Nasal Vaccines Could Help Stop COVID-19 From Spreading—If Scientists Can Get Them Right

SARSCoV-2, which is responsible for COVID-19 infects the body and causes it to enter through the nose or mouth. Once inside, it then begins reproducing.

What if the virus could not get into the upper airways? That’s the promise of nasal COVID-19 vaccines, which are meant to prevent infection by blocking the virus at its point of entry.

There is not yet a nasal COVID-19 vaccine available in the U.S.—and it’s not clear if or when there will be—but multiple research teams in the U.S., including the National Institute of Allergy and Infectious Diseases, and abroad are working on them. Russian scientists are currently testing their nasal Sputnik V vaccine on adult volunteers. In India, researchers have been approved for Phase 3 trials.
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Researchers are very excited by the possibility of nasal vaccines to combat COVID-19. “Yes with an exclamation point,” says Troy Randall, an immunologist at the University of Alabama at Birmingham, when asked if they’re worth exploring.

The majority of nasal vaccines are used in countries such as the U.S. where 76% have received at least one dose. Some research teams also study them for this purpose. But if they’re found to be effective and eventually authorized, they could also give young children and people who fear needles more options.

There’s a long road ahead. FluMist is the nasal vaccine that has been approved by the U.S. Food and Drug Administration for fighting a respiratory disease. It is available to protect against influenza in people between 2 and 49 years old. FluMist has been in production for many decades, but it was only briefly removed from the market because of efficacy problems. This could be a sign that vaccine researchers are still struggling to develop a nasal COVID-19 vaccination.

Researchers still believe that nasal vaccines could one day accomplish what the high-quality mRNA vaccines from Moderna and Pfizer BioNTech haven’t: slow down the transmission to end the pandemic.

Shot-in-the-arm COVID-19 vaccines introduce the body to genetic material from the SARS-CoV-2 virus, teaching the immune system what to do if it’s faced with the real thing. These shots have proven very good at preventing severe disease and death, but less adept at blocking infections—particularly against highly contagious Omicron.

Nasal vaccines could theoretically prevent many infections by conferring “local” immunity where it’s needed most: the nose. If it worked, a spritz would blanket the upper airways with defenses similar to those generated by the body after a brush with the actual virus, says Dr. James Crowe, director of Vanderbilt University Medical Center’s Vaccine Center.

“You get the best immunity to virus pathogens by mimicking, to the greatest extent possible, the actual infection without causing disease,” Crowe says. “Stopping a virus in its tracks, right at the front door, is very attractive.”

If done right, Crowe says, nasal vaccines could be highly effective—but developing them is difficult. They typically use live but weakened forms of a virus, which introduces a “Goldilocks” challenge, Crowe says. Weaken the virus too much and the vaccine won’t work; not enough, and it could overstimulate the immune system, leading to side effects. You must achieve the perfect balance.

It is also very different from the environment of the deltoid muscles, which are where shots are usually given. It’s a near-direct line to the brain, which clearly necessitates a different set of precautions, Crowe says.

Benjamin Goldman Israelow is an Yale School of Medicine professor. His co-authorship of a new study hasn’t been peer reviewed. This research examined mice’s responses to COVID-19 nasal and injected vaccines. Researchers found that mice responded better to being injected with COVID-19 vaccines first, and then given a nasal booster.

That may be because the upper airways are equipped with natural defenses against invading particles—they’re the body’s entry point for the outside world, after all—and thus do not always respond strongly when first introduced. “By giving that initial priming through the [injected] mRNA vaccine, we educate the immune system, so that by the time we give the intranasal boost, the immune system already knows to recognize this as foreign,” Goldman-Israelow says.

Another rodent study by Yale researchers, published in December, found that mice vaccinated with a nasal flu shot were less likely to catch influenza than those that received an injected vaccine—a finding that may also apply to other respiratory diseases, such as COVID-19. Similar results have been seen in animal studies by other researchers, which suggest that nasal vaccinations could prevent infections.

Of course, large clinical trials—some of which are underway in other countries—are necessary to know how a product will work in humans. “We cannot draw conclusions about whether a nasal COVID-19 vaccine is going to work or not work until we see the data,” says Dr. Hana Mohammed El Sahly, a professor of virology and microbiology at Baylor College of Medicine.

There have already been setbacks. A disappointing trial result led to Altimmune, a biopharmaceutical firm, stopping the testing of a nasal COVID-19 vaccination candidate.

The nasal vaccinations can be difficult to administer. In the early 2000s, long before the COVID-19 pandemic, a nasal flu vaccine used in Switzerland was found to be associated with Bell’s palsy, a form of facial paralysis that is typically temporary. It was not in clinical practice at the time of publication.

FluMist, the nasal flu vaccine used in the U.S. and first approved in 2003, hasn’t run into such safety issues, but it was briefly taken off the market due to efficacy problems. The U.S. Centers for Disease Control and Prevention’s vaccine advisory committee did not recommend its use in 2016, citing data that it had been only 3% effective during the prior flu season. The 2018-2019 season saw a reformulated vaccine being brought back to the market. In its current form, “it does seem to work, and the data are supportive of its continued use,” El Sahly says.

FluMist cannot be used by people over 50 or under 2. It’s also not recommended for immunocompromised individuals and some people who have lung conditions such as asthma. That’s because it contains a live but weakened virus: an effective way to prompt an immune response, but one that can lead to potentially serious side effects in people with underlying conditions.

“It’s a balancing act,” Randall says. “You want the vaccine to be effective, but you don’t want it to really hurt or cause [too much] inflammation.”

The advancements made in vaccine science make it possible to achieve that balance. In an effort to minimize side effects, the Yale group working on nasal vaccinations developed a formula that doesn’t contain adjuvants (a chemical often used in vaccines to stimulate a stronger immune response). The pandemic also means there’s lots of interest in and money available for developing new vaccine candidates, which hasn’t always been the case.

However, it will never be easy to develop a vaccine against viruses that are susceptible to mutations like SARS and CoV-2. That’s true whether researchers are developing a nasal vaccine or a shot in the arm, Randall says.

“We can ensure that the sequence that we selected is the one that actually ends up in the vaccine,” he says. But there’s no telling whether the sequence in the vaccine will be the one that “Mother Nature throws at us.” Such mismatches explain why the flu shot is far more effective in some years compared to others.

The mRNA-based COVID-19 vaccinations have been strong in protecting against serious disease and death. Omicron has proved to be the most effective variant at avoiding vaccine-acquired immune, which is causing unprecedented numbers of patients and straining health care systems. It is important to have a tool that prevents severe illness as well as infections.

“Really, the goal is to reduce or even eliminate transmission,” says Tianyang Mao, a graduate student at the Yale School of Medicine and co-author of the study on booster nasal vaccines for COVID-19.

It is now two years since the COVID-19 epidemic. But Yale’s Goldman-Israelow says his team is motivated to create a nasal vaccine not only for this pandemic, but also the next one. Having the technology ready and waiting could significantly strengthen our country’s response the next time a new threat emerges—just as decades of work on mRNA vaccines came to fruition just in time to help with the COVID-19 pandemic.

If nasal vaccines had been available sooner to complement the COVID-19 vaccines we already have, he says, they could have “helped reduce transmission and help prevent the continuation of the pandemic that we’ve seen.”


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