In 2017, three leading vaccine researchers submitted a grant application with an ambitious goal. At the time, no one had proved a vaccine could stop even a single beta coronavirus—the notorious viral group then known to include the lethal agents of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), as well as several causes of the common cold and many bat viruses. But these researchers wanted to develop a vaccine against them all.
Grant reviewers at the National Institute of Allergy and Infectious Diseases (NIAID) deemed the plan “outstanding.” But they gave the proposal a low priority score, dooming its bid for funding. “The significance for developing a pan-coronavirus vaccine may not be high,” they wrote, apparently unconvinced that the viruses pose a global threat.
How things have changed.
As the world nears 3 million deaths from the latest coronavirus in the spotlight, SARS-CoV-2, NIAID and other funders have had a major change of heart. In November 2020, the agency solicited applications for “emergency awards” to pursue pancoronavirus vaccine development. And in March, the Coalition for Epidemic Preparedness Innovations (CEPI), an international nonprofit launched in 2017, announced it would spend up to $200 million on a new program to accelerate the creation of vaccines against beta coronaviruses, a family that now includes SARS-CoV-2.
The threat of another coronavirus pandemic now seems very real. Beyond bats, coronaviruses infect camels, birds, cats, horses, mink, pigs, rabbits, pangolins, and other animals from which they could jump into human populations with little to no immunity, as most researchers suspect SARS-CoV-2 did. “Chances are, in the next 10 to 50 years, we may have another outbreak like SARS-CoV-2,” says structural biologist Andrew Ward of Scripps Research, one of the scientists who submitted the 2017 proposal NIAID rejected.
The agency has not given out any of its new awards yet, but Ward’s lab is already pursuing a vaccine targeting a subset of beta coronaviruses. Some two dozen other research groups around the world have similar pancoronavirus vaccine projects underway. Their approaches include novel nanocages arrayed with viral particles, the cutting-edge messenger RNA (mRNA) technique at the heart of proven COVID-19 vaccines, and cocktails of inactivated viruses, the mainstay of past vaccines. A few teams have even published promising results from animal tests of early candidates.
No pancoronavirus vaccine has entered human trials, and how to evaluate a candidate’s protection against diseases that have not yet emerged remains a challenge. Nor is it clear how such a vaccine might be used. One possibility: keeping it in reserve until a new human threat emerges. “We might be able to prime everybody to get a basic level of immunity” against the emerging virus, buying time to make a more specific vaccine, Ward says.
Despite the many unknowns, the rapid success of vaccines against SARS-CoV-2 has sparked optimism. This coronavirus doesn’t seem particularly difficult to foil with a vaccine, which raises hopes that the immune system can be trained to outwit its relatives, too. Survivors of SARS years ago provide more encouragement: Some of their antibodies—an immune memory of that viral encounter—can also stymie the infectivity of SARS-CoV-2 in lab dishes.
NIAID’s Barney Graham, who helped develop Moderna’s mRNA COVID-19 vaccine, shares the optimism about pancoronavirus vaccines. “Compared to flu and HIV, this is going to be relatively easy to accomplish,” he predicts.
EARLIER THIS YEAR, Hannah Turner, a technician at Scripps Research who works with Ward, took a cold, hard look at a now infamous protein: SARS-CoV-2’s spike, which enables the virus to infect cells and is at the heart of several successful COVID-19 vaccines. All coronaviruses have these spikes, which create the distinctive crownlike appearance that earned them their name, and most pancoronavirus vaccine efforts aim to rouse an immune response to some part of the spike protein.
On this February morning, Turner mixes labmade copies of the SARS-CoV-2 spike with “broadly neutralizing” antibodies harvested from COVID-19 patients. These antibodies powerfully prevent multiple variants of SARS-CoV-2, as well as the original SARS virus, SARS-CoV, from infecting susceptible cells in test tube studies. Turner then freezes the spike-antibody mixtures with liquid nitrogen and places the resulting crystals in a $4 million microscope the size of three refrigerators. It begins bombarding the samples with up to 200 kilovolts of electrons to map the spike-antibody complexes at atomic resolution—an increasingly popular technique called cryo–electron microscopy (cryo-EM).
What resembles a telescope view of lunar landscapes unfolds across four monitors. Turner’s trained eye spots the crystallized spike proteins, clumped together in groups of three called trimers and studded with antibodies. She points out one of the fanlike structures. “It’s pretty cool,” she says. “This is what you want to see.”
The computers over the next few days will sort through 1100 different angles of her sample, migrating the best views into software that creates a gorgeous “final map” of spike with an attached antibody, at a resolution that approaches 3 angstroms, about one-third the width of a single strand of DNA. By creating similar portraits of spikes from many different coronaviruses with broadly neutralizing antibodies bound to them, Ward hopes to identify short segments of the protein—so-called epitopes—key to that binding for all the pathogens. Those epitopes, Ward believes, are the key to designing a vaccine that can trigger a broad immune attack on coronaviruses.
An ideal pancoronavirus vaccine would protect us from all four of its genera—alpha, beta, gamma, and delta—but most researchers have more modest goals. “The further you go, the harder it gets” for a vaccine, says immunologist Dennis Burton of Scripps Research, who often collaborates with Ward.
Gamma and delta coronaviruses, mainly found in birds and pigs, are not known to infect humans, so vaccine developers have paid them little attention. There’s more interest in alpha coronaviruses because two cause colds in humans. But it’s the betas that attract the most effort, and in particular the sarbecoviruses, a subset that includes SARS-CoV-2 and SARS-CoV but not the more genetically distinct MERS and its relatives. Sarbecoviruses are Ward’s targets, and Burton is optimistic. “We already know you can get pretty damn good antibodies that work against both SARS-CoV and -2,” he says.
Ralph Baric of the University of North Carolina, Chapel Hill, who has studied coronaviruses for 35 years, sees this subgroup as the paramount threat. “That SARS-CoV-2 is here doesn’t mean that that’s going to provide any kind of serious protection against another sarbecovirus from coming out of the zoonotic reservoirs,” he says. And if a “SARS-CoV-3” jumped into a person infected with the current pandemic virus and created something more lethal by swapping genetic regions—and coronaviruses frequently recombine—that’s the making of a Hollywood horror film.
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