Why Nasal Sprays Are Poised to Be the Next Weapon for Fighting Covid

(Bloomberg Businessweek) -- Half a Greek alphabet and two years into the pandemic, the world is coming to terms with the notion that Covid-19 is here to stay. As new variants emerge, millions are still falling ill, increasing the risk of even harder-hitting strains. While coronavirus shots are among the greatest medical achievements of all time, reaching the market in less than a year and saving millions of lives, anyone who’s received three doses and still gotten infected will understand that the virus is a resilient opponent.

Marty Moore says he can beat it.

“Covid isn’t just a sprint, it’s a marathon,” says Moore, the relentlessly upbeat founder of Meissa Vaccines Inc. Today’s vaccines have largely won the sprint of preventing serious disease, “and thank goodness for that,” he says. “But now we need something else to gain control of the virus.”

Moore is among a growing cohort of virologists proposing we spray vaccines up people’s noses rather than inject them into arms. The advantage of that approach, they argue, is it can trigger the body to develop infection-blocking defenses in the sinuses and throat and allow it to start fighting illness much faster than an injected vaccine can.

There are only two ways to stop the spread of the disease, according to Christian Drosten, Germany’s most prominent virologist. One would be for enough people to build up protection via repeated illness that increases immunity at the front end of the respiratory tract. “The alternative would be to have a live vaccine that gets sprayed in the nose or throat,” he said on a podcast in March. Or, as Moore says, to build protection where the battle begins, like putting guards in front of a building rather than inside it.

In early 2020, Moore’s company was just beginning its first human test of a vaccine against respiratory syncytial virus, or RSV, which kills tens of thousands of children a year worldwide. Moore immediately saw the potential to retool his product to bring the coronavirus to heel and set to work adapting it. For the past year, Meissa has been conducting human trials of a candidate formula, and Moore expects to have results by this fall. That means it could start going into noses within a year if regulators fast-track it as they did the first round of Covid vaccines—a big “if” given pandemic fatigue and the growing sense of resignation about the disease. Yet with the progress he’s made so far, Moore says he’s more convinced than ever that nasal sprays can do the job. “People didn’t realize how long we were going to be fighting Covid,” he says. “It’s sinking in that there’s this new normal, and you are forced to accept it. But we don’t accept it.”

For any nasal spray Covid vaccine to make a difference, it will first have to overcome towering structural challenges, ranging from the scientific to the economic to the logistical. While the Pfizer-BioNTech and Moderna shots offer robust protection against hospitalization and death, their effectiveness against infection—running the marathon, in Moore’s analogy—fades as time passes and new variants emerge. Future vaccines should offer improvement when it comes to tolerability, length of protection, or ability to actually block infections, he says.

And that, he insists, is where nasal sprays can help—though they’re tough to pull off. It’s relatively easy to stick a needle in someone’s arm and get a precise dose of medication to the cells. With a squirt up the nose, it’s difficult to get the right amount, every time, past the body’s thicket of natural defenses: nostril hairs, sneezing, and the dense layer of mucus that lines the respiratory tract.

Those challenges help explain why, of the 153 Covid vaccines undergoing clinical trials, only a half-dozen are nasal sprays. Among the contenders, a team in China is using an influenza virus filled with genetic instructions for making a piece of the coronavirus spike, which the body learns to attack. Bharat Biotech International Ltd. of India, which makes a widely used Covid shot, employs a chimpanzee adenovirus to deliver the genetic information payload. And there’s a joint effort from New York-based Codagenix Inc. and the Serum Institute of India Pvt Ltd., which utilizes a weakened version of the coronavirus strain first seen in Wuhan, China.

Meissa’s candidate, too, uses a weakened virus to do the dirty work, making it a so-called live-attenuated vaccine. The advantage of this is that viruses are particularly deft at penetrating the body’s defenses to infect cells. But to employ them as a medicine, they first must be attenuated, or weakened, to make sure they’re safe. That’s no simple feat. If they’re too weak, they won’t trigger an adequate immune response. But the weakened virus, once inside the body, must also never mutate to the point that it might make a person sick. Because of this, the pharmaceutical industry in recent decades has focused on alternatives such as introducing only a piece of a virus, even if these approaches aren’t always as powerful. Live-attenuated vaccines are “an art that’s hard to master,” says Paul Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia. “You have to prove it’s attenuated enough that it doesn’t cause disease, but not so attenuated that it doesn’t induce a vigorous immune response.”

