Scientists Are Already Preparing for the Next Pandemic

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“Unless we’re screened for coronaviruses and then shot out into space, leaving all other animals and nature behind, we’re going to have coronaviruses.” So says Benjamin Neuman, PhD, chief virologist at Texas A&M’s Global Health Research Complex. Neuman is no stranger to coronaviruses — he has been working with them for decades. His expertise even landed him a spot on the international committee that named SARS-CoV-2, the virus that causes Covid-19. SARS-CoV-2 is the most recent member of the coronavirus family, which also includes the viruses that caused the SARS and MERS outbreaks.

The world’s changing climate and growing population increases the future threat of coronaviruses, and it’s a threat that Neuman doesn’t take lightly. Some viruses are very simple, he says. At the other end of the spectrum, there are coronaviruses. “These are viruses that are good at stealth, at sneaking around a cell and cutting the wires before any alarm bells start to ring.” It’s not surprising, he adds, that coronaviruses are found in all kinds of animals, including bats, pangolins, and humans.

A sneaky adversary

Stealth is part of what’s allowed SARS-CoV-2 to live the high life this past year, spreading from one continent and human to the next, often undetected. In addition to the serious illness and death it may cause (and has caused), this virus’s wanderlust has meant more opportunities for it to mutate, and with that comes a greater concern that vaccines — developed at record speeds and, overall still effective against current variants — might no longer protect us.

As mutations in SARS-CoV-2 arise, scientists are scrambling to figure out how each new variant might be different from the last, and if current vaccines can stop it. Neuman is one of many scientists taking a step back and looking at the bigger picture of coronaviruses — a picture not specific to SARS-CoV-2 or a Covid-19 vaccine.

“I like generalizable solutions,” he says. “You know, science is this pursuit of generalizable knowledge, so knowing how to defeat any coronavirus is important to me.” He is a firm believer that there are ways to do this.

Defeating any coronavirus, not just SARS-CoV-2

Neuman’s current work is focused on antivirals — drugs that kill viruses or keep them from replicating. Antivirals are different from vaccines, which teach your immune system to do the killing. So far, antivirals have proven widely unsuccessful against SARS-CoV-2 and are notoriously difficult to develop, in part because viruses are not alive. Much like the mythological undead feed off of the living, viruses invade our cells and use our bodies to do their bidding, which makes it hard to destroy them without destroying our cells as well.

Neuman sees incredible promise in continuing to pursue antivirals, but not without first seriously rethinking the current approach, which has mainly focused on making antivirals that will target parts of the virus likely to mutate.

“Some parts of the virus can change over the course of an outbreak, or even over the course of a single infection,” Neuman says. Those changes can ultimately render a drug ineffective. “If you attack those small changes with drugs, what you quickly get is a resistant variant.” In SARS-CoV-2, mutations are popping up in the spike proteins — proteins that stick off of the virus’s surface and give it a crownlike halo. The spike is the part of the virus that has been the target of much antiviral and vaccine development.

Although these vaccines and antivirals could be effective enough to get us out of the current pandemic, they might be so specific to SARS-CoV-2 that they’re unusable against a future coronavirus that comes down the pike. Because of this, Neuman believes we should shift our focus toward parts of the virus that are less likely to mutate.

This is not just a matter of “creating this mRNA capability and then going home,” because we don’t know if sinister viruses of the future will be as easily addressable as SARS-CoV-2.

Attacking the linchpins that hold SARS-CoV-2 together

“A good antiviral will bind to one of the fundamentally important parts of the virus, like an enzyme,” says Neuman. And even when those parts do change, he says, the virus will struggle to replicate, which makes disease progression unlikely. In that approach, “you’re attacking the linchpins that are holding all of these parts of the virus together,” says Neuman, “and that’s going to be useful today and in the future.”

Neuman’s collaborators are developing drugs that inhibit these fundamental enzymes. If they are successful in a test tube environment, the plan is for Neuman and the team to introduce these inhibitors into cells in a dish. If some of those inhibitors are successful, the next step would be to test them against a range of coronaviruses, collected from Covid-19 patients as well as from the natural environment, including local sewers.

Neuman and his team want to know not only if these drugs are effective against a range of coronavirus variants, but at what stage in the virus’s replication cycle they affect it. That understanding is essential for considering when to give the drug to a patient.

Timing is everything — just look at what we learned from remdesivir.

The repurposed Ebola drug was a much-touted early entrant for Covid-19 treatment. Remdesivir was designed to block a key enzyme many viruses — not just SARS-CoV-2 — need in order to replicate their RNA, yet data on its effectiveness comes from patients who were already hospitalized when the virus had multiplied and spread enough to cause Covid-19.

“If you start the therapy too late, it will miss its mark,” says Neuman. By the time a patient has checked into a hospital, their immune system is in overdrive. At that point, the goal is to dampen down the patient’s immune response so that their lungs don’t fill with fluid. For remdesivir to have a chance at being really effective, he explains, it needs to be given much earlier — long before a patient requires hospitalization. It may be that remdesivir works better than current data would show, but even so, Neuman believes that combining it with other treatments would bring a greater likelihood of success.

