coronaviruses?

The invention of COVID-19 vaccines will be remembered as a milestone in the history of medicine, creating in a matter of months what had before taken up to a decade. But Dr. Kayvon Modjarrad, director of the Emerging Infectious Diseases Branch at Walter Reed Army Institute of Research in Silver Springs, Maryland, isn’t satisfied.

“That’s not fast enough,” he said. More than 2.3 million people around the world have died, and many countries will not have full access to the vaccines for another year or two: “Fast — truly fast — is having it there on day one.”

There will be more coronavirus outbreaks in the future. Bats and other mammals are rife with strains and species of this abundant family of viruses. Some of these viruses will inevitably spill over the species barrier and cause new pandemics. It’s only a matter of time.

Modjarrad is one of many scientists who for years have been calling for a different kind of vaccine: one that could work against all coronaviruses. Those calls went largely ignored until COVID-19 demonstrated just how disastrous coronaviruses can be.

Now researchers are starting to develop prototypes of a so-called pancoronavirus vaccine, with some promising, if early, results from experiments on animals. Dr. Eric Topol, a professor of molecular medicine at the Scripps Research Institute in San Diego, thinks scientists should join together in another large-scale vaccine-creation project immediately.

“We have to get a real workforce to accelerate this, so we can have it this year,” he said. Topol and Dennis Burton, a Scripps immunologist, called for this project on broad coronavirus vaccines Monday in the journal Nature.

After coronaviruses were first identified in the 1960s, they did not become a high priority for vaccine makers. For decades it seemed as if they only caused mild colds. But in 2002, a new coronavirus called SARS-CoV emerged, causing a deadly pneumonia called severe acute respiratory syndrome, or SARS. Scientists scrambled to make a vaccine for it.

Since no one had made a coronavirus vaccine for humans before, there was a huge amount to learn about its biology. Eventually, researchers chose a target for immunity: a protein on the surface of the virus, called spike. Antibodies that stick to the spike can prevent the coronavirus from entering cells and stop an infection.

Public health officials in Asia and elsewhere did not wait for the invention of a SARS vaccine to get to work, however. Their quarantines and other efforts proved remarkably effective. In a matter of months, they wiped out SARS-CoV, with only 774 deaths along the way.

The danger of coronaviruses became even clearer in 2012, when a second species spilled over from bats, causing yet another deadly respiratory disease called Middle East respiratory syndrome. Researchers started work on MERS vaccines. But some researchers wondered if making a new vaccine for each new coronavirus — what Modjarrad calls “the one bug, one drug approach” — was the smartest strategy. Wouldn’t it be better, they thought, if a single vaccine could work against SARS, MERS and any other coronavirus?

That idea went nowhere for years. MERS and SARS caused relatively few deaths and were soon eclipsed by outbreaks of other viruses such as Ebola and Zika.

In 2016, Maria Elena Bottazzi, a virus expert at Baylor College of Medicine, and her colleagues applied for support from the U.S. government to develop a pancoronavirus vaccine but did not receive it. “They said there’s no interest in pancorona,” Bottazzi recalled.

Her team even lost funding for developing a SARS vaccine after they showed that it worked in mice, was not toxic to human cells and could be manufactured at scale. A coronavirus that had disappeared from view simply wasn’t a top priority.

Without enough money to start clinical trials, the scientists stored their SARS vaccine in a freezer and moved on to other research. “It’s been a struggle,” Bottazzi said.

Dr. Matthew Memoli, a virus expert at the National Institute of Allergy and Infectious Diseases, looks back at those decisions as an enormous blunder. “It’s a failure of our system of science,” he said. “Funders tend to chase after shiny objects.”

Three years later, a third dangerous coronavirus emerged: the SARS-CoV-2 strain that causes COVID-19. Although this virus has a much lower fatality rate than its cousins that cause SARS and MERS, it does a far better job of spreading from person to person, resulting in more than 106 million documented cases around the world and still climbing.

All the lessons that researchers had learned about coronaviruses helped them move quickly to make new vaccines for SARS-CoV-2. Bottazzi and her colleagues used the technology they had created to make SARS vaccines to make one for COVID-19, which is now in early clinical trials.

Other researchers used even newer methods to move faster. German company BioNTech created a genetic molecule called messenger RNA that encoded the spike protein. Partnering with Pfizer, the companies received U.S. government authorization for their vaccine in just 11 months. The previous record for a vaccine, against chickenpox, was four years.

Although the COVID-19 pandemic is still far from over, a number of researchers are calling for preparations for the next deadly coronavirus.

“This has already happened three times,” said Daniel Hoft, a virus expert at Saint Louis University. “It’s very likely going to happen again.”

Researchers at VBI vaccines, a Cambridge-based company, took a small step toward a pancoronavirus vaccine in the summer. They created viruslike shells studded with spike proteins from the three coronaviruses that caused SARS, MERS and COVID-19.

When the researchers injected this three-spike vaccine into mice, the animals made antibodies that worked against all three coronaviruses. Intriguingly, some of those antibodies could also latch onto a fourth human coronavirus that causes seasonal colds — even though that virus’s spike proteins were not included in the vaccine. The scientists have made this data public but have not yet published it in a scientific journal.

David Anderson, VBI’s chief scientific officer, said it was not clear why the vaccine worked this way. One possibility is that an immune cell presented with several versions of a protein at once doesn’t make antibodies against just one. Instead, it makes a compromise antibody that works against them all.

“You’re educating it,” Anderson said, although he cautioned that this was speculation for now.

Last month, Pamela Bjorkman, a structural biologist at Caltech, and her colleagues published a more extensive experiment with a universal coronavirus vaccine in the journal Science. The researchers attached only the tips of spike proteins from eight different coronaviruses to a protein core, known as a nanoparticle. After injecting these nanoparticles into mice, the animals generated antibodies that could stick to all eight of the coronaviruses — and to four other coronaviruses that the scientists had not used in the vaccine.

Modjarrad is leading a team at Walter Reed developing another vaccine based on a nanoparticle studded with protein fragments. They anticipate starting clinical trials on volunteers next month. Although the vaccine currently uses protein fragments only from SARS-CoV-2 spikes, Modjarrad and his colleagues are preparing to retool it as a pancoronavirus vaccine.

Hoft of Saint Louis University is working on a universal vaccine that does not rely on antibodies to the spike protein. Collaborating with Gritstone Oncology, a California-based biotech company, he has created a vaccine that prompts cells to make surface proteins that might alert the immune system as if a coronavirus — any coronavirus — were present. They are now preparing a clinical trial to see if it is effective against SARS-CoV-2.

“We are interested to develop maybe a third-generation vaccine, which would be on the shelf and ready for the future outbreak,” Hoft said.

Topol believes scientists should also explore another strategy: searching for pancoronavirus antibodies made by our own bodies during infections.

Researchers studying HIV and other viruses have discovered, amid the billions of antibodies made during an infection, rare types that work against a huge range of related strains. It might be possible to create vaccines that coax the body to make abundant amounts of these broadly neutralizing antibodies.

Coronaviruses are similar enough to each other, Topol said, that it might not be that hard to build vaccines that make broadly neutralizing antibodies. “This is an easy family of viruses to take down,” he said.

The search for a pancoronavirus vaccine may take longer than Topol’s sunny expectations. But even if it takes a few years, it could help prepare the world for the next coronavirus that jumps the species barrier.

“I think we can have vaccines to prevent pandemics like this,” Memoli said. “None of us wants to go through this again. And we don’t want our children to go through this again, or our grandchildren, or our descendants 100 years from now.”


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