One Vaccine to Rule Them All

The pandemic is at its worst, globally, and expert eyes are trained on the role of new variants. Catastrophic surges are tearing across places where some thought the darkest days were already over. In India, where hospitals are running out of oxygen and COVID-19 cases are increasing exponentially, officials are concerned about a “double mutant” version of SARS-CoV-2 called B.1.167. In Brazil, where more than 2,500 people are dying every day, the government is urging people not to get pregnant for fear of variants like P.1. And such variants are giving rise to further variants, as mutations layer on mutations.

The potential implications of this viral evolution are profound. Last month, the United States’ CDC released a three-tiered system to guide in prioritizing the emerging risks. A “variant of interest” is an especially dangerous strain that hasn’t yet spread widely. If it does, it elevates to a “variant of concern.” Five variants of concern are currently circulating in the U.S. (B.1.1.7, B.1.351, P.1, B.1.427, and B.1.429). Finally, above this category are the most ominous: “variants of high consequence.” These may evade COVID-19 tests and treatments, and even escape existing vaccines. The world doesn’t have any of those variants—that we know of. At least not yet.

As the virus continues to spread wildly around the world—at this point, 5 million new infections are being identified every week—further mutation is inevitable. In an attempt to stay ahead of this, earlier this month the White House announced a $1.7 billion investment in surveillance of the viral genome. By constantly mapping mutations and new variants as they arise, perhaps their worst effects could be avoided. At the same time, designing countermeasures for each one may end up being like chasing the horizon: By the time we’ve come to understand the full potential of a variant, containing it may no longer be possible. Meanwhile another, even more problematic one may already be taking hold.

Tracing and reacting to individual variants is such an enormous challenge that some experts believe we need a more comprehensive approach, and soon. “Rather than playing whack-a-mole with each new problematic variant,” Anthony Fauci told me last week, “it just makes sense to me to use all of our capabilities to really go for a universal SARS-CoV-2 vaccine.” That is, one that can protect us no matter which direction this virus goes, setting up at least partial immunity to any variant that may arise. “If we don’t, we’re going to be constantly chasing things, as opposed to getting it off the table.”

Dozens of research teams have already taken up the challenge, and meeting it is within their reach. But doing so would be just the beginning. “A universal SARS-CoV-2 vaccine is step one,” Fauci said. Step two would be a universal coronavirus vaccine, capable of protecting us not only from SARS-CoV-2 in all its forms, but also from the inevitable emergence of new and different coronaviruses that might cause future pandemics. The race to create such a vaccine may prove one of the great feats of a generation.

The basic problem is that our cells think a coronavirus is their friend. Each viral particle is coated in proteins, referred to as its “spike” proteins (though they more closely resemble scepters or moldy ice-cream cones). The tip of each one looks deceptively like a normal, human signaling molecule, so a healthy cell binds to the tip as usual. That’s its last mistake. The virus then snaps the top off its spike, plunges the remainder through the surface of the cell, and injects its RNA. Now it can use the cell to make millions of copies of itself, which eventually burst out, leaving the cell for dead.

All the ways the SARS-CoV-2 virus has brought the world to its knees—and all the doom that its mutations may bring—begin with one submicroscopic protein. As devious as the spike may be, it’s also an excellent target for vaccines. The current vaccines teach immune cells to recognize the spike protein, so that it can be bound and neutralized before it impales our cells..

But the spike is slightly different in each variant. “The current vaccines are based on the genetic code of the original strain found in Wuhan,” Pamela Bjorkman, a bioengineering professor at Caltech, explains. This exact strain is no longer in circulation, so the vaccines are already slightly imperfect fits for the variants many of us may encounter. At this point, the changes to the spike protein are not so dramatic as to render first-generation vaccines ineffective, Bjorkman says, “but that won’t necessarily hold as the virus continues to mutate.”

The challenge, then, is to create a vaccine that will anticipate such changes—teaching the immune system to recognize and fight off variants that may not even exist yet. One potentially powerful approach would be to target a part of the spike protein that doesn’t evolve as quickly as the others. At the University of Texas at Austin, Jason McLellan’s lab has focused on the stem of the SARS-CoV-2 spike protein, which doesn’t mutate as often as the tip. In theory, a vaccine that teaches the immune system to recognize the stem would induce protection against many or even all the variants at once—as long as they continue to share this similar stem. In practice, though, antibodies against the spike stem may have trouble recognizing and binding to their target if it’s tucked away in the protein structure.

Bjorkman’s lab has been working on another solution, one that’s guaranteed to generate an immune response: a vaccine that carries several different versions of the part of the spike that binds to human cells. This assortment can be arrayed on tiny synthetic skeletons, constituting “mosaic nanoparticles.” When Bjorkman’s team injected mice with a prototype multi-strain vaccine last year, they found that it produced antibodies against every form of spike protein that was in the mosaic.

