Are COVID Nasal Vaccines Our Ticket Out of the Pandemic?

Kathleen Doheny

November 08, 2022

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

In the not-so-distant future, protection against COVID-19 may become easier, more complete — and sting less.

We'd walk to our mailbox, collect a small package there, and self-administer a nasal vaccine booster dose, meant not only to prevent us from getting sick but from getting infected at all and transmitting the virus.

Dr David T. Curiel

The scenario is possible, according to David T. Curiel, MD, PhD, distinguished professor of radiation oncology at Washington University in St. Louis. His vision of the future sounds especially credible given his track record. He's widely known as the father of the mRNA vaccines against COVID developed by Moderna and Pfizer/BioNTech, as he first published research that was the foundation for those vaccines in 1995.

When he approached pharmaceutical companies, well before the pandemic, showing them his "beautiful vaccine data," he was told there would be no use for them, he said.

Now, of course, those mRNA vaccines have saved millions of lives. But the pandemic is still here, despite public fatigue and sentiment that it's over, and more needs to be done. While the intramuscular vaccines prevent severe illness and death, with the advent of each new variant they increasingly don't prevent transmission of the SARS-CoV-2 virus that causes COVID.

And that's where nasal vaccines could come in, according to Curiel and numerous other experts.

As of November 4, Airfinity, a health data company, is tracking 116 intranasal vaccines in development, including 23 in clinical stages. Seven of those 23 are in phase 3 trials. Nasal vaccines are already approved elsewhere, including India, Russia, and Iran. China has an inhaled COVID vaccine.

Some research is investigating nasal vaccines as boosters; others as the original vaccination in those not yet vaccinated.

The Power of Mucosal Immunity

Dr Eric Topol

Nasal vaccines provide what's known as mucosal immunity, stopping the virus at the entry point to the body. "The whole idea is, you are building up protection at the entry level of the upper airway," said Eric Topol, MD, executive vice-president of Scripps Research, La Jolla, California. (Topol is editor-in-chief of Medscape.)

With the nasal vaccine, "it's much harder for the virus to get rooted in the mucosa, which is where it has to enter. So that's how we protect against infections and that's how we protect against spread," he said. And if the virus can't infect people, of course, it can't spread.

"That's what we need right now," Topol said. "That's the missing link to get us out of the pandemic." He has long urged the development of nasal COVID vaccines, often explaining their benefits in editorials and on Twitter.

Dr Michael W. Russell

The idea is gaining ground among infectious disease experts, and for good reason. "The mucosal immune system and the circulatory immune system are separate," said Michael W. Russell, PhD, professor emeritus of microbiology and immunology at the University at Buffalo, New York, who has also written about the value of mucosal immunity in fighting the pandemic. "There is some cross talk, but they are largely independent."

"If you generate antibodies in the blood, these generally don't reach mucosal secretions in any significant amount," he said. "The antibodies in the mucosal secretions don't reach the blood."

The most robust immunity against COVID-19, according to Russell, comes when infection in the mouth and upper respiratory tract results in the secretion of immunoglobulin A (IgA) antibodies, giving mucosal immunity.

For the nasal vaccines in development, the goal of all is to induce mucosal immunity. Some of the vaccines are live attenuated (weakened virus) versions of the SARS-CoV-2 virus, which elicit an immune response. Others use an inactivated (or replication-incompetent virus incapable of infecting cells) version of a common cold virus, or adenovirus, to deliver an antigen and trigger an immune response.

"Prime and Spike" Approach

With the nasal vaccines, scientists are studying a new vaccination approach, known as "prime and spike." As protection from the intramuscular vaccine injections, which most people have received, wanes after a few months, breakthrough infections occur.

But, by following up that shot with a nasal vaccine, mucosal immunity at the entry point of the virus can be achieved.

Dr Benjamin Goldman-Israelow

"We are leveraging preexisting immunity from the vaccine," said Benjamin Goldman-Israelow, MD, PhD, assistant professor of medicine and infectious disease physician at Yale School of Medicine, New Haven, Connecticut, who with his colleagues recently published the results of the approach in animal studies. 

Those animals given a nasal vaccine after an mRNA vaccine had a stronger immune response than those given just the mRNA vaccine or those not vaccinated. In some instances, the researchers were also able to show some decrease in transmission, Goldman-Israelow said.

Progress, or Lack of, So Far

One nasal vaccine, developed by scientists at the University of Oxford and AstraZeneca, has not panned out. The vaccine uses a weakened version of a common cold virus, or adenovirus, genetically modified so it can't replicate in people.

