On October 21, the Centers for Disease Control and Prevention gave most of the US population permission to get a Covid vaccine booster—a shot in such high demand that 10 million people somehow obtained it in advance of that approval in an effort to feel a little safer. Two days after that, the government of the United Kingdom made things feel a little less safe: It announced the emergence of Delta-plus, a new variant that already accounts for 6 percent of cases in that country, and is even more infectious than the highly transmissible Delta.
Those back-to-back events captured the nauseating pandemic roller coaster: Things are getting better. No, they’re not. Yes, they are. No, they’re definitely not. The endless repetition is exhausting. It has led a loose coalition of scientists to ask: What if we could just make the roller coaster … stop?
In a fistful of papers and preprints published in the past six months, these research teams propose a “universal coronavirus vaccine” that could protect against this entire viral family. That means the current SARS-CoV-2 version, any variants that might escape the protection of existing vaccines, and any future coronavirus strains that might emerge to cause new pandemics.
It is a complex project, and no group is close to reaching the goal. Universal vaccines against other recurrent, genetically variable diseases—see, especially, influenza—have been pursued unsuccessfully for years. But researchers think one for coronaviruses might be more achievable, both because this virus is less genetically complex than the one that causes the flu, and also because the threat of another coronavirus pandemic feels uncomfortably real.
After all, SARS-CoV-2 is the third coronavirus to become a major cause of human disease within two decades, after SARS in 2003 and MERS in 2012. Historic epidemiology suggests there were waves of coronavirus infections in the 20th century, the 19th century, and possibly across millennia. And it’s possible that thousands of not yet identified coronaviruses lurk in bats, wildlife, and domesticated animals, poised for the opportunity to leap between species and trigger havoc.
“This isn’t the first coronavirus pandemic we’ve experienced, and it’s not going to be the last, since in less than 20 years we have encountered three coronaviruses that have pandemic potential,” says Pablo Penaloza-MacMaster, a viral immunologist and assistant professor at Northwestern University, and senior author on several papers outlining approaches to a universal vaccine. “We want to be ready for the next pandemic, and the way to do that is to prepare.”
These research teams aren’t the only ones to feel some urgency working on this. In March, the nonprofit Coalition for Epidemic Preparedness Innovations, a public-private partnership that funnels government and philanthropic money to worthy projects, announced it would commit up to $200 million to support universal coronavirus vaccine research.
But here’s the challenge: To make a vaccine that protects against multiple types, strains, or variants of a virus, researchers have to find some feature that they all have in common and that our immune system reacts to. Then they have to incorporate that feature into the vaccine. With the flu, for instance, each new strain arrives bearing tiny changes in a feature called hemagglutinin, a hammer-shaped protein on the virus’s surface that binds to receptors on lung cells. Because every hemagglutinin is different—researchers actually subdivide flu viruses based on how divergent these proteins are—the search for a universal flu vaccine has focused on trying to redirect the immune system’s attention from the variable head of the protein to the handle-like, less variable stem.
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That research has remained promising for several decades without nailing its target. The first universal flu vaccine to enter a Phase III trial, in 2018, failed out of that trial two years later. Several rival formulas are in trials now.
Coronaviruses are less diverse than flu viruses are, but they nevertheless are variable. The original SARS virus and its Covid-causing cousin, for instance, share about 80 percent of their genome; but the virus behind Covid and the one that causes MERS, for instance, are only about 50 percent alike.
This is because the coronavirus family is made up of four groups or genera—alpha, beta, gamma, delta—with subgroups inside those. The alpha and beta flavors attack humans, and the gamma and delta groupings mostly reside in animals. Within the human-affecting groups, the alphas mostly make up what are now common cold viruses—though they might have been pandemic viruses at some point in the past. The betas are mostly the cause of severe disease. And within the betas, there are all kinds of subsidiary arrangements: the sarbecoviruses, including SARS 1 and SARS 2; the merbecoviruses, chiefly MERS; the embecoviruses, which also cause cold symptoms; and, well, it goes on. You can see the problem.