A related approach is to start with mRNA, just as the Pfizer and Moderna vaccines do. But instead of including the code for only one strain, you could tie together mRNA that codes for many different spike-protein binding sites—including the common mutations seen in dangerous variants. David Martinez, of the University of North Carolina at Chapel Hill, and his colleagues recently reported promising mouse experiments (their work is under review) with mRNA from different coronaviruses, welded into a “chimeric spike” mRNA vaccine. When given to mice, the hybrid vaccine effectively generated antibodies against multiple spike proteins, including the one associated with a key variant of concern in the U.S.

To make a universal SARS-CoV-2 vaccine that provides long-term protection, we may need to think beyond the spike, Baozhong Wang, a biologist at Georgia State University, says. “Broad, neutralizing antibodies to conserved areas in spike protein are important, but not the whole” solution, Wang says. T-cell responses in the lungs will be crucial, too, because they catalog memories of past respiratory viral pathogens. These responses are predominantly induced by proteins inside the virus, Wang explains, such as the nucleoproteins and enzymes that help it reproduce, rather than its spike. His approach is to load a nanoparticle with parts of different spike proteins.

Fauci believes that many of these ideas could pan out and that a universal SARS-CoV-2 vaccine might even be available before the pandemic is over. He has spent years working on a vaccine that targets a conserved region of the influenza virus, with the similar aim of protecting against every possible flu strain. The project has yet to find success. (Even our seasonal-flu vaccines aren’t especially reliable, averaging about 50 percent effectiveness.) But SARS-CoV-2 poses fewer obstacles, he said, because its genome is smaller than influenza’s and less prone to mutation. Martinez agrees: As bad as this pandemic is, he says, in this genetic sense, “we got really lucky.”

“This virus is going to hang around for another couple of years before the world suppresses it, if we’re lucky,” Fauci told me. “I can’t guarantee that we’ll get a universal vaccine in place for this virus, but certainly we need it for the next one.”

A universal SARS-CoV-2 vaccine may prove necessary to end this pandemic. It’s also possible that the current generation of SARS-CoV-2 vaccines will hold up pretty well, and we’ll require only a basic booster here and there. But even when this particular coronavirus has been suppressed, we’ll still need to find a way to protect ourselves against others that lie in wait.

Thousands of related pathogens are estimated to be circulating among various nonhuman species, and some could make the jump to us at any time. In just the past 18 years, three coronaviruses have caused devastating human diseases (SARS, MERS, and COVID-19). “It’s not a question of if but when another pandemic coronavirus emerges,” Martinez says.

Bjorkman shares this certainty. “This isn’t going to be the last one,” she says. “We’re going to have SARS-CoV-3 and SARS-CoV-4. Everyone said this before the current pandemic. Most of the world ignored them. To do so again would really be burying your head in the sand.”

The technology already exists to create a vaccine that protects humans from many coronaviruses at once. Vaccinating against all of them is a more elaborate challenge than taking on one or a few, but hypothetically possible. Though the broadest vaccine isn’t likely to come from discovering a single, conserved region of the spike protein that all coronaviruses share, and that also reliably stimulates our immune system. This would be something like finding one spot that will blow up the entire Death Star—a little too easy. But we could find an array of frequently conserved regions that turn up in many coronaviruses.

The act of loading multiple targets into one vaccine is not difficult, according to Bjorkman. The postdocs in her lab can quickly create the proteins at the head of the spike and attach them to nanoparticles. “They’re really easy to make,” she says modestly. The central challenge is in knowing which targets to include and making sure that they stimulate the immune system effectively.

“The real issue is better understanding the universe of coronaviruses,” says Wayne Koff, a biochemist and the head of the Human Vaccines Project. It’s theoretically possible to learn the major changes in the viral genome that make them most likely to spread widely and devastatingly in humans, so that our bodies can develop at least partial recognition of whichever dangerous new coronaviruses may come along: “What we’re especially concerned about are the coronaviruses that we don’t even know about yet.”

Koff believes we can figure out which common features or mutations could allow for such a vaccine, as we understand the coronavirus family tree at a more and more granular level. “If animal ecologists can gather enough data from the field, you create an algorithm to find the ones that have the greatest potential to jump species, and then the ones that would kill people,” he says. In his vision, supercomputing and advances in machine learning and modeling would accelerate the predictive process.

The project to create a truly universal coronavirus vaccine would encapsulate a variety of disciplines: cellular and systems biology, immunology, genetics, artificial intelligence, and structural modeling, to name a few. So the coalition to accomplish this would need to be broad, Koff says. The U.S. investment in tracking viral genomes could create a small piece of the infrastructure necessary for tracking many other viruses. Similar efforts will be needed around the world, in order to keep abreast of constantly changing viral maps. Koff estimates that the governments of the G7 nations would have to come together with the private sector, the World Health Organization, and nonprofits such as the Bill & Melinda Gates Foundation in order to make the system work. “It might cost billions, but this pandemic alone has cost trillions,” Koff says. “We didn’t learn after SARS, MERS, HIV, swine flu—but maybe this time we will.”