Mucosal vaccines against COVID-19 have potential to prevent even mild infections and stop transmission – a challenge current vaccines are unable to address. But it's too soon to declare these vaccines -- delivered nasally, orally, or transdermally -- the solution that could quash the pandemic, experts say.
It's still "early days" for these immunizations, said William Schaffner, MD, an infectious diseases physician at Vanderbilt University in Nashville, Tennessee. There is hope that intranasal vaccines will be able to cut transmission, but "it's more anticipated than demonstrated at the present time," he said.
He and other experts point to a lack of data on the efficacy of mucosal COVID vaccines in humans and many challenges ahead for development and evaluation of efficacy.
At least 12 nasal vaccine candidates for COVID are in development, four of which have reached phase III clinical trials.
The only approved intranasal vaccine of any type in the U.S. is FluMist, a live attenuated vaccine against influenza. Some countries, however, have already approved mucosal vaccines for COVID. Earlier this month, China approved an as a booster and India gave the green light to an , both based on adenovirus vectors.
Reaching Sterilizing Immunity
Like most respiratory viruses, SARS-CoV-2 enters the body through mucous membranes such as the mouth, nose, and throat. After the virus makes contact on the mucosal surfaces, it multiplies, traveling from those entry points through the bloodstream to other parts of the body.
The idea is that mucosal vaccines could bolster immunity at these viral entry points, stopping the pathogen from implanting, multiplying, and transporting itself throughout the body.
"We know that if you can induce immunity in the nose, that often is much more effective in preventing infection," said Kathryn Edwards, MD, a professor of pediatrics and vaccine researcher also at Vanderbilt University. "It's an attractive hypothesis to think we could begin to make weakened COVID vaccines that might be able to stimulate local immunity and really prevent infection."
There's some evidence accruing that higher levels of mucosal immunity do just that. For example, a research letter published in the New England Journal of Medicine showed that triple-vaccinated healthcare workers with higher levels of anti-spike mucosal immunoglobulin A (IgA) had a with the Omicron variant (RR 0.35, 97.5% CI 0.11-0.91).
Current injectable vaccines, which help prevent progression to severe infection and death, do induce some level of mucosal immunity -- but at typically very low levels, experts noted.
"Current vaccine strategies are really effective and are great at preventing disease," said Benjamin Goldman-Israelow, MD, PhD, assistant professor of internal medicine and infectious diseases at Yale School of Medicine in New Haven, Connecticut.
"We do think that further immunization and further immunity within the respiratory tract has the potential to reduce transmission even more," he said in an interview. "Could that further dampen the pandemic? Could it further inhibit viral evolution and the emergence of variants? All those things, we think, are very important."
How Effective Are Nasal Vaccines?
Animal studies evaluating the efficacy of mucosal vaccines for COVID-19 suggest that these vaccines might do a better job at preventing infection.
Goldman-Israelow and colleagues , showing that a nasally-delivered, unadjuvanted spike protein booster that was administered after an intramuscular mRNA shot induced mucosal immunity, both reducing viral load in the respiratory tract and preventing lethal illness.
Additionally, Ahmed Hassan, PhD, and colleagues at the University of Washington in St. Louis, found that a single-dose, adenovirus-vectored intranasal vaccine reduced risk of infection in rhesus macaques in both the upper and lower respiratory tracts.
A combination approach appeared promising in mouse-model research led by Matthias Tenbusch, PhD, of University Hospital Erlangen, Germany. An intranasal booster with adenoviral vectors induced high levels of mucosal IgA and lung-resident memory T cells, enhanced mucosal neutralization of SARS-CoV-2, and provided complete protection against infection in mice.
"Our data thus suggest that mucosal booster immunizations after mRNA priming is a promising approach to establish mucosal immunity in addition to systemic responses," Tenbusch's group wrote.
Biotech company Codagenix on its live attenuated intranasal vaccine, CoviLiv, which showed a strong cellular immune and mucosal antibody response against Omicron BA.2.
However, there is still very little data describing the efficacy of intranasal vaccines in humans. Understanding how effective intranasal vaccines will be in preventing human infection and transmission will have to wait on phase III clinical trial results.
Obstacles to Development
Despite the promising premise, it won't be easy to assess clinical efficacy, said John Moore, PhD, professor of microbiology and immunology at the Weill Cornell School of Medicine in New York City.
Determining correlates of protection -- that is, how much of an immune response will prevent infection -- is challenging in a population that has been largely exposed to the virus, he told 鶹ý.
"It's a worthwhile concept, but it's going to be challenging to prove that it's better than what we already have," Moore said. He added that further research should also determine whether nasal vaccines will induce both mucosal and systemic immunity such that they could be used alone instead of only as a booster.
Additionally, it is difficult to produce a long-lasting and effective immune response with mucosal formulas. FluMist, for example, was discontinued for a period following recommendations from the CDC's Advisory Committee on Immunization Practices (ACIP), after it was shown to be less effective than injected flu vaccines in kids over several seasons. Now, the vaccine is recommended for young children but not for adults over age 49.
Gregory Poland, MD, a vaccine researcher at the Mayo Clinic in Rochester, Minnesota, added to the list of questions around these vaccines: What will durability and efficacy look like across age groups? Will the antibodies generated neutralize all the variants?
While intranasal vaccines for COVID are a potentially great answer for crowded environments, such as the military, college campuses or schools, Poland added: "Is it the answer for infants and older adults, the ones who actually are most likely to be hospitalized or die? Unlikely without some kind of scientific advance that hasn't yet happened."
Still, Poland said that finding a vaccine that could indeed block transmission could be crucial to the public health approach at this stage of the pandemic.
"I think that's really important if we can do it," he said, noting that at least 100,000 people will likely die of COVID each year at the rate the virus is spreading. "So yeah, blocking transmission? That would be a godsend."