One vaccine to rule them all. That was the blue sky goal for a new global collaboration with hopes to beat coronaviruses. I’m not just talking about SARS-CoV-2, the virus responsible for our current pandemic. I’m talking about all coronaviruses—past, present, and future—even those that haven’t yet made the leap into humans.

Published in Science, the unique collaboration tapped nearly 200 scientists crossing academic and industry borders, and asked: do coronaviruses have a shared pressure point? If so, can we exploit it to engineer a universal vaccine against the entire viral family?

Short answer: yes, and maybe. The team brought the whole modern biology toolshed to decipher three coronaviruses: SARS-CoV-2, SARS-CoV-1, and MERS-CoV, each of which has wreaked havoc on human society. By analyzing how these viruses interact with human cells, the team was able to find a handful of critical shared proteins that the viruses use to hijack our bodies.

They didn’t stop at the hand-waving hypothesis stage. Using CRISPR, one group systematically tested these vulnerable viral proteins to see which ones destroyed the virus’ ability to replicate. The baton then got passed again to another group, which used hundreds of thousands of medical billing data from people who either tested positive or were presumed positive for Covid-19, to verify those viral protein candidates. The result is a playbook on how to beat an entire family of dangerous viruses.

Remember: these viral pressure points aren’t just for SARS-CoV-2. They’re shared among all currently known coronaviruses that made the leap from animals to humans. While it doesn’t mean that any and all coronaviruses—including those we haven’t yet had the displeasure to meet—will have the same vulnerability, it’s a start. Because the bitter truth is that when it comes to coronavirus epidemics or pandemics, scientists agree on one thing—there are more in our future. And it’s high time to start playing offense.

Profile of a Killer

Coronavirus is almost synonymous with Covid-19, social distancing, and frustration. But it’s not one virus—it’s a whole family.

The good news is that we’re already well acquainted with some members of the family. One estimate suggests these buggers have been around for 10,000 years, and we’re aware of dozens of strains, with seven that can infect humans. Many coronaviruses just cause a sniffle or light cough—also known as the common cold. The problem sparks when a viral strain, normally happily living in a bat, pig, or rodent, completely benign, mutates enough to be able to infect humans. Adding to the series of unfortunate events, the virus gets the opportunity to make that dreary carrier-to-human hop. The strain then becomes dangerous to humans, we don’t have any immunity against it—and the virus blazes through our population like wildfire.

But here’s the thing: coronaviruses are genetically similar. In other words, many members are likely to enter human cells with similar protein “keys,” and replicate inside cells with a shared molecular machinery. Rather than tackling coronavirus assaults one-by-one as they occur like whack-a-mole, it makes far more sense to find their common Achilles heel.

Molecular Social Distancing

Coronaviruses enter and replicate inside a human cell with a protein handshake.

To enter a cell, proteins on the virus grab onto a protein dotted on our cells. Our naïve cells invite the virus in, often through an additional molecular process. Once inside, like a bad house guest, the virus then overrides our cells’ internal machinery to make copies of itself, damaging our cells in the process.

In academic speak, protein handshakes are called “protein interactions,” where the virus and the human cell physically snuggle together to help the virus gain access and replicate. Identify and force apart those interactions, and we can block the virus from attacking our cells.

That’s where the new study began. Based on early work on the genome of SARS-CoV-2 and its interaction with 300 human proteins, the group expanded their computational analysis to SARS-CoV-1 and its cousin, MERS-CoV to fish out any commonalities. The overlap was surprisingly large, though each virus strain had its own bag of tricks. For example, in order to replicate efficiently in a human cell, all three viruses used a myriad of similar proteins (dubbed proteins “N”) to interact with the cell’s normal protein-making factory.

Common Achilles Heels

Moving from theory to practical validation, the group then used CRISPR and RNA interference—a Nobel Prize-winning technique that silences the message of a gene—to snip out over 300 viral proteins from the screen, one by one. They then infected human cells in Petri dishes with these kneecapped mutants to see if they could still replicate and thrive.

The result was a lofty number of 73 proteins necessary for coronaviruses to replicate themselves. Some were familiar to scientists and validated the viral map: PGES2 (catchy, I know), for example, interacts with the common “N” proteins on all three viruses—validating the previous computer modeling results.

But do they do anything in real life? In their next gargantuan step, the team analyzed data from roughly 740,000 people who had either tested positive for Covid-19 or were presumed positive. Here’s the kicker: some people were prescribed a drug called indomethacin, which grabs onto PGES-2, and potentially rips it away from the viral “N” protein—hence, molecular distancing. With the protein handshake between virus and human cells now gone, it means that the virus can’t replicate itself as normal, at least in theory.

Medical billing data suggests that might be the case. People who took indomethacin were less likely to end up in the hospital or require inpatient services than those who took another similar drug that didn’t target PGES-2.

In other words: using computer modeling, genetics, molecular biology, and real-world data, the team may have found a human-viral protein handshake that’s conserved across the three most deadly coronaviruses in our history.

Eyes on the Prize

That’s not the only interesting protein handshake pair. The team drew up multiple “viral maps,” which comprehensively document how viral proteins interact with hosts. Each becomes a target for a multi-shot coronavirus vaccine that can target all three strains.

Unfortunately, there are no promises that these common vulnerabilities can ultimately protect us from other, yet unknown, coronaviruses. Viruses are contortionists, with an insane ability to flexibly adapt to their hosts—like us. It’s why universal vaccines are such blue sky projects, especially when we don’t yet have one effective for just Covid-19.

But if the pandemic has taught us anything, it’s that we have to fight back. Not reactively, but proactively.

The study paints two roads towards a hopeful future. With one, it showed how global collaboration rapidly merged theoretic and lab studies with existing clinical data. In practical terms? Faster identification, approval, and deployment of existing drugs against a new coronavirus strain.

The other road is rockier but with an even brighter end. The team basically drew up a scientific recipe to potentially end coronaviruses once and for all. This is just the beginning. But as Dr. Pedro Beltrao, a study leader at EMBL’s European Bioinformatics Institute, said, “After more than a century of relatively harmless coronaviruses, in the last 20 years we have had three coronaviruses which have been deadly…We have the capability to predict pan-coronavirus therapeutics that may be effective in treating the current pandemic, which we believe will also offer therapeutic promise for a future coronavirus as well.”

Image Credit: Felipe Esquivel Reed/Wikimedia Commons

Shelly Xuelai Fan is a neuroscientist-turned-science writer. She completed her PhD in neuroscience at the University of British Columbia, where she developed novel treatments for neurodegeneration. While studying biological brains, she became fascinated with AI and all things biotech. Following graduation, she moved to UCSF to study blood-based factors that rejuvenate aged brains. She is the ...

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