“For the sarbecovirus subgenus, which includes the original SARS virus from 2003 and all of the variants of SARS-CoV-2, I think that the prospect of a universal vaccine is more readily achievable,” says David Martinez, a viral immunologist and postdoctoral researcher at the University of North Carolina. “As we expand out into, for example, a vaccine that could also cover MERS coronavirus, then that becomes more difficult, because the vulnerable parts that a vaccine needs to target on the virus are far more different in MERS compared to SARS and SARS 2.”
Martinez was first author on a paper published in Science in June in which researchers from UNC, Duke University, and the University of Pennsylvania created a chimeric mRNA vaccine, assembled from bits of the spike proteins from an array of coronaviruses including SARS-CoV-2, and demonstrated—in mice—that the formula could create cross-protection against multiple viruses in the family.
Other teams are following that broad approach of enhancing immune response by piecing together subunits of the spike, which is the portion of the virus that allows it to bind with and then fuse to human cells to hijack them for reproduction. In May, for instance, Duke scientists who had previously been working on a vaccine for HIV adapted a nanoparticle from that research and studded it with multiple copies of the Covid virus’s receptor binding domain, a component of the spike protein. They showed in Nature that the assembled particle, injected into macaques, created cross-protection against SARS-CoV-2, some of its variants, the original SARS virus, and bat coronaviruses as well.
A multi-institution team of researchers led by scientists at the Walter Reed Army Institute of Research published a similar nanoparticle approach in September, also working in macaques. Their work is now slated to move into a Phase I trial—meaning that it would be a small trial measuring only safety, not effectiveness—that appears to be the first human test of a universal coronavirus vaccine approach.
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As with attempts to build a universal flu vaccine, researchers pursuing one for coronaviruses have to balance between selecting the most immunogenic elements of a virus, which might differ between strains or variants, and picking ones that are the most similar but may not stimulate the strongest response.
“It’s very straightforward with the sarbecoviruses, because they have a spot where the structure and the amino acids are conserved on the receptor binding domain,” says Barton Haynes, a physician and professor and director of the Human Vaccine Institute at Duke, and coauthor on that Nature paper with Kevin Saunders, the institute's director of research. “There are fewer of those that have conserved amino acids between the MERS-like viruses and the other viruses.”
One approach down the road, Haynes suggests, may be to concoct multiple candidates, each targeting a group or subgroup of the family, and then combine them in a multivalent, all-coronavirus vaccine. Another option, published in September by the team led by Penaloza-MacMaster, is to concoct a vaccine that includes both spike proteins and also nucleocapsid proteins from elsewhere in the virus. Other efforts are examining vaccines incorporating other parts of the spike protein, such as the fusion peptide, which appears to be similar across coronavirus strains.
Almost all of these efforts are still proofs of concept—promising, but with steps to go. A few have been tested in pigs or non-human primates, but many have not moved beyond mice. “Mice are great models for initial research in the lab. They're relatively inexpensive, and they can really drive research forward,” says Justin Richner, a viral immunologist and assistant professor at the University of Illinois at Chicago, and coauthor with Penaloza-MacMaster. “But these studies need to be done in models that recapitulate human disease.”
To move closer to a new human vaccine, researchers will need to confront some of the questions now playing out in the debate over boosters for the current Covid vaccines—asking, for instance, whether the goal of vaccination is to prevent all infection and transmission, or only severe illness and death. They also will have to predict which branch of the coronavirus family tree might give rise to the next threat, and determine whether the protection offered by a vaccine could stretch that far. And, finally, they will have to depend on support from policymakers and funders, to continue with basic science that might not deliver a product for years to come.
“We know there are numerous viruses in animal reservoirs throughout the entire globe, and we know some of these viruses can potentially spread into humans and cause vast outbreaks. So there is a renewed interest to develop medical countermeasures against these pandemic viruses, and other infectious diseases with pandemic potential,” Richner says. “There was a big push for this after September 11, to create countermeasures against bioterrorism and against any emerging viruses. But a lot of that funding wasn't renewed.”
The question will be whether politicians and a public exhausted by the current pandemic will be willing to take the risk of confronting—or even make the effort of imagining—the next emergent threat.
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