Even if you clear those hurdles, nasal spray vaccines can still be a tough sell. Consider FluMist, the influenza fighter that’s the only one ever to make it to market. Since its debut in 2003, it’s failed to live up to predictions that it would dominate the field. It’s an attenuated form of the flu virus, designed to replicate only in the cooler temperatures of the nose, not the lungs or other, warmer parts of the body. Yet regulators, fearing the safety mechanism might fail in the elderly, are reluctant to recommend it to anyone older than 50, the biggest chunk of the flu vaccine market.

And it’s traditionally been tough for startups to break into a business long dominated by the likes of Pfizer, Merck & Co., Sanofi, and GlaxoSmithKline. To start selling a product, companies must clear an exceptionally high bar in terms of safety and show clear superiority over existing options. The pandemic blew open that dynamic, catapulting technologies such as messenger RNA to center stage. That enabled the meteoric rise of Moderna and Germany’s BioNTech, which co-developed its product with Pfizer. And it has brought in multitudes of investors, allowing smaller players to compete in a market that brokerage Jefferies LLC predicts will reach $50 billion by 2025. Moore says he can win a piece of that business, even though his company remains tiny compared to many other newcomers.

To appreciate the promise of nasal sprays, it helps to understand what happens when the coronavirus infects you. First, messenger cells capture bits of the virus from your airways, sense something is wrong, and make an hourslong journey to the nearest lymph node to warn of the intruder. If you’ve had your Covid shots, there are B cells and T cells on hand, ready to fight back. These weapons multiply and begin a slow voyage through the body in search of the virus. This works well in preventing severe Covid, but it all takes a couple of days to play out while the virus is replicating fast, so people often infect others before they know they’re sick.

A nasal spray might more accurately mimic the natural protection a person gains from a recent infection. That’s because once the immune system encounters the virus (in this instance, from the nasal vaccine), it stations Covid-ready B and T cells in the nose and throat. What’s more, it fosters the development of antibodies called IgA, which take up residence in the mucus lining and can stop the virus from ever reaching the cells lining your airways. You can’t get that from a shot, only from a vaccine that enters the body as a virus would. And the added protections give the immune system an advantage of as much as a day and a half in fighting Covid, says Frances Lund, director of the Immunology Institute at the University of Alabama at Birmingham. “You get a jump-start on clearing it out,” she says. “Your viral load is going to be lower, which means fewer clinical symptoms for you and less virus that you can spew out to everybody else.”

Nasal delivery works best with live-attenuated vaccines, Moore says, because they’re so effective at getting to the most important cells. And Meissa employs a new way of attenuating a virus that can uncouple it from the safety-vs.-efficacy seesaw. The approach is inspired by its work with RSV, which has been weakened not by making it harder for the virus to replicate—the traditional method—but by genetically removing its ability to hide from the immune system. In theory, you could get dosed with a large amount of this mutant version of RSV, generating a massive immune response while posing little to no threat of making you sick. “If you block the blocker, then you unleash the immunogenic potential of that virus,” Moore says.

To make its Covid vaccine, Meissa stuck the coronavirus spike protein onto the RSV shell. In tests on monkeys, the company found its product induced antibodies both in the mucus and in the blood, protecting the animals from the virus. Meissa is about halfway through an early-stage clinical trial in 130 people, for which it has reported positive preliminary data showing no serious safety problems, an indication that the virus has been well attenuated. Meanwhile, a single dose stimulated about the same level of IgA antibodies as what’s seen in people recently infected with Covid.

The company expects to produce full results from the human trial this year. It’s already added participants to test it as a booster and plans to soon begin studying it in children. Ultimately the product could be particularly well suited to kids, Moore says, as they tend to be afraid of needles and they play a big role in spreading most respiratory diseases.

