When SARS-CoV-2, the virus that causes COVID-19, infiltrates the body, it typically enters through the nose or mouth, then takes root and begins replicating.
But what if it could never get a foothold in 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 testing a nasal form of their Sputnik V vaccine in adult volunteers, and researchers in India have gotten approval for a Phase 3 trial.
Many researchers are excited about the prospect of nasal vaccines for 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.
In countries like the U.S., where about 76% of people have had at least one dose of the COVID-19 vaccine, nasal vaccines would by default be used primarily as booster shots, and some research teams are studying them specifically in this capacity. 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. While oral vaccines are fairly common, the only nasal vaccine cleared by the U.S. Food and Drug Administration to fight a respiratory pathogen is FluMist, which is used to prevent influenza among people ages 2 to 49. FluMist was in development for decades but was briefly taken off the market due to efficacy issues, which could foreshadow the challenges awaiting vaccine researchers working to create a nasal COVID-19 vaccine.
Still, researchers hope that nasal vaccines may one day do what even the highly effective mRNA vaccines made by Pfizer-BioNTech and Moderna have not: slow transmission enough to bring the pandemic to an end.
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. The balance has to be perfect.
The nose is also a very different environment than the deltoid muscle, where shots are typically given. It’s a near-direct line to the brain, which clearly necessitates a different set of precautions, Crowe says.
The upper airways are also built to encounter foreign substances and thus may not respond as readily to a vaccine, says Benjamin Goldman-Israelow, an instructor at the Yale School of Medicine. He co-authored a recent study, which has not yet been peer-reviewed, that examined how mice responded to nasal versus injected COVID-19 vaccines. The research found that mice mounted a stronger immune response when they were injected first and then boosted with a nasal vaccine, as opposed to getting a nasal vaccine alone.
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. Animal studies from other research teams have also shown promising signs that nasal vaccines may prevent infections, particularly when given as boosters.
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.
Already, there have been setbacks. Last year, the biopharmaceutical company Altimmune stopped testing a nasal COVID-19 vaccine candidate due to disappointing trial results.
Nasal vaccines are difficult to get right. 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. By the time that research was published, it was no longer in clinical use.
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. A reformulated version of the vaccine returned to market for the 2018-2019 season. In its current form, “it does seem to work, and the data are supportive of its continued use,” El Sahly says.
Still, FluMist is not authorized for people who are 50 and older or younger than 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.”
Leaps in vaccine science have made it easier, if not easy, to find that balance. The Yale team working on nasal vaccines, for example, created a formula that does not contain an adjuvant (a material often added to vaccines to stoke a stronger response from the immune system) in hopes of reducing side effects. 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.
But creating a vaccine to fight viruses that mutate frequently, like influenza and SARS-CoV-2, will always be challenging. 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.
So far, mRNA-based COVID-19 vaccines have held up well against new variants, providing strong protection against severe disease and death. Omicron, however, has been the best variant yet at dodging vaccine-acquired immunity, causing record-shattering numbers of cases and straining the health care system. That underscores the need for a tool that can prevent infections as well as severe disease.
“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.
Two years into the COVID-19 pandemic, the need is clear. 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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