In a report on its phase 1 trial, researchers said they administered the nasal spray to 30 participants who had not yet been vaccinated, but found the mucosal antibody responses were only seen in a minority of them.

Systemic immune responses were also weaker when compared with what is seen in intramuscular vaccines. In mid-October, the researchers said they will halt research on it.

Among other research under way:

Dr Shankar Musunuri

Ocugen: Ocugen has an exclusive license agreement with Washington University in St. Louis to develop its nasal vaccine, created there by Curiel and Michael S. Diamond, MD, PhD, professor of medicine, molecular microbiology, and pathology and immunology. It's the same vaccine already authorized for emergency use in India, said Shankar Musunuri, PhD, Chairman, Chief Executive Officer, and cofounder of Ocugen In., Malvern, Pennsylvania.

Now, Ocugen has initiated discussions with the US Food and Drug Administration (FDA) to design the clinical trial in America. It's an adenovirus-vectored vaccine with a stabilized spike protein.

"It's a single booster, so development will be fast," Musunuri said. It will be tested in those who already had a primary series of COVID vaccines.

Dr J. Robert Coleman

Codagenix: CoviLiv, a live-attenuated (weakened form of the virus) intranasal vaccine, performed well in a phase 1 study, according to J. Robert Coleman, PhD, cofounder and Chief Executive Officer of Codagenix, Farmingdale, New York.

He said in phase 1, "[I]t was as safe as placebo and we saw a 100% seroconversion or antibody response rate." Because the vaccine expresses all the SARS-CoV-2 proteins, not just the spike, the hoped-for result is to induce broad immunity against variants.

Now, the company has initiated dosing in phase 3, in collaboration with the Serum Institute of India. The research is part of the World Health Organization's Solidarity Trial Vaccines effort to evaluate COVID vaccines.

Dr Marty Moore

Meissa Vaccines: Meissa is involved in a phase 1 study of its nasal vaccine, which it initially investigated as a primary vaccine but now is testing as a booster, said Marty Moore, PhD, chief scientific officer and founder of Meissa Vaccines, Redwood City, California.

Initial data in the trial's 49 participants show the nasal can stimulate an IgA antibody response similar to what is seen after infection with COVID, but safely.

"We should be wrapping this up in the next quarter or two. What we are seeing so far is outstanding safety and good immune responses," Moore said.

Few Precedents

The United States has little experience with nasal vaccines. Consumers are likely most familiar with FluMist, a nasal spray for flu prevention approved for ages 2 through 49.  

In a recent study, from 2019, researchers found the nasal spray inferior to the flu shot in youth ages 2 to 17. However, in an earlier study, published in 2007, the nasal flu vaccine worked better than the shot in young children up to about 5 years old.

FluMist "did blaze the trail," Coleman of Codagenix said. "Usually the first in class is not the best in class." However, he said, the research on FluMist shows you can have high efficacy with lower antibody rates compared with an injectable.


A lack of funding is a huge barrier to nasal vaccine development. Observers say Operation Warp Speed 2.0, meant to promote development of new COVID vaccines, has fallen flat. Without funding, experts worry, the United States will fall far behind other countries.

Company officials involved in nasal vaccine research said they are waiting on more specific guidance from the FDA on criteria that must be met to get an emergency use authorization (EUA) for the nasal vaccines. The FDA issued its guidance on EUAs for COVID vaccines in 2021 and 2022.

Another barrier is vaccine fatigue, but proponents of the nasal vaccines say the new delivery method will be more appealing and more convenient, and especially more attractive to needle phobics and children.

How Soon?

Experts' predictions vary on how soon that nasal vaccine could be at the pharmacy (or your mailbox). Topol is optimistic. If all goes well, a nasal vaccine could be authorized by early next year, he predicted.

The nasal vaccine's role in the United States will be to take the place of boosters, he and others said.

Musunuri of Ocugen said its vaccine may be ready for the 2023-2024 season. Coleman of Codagenix, a self-described pragmatist, estimates availability by late 2023, if all goes well.

Acceptance of the nasal vaccines, then, would also hinge on turning around public perception that the pandemic is over and that another shot — or spray — will provide more protection.

Curiel, who's faced pessimism before, thinks it will be accepted. "I think the user-friendly aspect of a non-invasive vaccine will be a way to traverse vaccine hesitancy," he said.

Goldman-Israelow is a consultant for Xanadu Bio, developing a nasal vaccine. No others reported relevant financial relationships.

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