In lab studies, Meissa’s vaccine has offered significant protection against the alpha and beta variants, and tests for delta and omicron are in the works. Moore says the vaccine’s potential ability to protect against a range of strains may be a result of its physics. Whereas many vaccines—including mRNA—offer a rigid version of the coronavirus spike to the immune system, the live-attenuated approach sends the spike right into the wilderness of the body. During its journey it gets bent this way and that, just like a virus does as it seeks to latch on to cells. This exposes the immune system to a fuller picture of the spike in action, giving it “better coverage to mismatched strains,” Moore says.

Moore has been fixated on respiratory viruses since his days as a graduate student at the University of Georgia. But in the early 2000s, as he was presenting his doctoral research into a type of adenovirus that infects mice, a distinguished professor stood up and said, “Nice work, Marty. Next time pick an important virus,” Moore recalls. Taking the feedback to heart, he holed up in a library and built a spreadsheet to identify viruses that affect humans but get scant attention. His analysis revealed two candidates. The first was a coronavirus that had just emerged in China, causing severe acute respiratory syndrome, or SARS. That disease would vanish within months. The second was RSV.

Long a thorny challenge in virology, RSV infects almost everyone by their second birthday, then repeatedly throughout life. It typically inflicts just a common cold, but it can be dangerous for young children, with their smaller airways. During postdoctoral research at Vanderbilt University, Moore devised a way to reliably produce RSV of a specific genetic design, giving him a platform for dissecting the virus, which he further developed after landing a faculty position at Emory University in Atlanta.

Scientists had been stuck when it came to producing vaccines against RSV. In the 1960s, when they tried giving infants an inactivated form of the virus, the approach backfired, killing two trial participants. And they’d abandoned efforts to create a live-attenuated vaccine for it, because every time they weakened the virus enough to make it safe to administer to kids, it no longer elicited a sufficiently strong immune response.

Moore conceived of a new approach. The reason RSV can repeatedly infect us has nothing to do with quick mutations, which are a key factor for influenza and, to a lesser extent, the current coronavirus. Instead, its proteins block the immune system’s ability to see that it’s there. What would happen, he wondered, if you were to remove the proteins that let RSV sneak in undetected? Theoretically, you could spray that genetically engineered RSV into the nose, where it might replicate like normal—leading the immune system to unleash a barrage of B and T cells to kill it. Those weapons would then remain in the nose and throat, offering protection for months and perhaps as long as a year or two. It would be a new way to deliver a live-attenuated vaccine for various respiratory diseases.

When Moore presented this idea at a conference in Portugal in 2013, a big pharma company offered to license the technology, but he wanted to develop it himself. In 2014 he started Meissa Vaccines, naming it after the star in the Orion constellation that forms the mythical hunter’s head. In 2017, Meissa landed a spot at JLABS, an incubator space in San Francisco backed by Johnson & Johnson, allowing Moore to apply for federal business grants. He and co-founder Roderick Tang, a scientist who’d worked at the company behind FluMist, quit their jobs to focus full-time on Meissa. Moore moved his family to California and devoted himself to raising funds, while Tang spent his days in the lab seeking to prove that Meissa’s genetically modified version of RSV could make for a safe and powerful vaccine.

In 2019, the company got $30 million from a venture capital firm and filed paperwork with U.S. regulators to start clinical trials. After a hiring spree that made things crowded in the tiny space at JLABS, Moore mapped out a plan to move into a bigger office near Stanford. As 2020 began, Meissa was on the cusp of spraying the first dose of its RSV vaccine into an actual human, a culmination of his life’s work.

On a Saturday in mid-January, Moore rose at 4 a.m. in his San Carlos, Calif., home. Under the yellow streetlight streaming into the room, he filled a mug of coffee and settled in behind a wooden desk that had once belonged to his father. Scientists had just posted the genome sequence of a novel pathogen wreaking havoc in Wuhan, and Moore downloaded the code. Feeding it into his laptop, he arranged four rows of genetic sequences on his screen, stacked on top of one another like sheet music. Each corresponded to the spike protein of a coronavirus, and Moore was shocked when his eyes scanned a portion of the spike’s genetic makeup that suggested the virus could quickly latch on to human cells. “You look at that sequence and think, ‘A lot of things can happen, and most of them are bad,’ ” he says.