Ganging up on SARS-CoV-2

Antivirals have been shown to work best in combination with other antivirals. “Antivirals can gang up on a virus in ways that other therapeutics struggle to do,” says Neuman. It’s the strategy used to tame HIV. Three different drugs are often used, and each “pins down” a key part of the virus. The result, he says, is “brutally effective.”

The threat of SARS-CoV-2 mutations that could evade current vaccines seems to be on everyone’s mind right now. Neuman sees antivirals as a way of saving lives by buying the immune system time if something should pop up that’s not responsive to vaccines, whether that be a SARS-CoV-2 variant or a different coronavirus altogether. “Antivirals have a place,” he says, “which is to complement and assist vaccines and other kinds of therapeutics. Think of the antivirals as being there to put the virus in a headlock while the immune system beats it up.”

In the case of vaccines, Neuman sees mRNA vaccines as one of humanity’s greatest assets right now. Compared to traditional vaccines that are often protein-based (whooping cough, HPV, hepatitis B, and others fall into this category), mRNA vaccines put your cells in charge of making those proteins, and that makes it easier to modify them and scale up their production.

The ability of mRNA vaccines to “turn on a dime,” as Michael Farzan, PhD, puts it, should a viral mutation arise, make them a powerful tool in the arsenal against coronaviruses. Farzan, chair of the department of immunology and microbiology at the Scripps Research Institute, says their promise extends far into the future. ”We’ll be playing whack-a-mole with these viruses for some time and we’re going to need to be able to modify vaccines against them.”

With a more generalized approach for antivirals and vaccines, Farzan sees a not-too-far-off future without any infectious disease.

Pandemic preparedness includes having options

In 2003, Farzan and his collaborators were the first to identify ACE2 as a receptor for the original SARS, SARS-CoV. ACE2 is a protein on our cells that grants SARS-CoV — and as it turned out, SARS-COV-2 — access into our cells. “I get bragging rights on that one,” he laughs. “No one noticed for decades, but now it’s become important again.”

Although Farzan describes himself as a fan of mRNA vaccines, he is cautious about expecting too much of them. Scientists are still working to understand how our immune systems might respond differently to mRNA vaccines versus other vaccine types. We don’t yet know how long our post-vaccination immunity will last, even in the case that the vaccine we received is effective against all SARS-CoV-2 variants.

He says that this is not just a matter of “creating this mRNA capability and then going home,” because we don’t know if sinister viruses of the future will be as easily addressable as SARS-CoV-2. “We need to be working to understand the limits and strengths of mRNA as a vaccine strategy,” says Farzan. And while we do, we need to have multiple tools at our disposal. “We need backups, we need options,” he says.

Farzan and his lab are hard at work on a vaccine that targets the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, a region far less likely to mutate than other regions of the spike. This is the same region targeted by the Pfizer-BioNTech BNT162b2 vaccine. The difference is that Farzan and the team are aiming to make the RBD particularly immunogenic — in other words, designed to get a stronger, longer-lasting response from the immune system.

Although they’d love their findings to be incorporated into an mRNA vaccine design, they’re adding another egg to the coronavirus vaccine basket by also creating a protein-based version that’s stable enough to ship in powder form and then hydrate upon arrival. Although this vaccine would not have that “turn on a dime” versatility of an mRNA vaccine, it would circumvent the super cold temperatures needed to ship and store an mRNA vaccine, which has been an issue during this pandemic. “It would be incredible to be able to avoid the cold chain issue altogether,” says Farzan.

Moving beyond one-bug-one-drug

Like Neuman, Farzan sees antivirals as an important piece of the pandemic preparedness puzzle. “We need to get beyond one-bug-one-drug,” he says.

Developing an antiviral specific to SARS-CoV-2, he believes, is shortsighted. “But we also don’t want to be trying to create a drug that targets every kind of virus,” he cautions. “The most effective antivirals will knock down a class of viruses.” That class could be coronaviruses, but it could also be influenza viruses, Ebola viruses, and other infectious diseases that may pose a threat. In fact, with a more generalized approach for antivirals and vaccines, Farzan sees a not-too-far-off future without any infectious disease.

“Infectious diseases are the lowest hanging fruit right now — they’re easier to address than cancer, or heart disease, or neurodegenerative diseases,” he says. When compared to all of the other things killing humans, Farzan believes we have the tools to eliminate infectious diseases.

“There’s no new technology that needs to be invented to make this happen,” he says, enthusiastically. “We’re at this unique moment in human history where we have technology that can move faster than a virus can evolve.”

Although Farzan is confident that the science to prevent the next pandemic already exists, he reflects on the brief window of time when he studied the SARS coronavirus 20 years ago, before returning to his lab’s main research focus — HIV. He recalls a quick disbanding of researchers who had stepped up to study the coronavirus. “There was not a sustained effort,” he says. “We were all onto the next thing and we’d already forgotten about the last one.” He hopes that’s not the case for SARS-CoV-2, and that scientists will continue to work together and openly share their findings.

But even if they do, the last year has made it painfully clear to Farzan that science and scientists alone will not save us from the next pandemic. “It’s almost to the point where the scientists are less necessary than the process-control people,” he says. He thinks having centralized national and international facilities for quickly scaling up a pandemic response — which would include manufacturing and distributing a vaccine or antiviral — are essential as we move forward.

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