As he pondered developing a vaccine against the new virus, Moore feared he might jeopardize everything he’d been chasing for two decades with RSV. Yet the stakes were obvious and overwhelming. The coronavirus, he suspected, would be with us for years, and few scientists would attempt to stop it with a nasal spray. So he grabbed a pen and pad and sketched out how he might insert the coronavirus spike into Meissa’s RSV platform.

As patients around the world flooded hospitals, Moore settled on various virus constructs that might work as a vaccine. The crucial step—which each version tried to accomplish in a slightly different way—was attaching most of the coronavirus’s spike to the root of RSV’s surface protein. Absent this connection, the RSV platform would expel the spike, rendering the candidate useless. The Meissa team translated those models into a genetic sequence and ordered small vials of a solution containing that DNA from a supplier.

With the Bay Area in lockdown, Moore phoned Mariana Tioni, a newly hired virologist, to ask if she’d be willing to come into JLABS. She said yes, and soon she, Tang, and Moore were spending their days clad in N95 masks, booties, smocks, and hair covers. Returning home at night, they’d change clothes in the garage and sleep isolated from their families.

When the DNA samples arrived, the trio injected them one by one into cells, using the process Moore had developed at Vanderbilt. The goal is for the cell to start pumping out copies of the genetically engineered virus, a process that can take days. The team inserted a fluorescent protein marker that glows red if the virus is spreading. Meissa’s first few attempts showed no glow, fueling fears the idea wasn’t going to work. Then, a couple of days after injecting a candidate known as MV-014-210, Moore peered into a microscope, focused the lens, and saw a sea of red. “We were jumping up and down,” he recalls. For the next month, the team harvested the mutant virus while planning the animal experiments required to convince regulators that the vaccine was safe and promising enough to justify testing on humans.

By that point, Pfizer and Moderna had started human trials for their mRNA candidates, and governments began directing all their resources toward the leaders. In November 2020, when the companies presented data showing their vaccines were more than 90% effective, many people proclaimed the pandemic’s end was near.

Moore was pleased that his rivals had developed their vaccines so quickly, and he looked forward to getting shots himself. But he disagreed with the notion that the pandemic was almost over. He’s been proven right: Even as deaths have fallen by half globally in the past year, daily infections have roughly doubled—a testament to both the strengths and limitations of Covid shots. The bar for new candidates, though, has gotten higher because they must unseat established products.

There’s reason to believe nasal sprays might, at minimum, serve as effective boosters for those who’ve been vaccinated or gotten infected with Covid. Lymph nodes in these people will already have coronavirus-ready B and T cells, so only a small amount of a vaccine would need to penetrate the nose’s defenses—at which point the immune system, recognizing a familiar foe, would spring into action.

Moore acknowledges there’s a long road ahead to prove his Covid candidate is safe, effective, and superior in at least some respects to the shots. If trial results are strong, the next step would be broader tests, which can cost hundreds of millions of dollars—many multiples of the capital Moore currently has. “They need a lot more money to do this right,” says Sam Fazeli, an analyst at Bloomberg Intelligence.

Meissa has relocated to a bigger facility, allowing Moore to increase his staff to about 25 people. They’ve expanded the study of their RSV candidate into infants and are doing early work on fighting two other respiratory viruses. Even if Meissa’s spray arrives too late to have a big impact on Covid, the company aims to be prepared to quickly make a vaccine in response to the next pandemic. And for now, Moore remains convinced there’s ample reason to build immunity against Covid in the nose and throat. “You’re going to need this, you’re going to want this, because it’s the endgame,” Moore says. Sure, boosters of the current vaccines can reduce infections, but only temporarily, like tapping snooze on an alarm clock. “Then it just repeats,” he says. “If you want to stop hitting the snooze button, we need to actually block transmission.”

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