In a collective display of scientific advancement, the Covid-19 vaccines from Pfizer, Moderna and Johnson & Johnson seem to be astoundingly effective at preventing severe disease and death from Covid-19. All are intramuscular, meaning they are injected into the muscle tissue. Once the vaccine materials seep into the bloodstream, they induce the creation of antibodies, which then circulate in the blood throughout the body, protecting some of the most vital organs and creating what’s called systemic immunity. This immune response protects the body from serious illness and death, but the response only builds after the virus has fully entered the body.

Their ability to protect the human body from Covid-19 illness is truly incredible, but the SARS-CoV-2 virus still has an entryway into the body left unprotected by the vaccines: the nose and mouth. Those two gateways, and their ability to transmit the virus, are what mask mandates all about. Face coverings have been shown to impede the spread of the aerosol virus, protecting their wearers and those around them from infecting each other.

But what if a new, intranasal vaccine existed?

With a spritz up the nose, such a vaccine would travel through the upper respiratory tract, encouraging the body to produce protective antibodies there. If successful, this immune response would both neutralize the virus on its way in before making a person sick, and it would ensure that no live virus escapes when they exhale, cough or sneeze. While early data on efforts to promote mucosal immunity is promising, companies are still in early-stage clinical trials and a marketable, intranasal Covid-19 vaccine may be a year out.

“For real control of the pandemic, what we want to do is not just prevent serious disease and death—as good as that is in itself—but we want to be able to break the chains of transmission,” says Michael Russell, a mucosal immunologist with the University of Buffalo.

The existing vaccines achieve systemic immunity by spurring the production of antibodies called immunoglobulin G, or IgG and killer T cells. These cells and proteins are highly effective at neutralizing the virus before seriously damaging our key organs. But to prevent the virus from entering into the body in the first place, scientists likely need to target the mucosal system. The moist tissue lining the nasal and mouth are part of the mucosal system, which stretches from there all the way through the gastrointestinal and reproductive tracts. Here, a different class of antibodies exude from the mucosa to neutralize viruses and other intruders. The mucosal system secretes specialized antibodies called Immunoglobulin A or IgA. When faced with an intruding virus or bacterium, the mucosa releases IgA to neutralize it.

If a Covid-19 vaccine can create a strong mucosal immune response, the body may be better equipped to stop the virus before it makes its way to essential organs, like the heart and lungs. Plus, secretory IgA antibodies in the mouth and nose are more potent against SARS-CoV-2 than the IgG antibodies induced by intramuscular vaccines, according to a study published in Science Translational Medicine in January. Proponents of intranasal vaccines are hopeful that boosting secretory IgA in this way would be a step up from the protection offered by the existing vaccines.

For the body to create the secretory IgA antibodies necessary to neutralize incoming virus, many scientists think a vaccine needs to be applied along the natural route of infection. This means administering the vaccine through the nose via a nasal spray and letting it travel through the mucosa.

Injected Covid-19 vaccines don’t appear to elicit much of an antibody response in the mucosa, says Michal Tal, an immunologist at Stanford University and team lead of the Stanford Saliva Study—an effort to track antibodies that are secreted in saliva from people who have been vaccinated. Many people who have been naturally infected with Covid-19 seem to create a mucosal immune response early in the infection, but for those relying on a vaccine to build their immunity, an intranasal vaccine may provide a necessary IgA supplement to their systemic immunity.

“To protect the nose from being a site where infection can get in and infection can get back out, you really have to have IgA there,” Tal says.

Globally, five intranasal vaccine candidates are currently undergoing clinical trials, according to the World Health Organization . Scot Roberts, chief scientific officer of Altimmune, the only U.S. company with an intranasal vaccine in clinical trials, is betting that such an intranasal vaccine will be the best way to stop viral transmission while also protecting the body from disease. “You can only get this mucosal antibody response when you do intranasal administration, because it's a very localized immunity,” he says.

Recent research indicates that the Pfizer and Moderna vaccines may reduce viral load and asymptomatic transmission. A study by the CDC published last month shows that health care workers in eight U.S. locations saw a 90 percent reduction in Covid-19 transmission rates after being fully vaccinated with one of the mRNA vaccines. Another study, by Israeli researchers and published in Nature Medicine in March, indicates that the Pfizer vaccine significantly reduced viral load 12 to 37 days after vaccination—a key indicator of diminished transmission.

Still, the current vaccines haven’t proven to completely block transmission. Part of the reason why, Tal says, is because transmission can stem from different parts of the respiratory tract for different individuals. Some infected individuals, vaccinated or not, may not spread the virus unless they’re in close contact with others. Tal says scientists think this kind of spread originates from virus living in the nose. But other people, who act as “superspreaders,” may carry and spread aerosols of highly infectious virus from the lungs or the nose or both. Intramuscular vaccines can neutralize the virus in the lungs, but without mucosal immunity conferred through an intranasal vaccine, scientists say no way likely exists to fully stop transmission from the nose.

Tal adds that she was “a little surprised” to learn that most of the original Covid-19 candidates under Operation Warp speed were to be administered intramuscularly, despite dealing with a mucosal pathogen. But during that point in the pandemic, when death and hospitalization rates were skyrocketing, creating a formula to prevent death was paramount.

“From a public health perspective, the most important key mission is to bring down deaths and hospitalizations,” Tal says. “So, you want to go with an intramuscular formulation where you know you're going to get really great circulating antibodies, which intranasal may not be as optimal for.”

Now that more than 175 million doses of vaccine have been distributed in the U.S., scientists are looking to do more. Blocking transmission is especially important in attempts to rein in emerging viral variants. After entering the body, genetic mutations in the virus sometimes help it become more infectious or successful at evading immune responses. When this happens, the new version of the virus replicates and eventually becomes a new variant. However, if the virus is unable to breach the mucosal and systemic immune systems, it cannot live and replicate in the nasal passages or body. And if transmission is blocked, it becomes more difficult for variants to spread through a population.

Intranasal and oral vaccines are not novel concepts. Intranasal flu vaccines like FluMist, developed by AstraZeneca, were used for decades in the U.S. In the last decade, however, they became variably effective against the circulating flu strains, causing the CDC to revoke its recommendation for their use for several years. Previous intranasal flu vaccines introduce some weakened virus and allow it to replicate in the respiratory tract to create an immune response. Roberts says his company’s Covid vaccine, AdCOVID, will be safer because it introduces a larger amount of vaccine and the viral vector isn’t able to replicate in the body and make someone sick.

History offers a precedent to a second wave of vaccines adding a layer of protection for public health. The initial Salk polio vaccine, for instance, was first introduced as a shot. Though it was effective at preventing illness, the shot didn’t stop infection. The poliovirus mostly affects the intestines, which are lined with mucus. So, scientists, including Albert Sabin, developed an oral vaccine that, when swallowed, came in direct contact with the gut mucosa to boost the mucosal immunity and stop infection and transmission. A Covid-19 intranasal vaccine would directly affect the mucosa in the same way.

“That polio story is completely analogous to what we're doing, except we're doing it in the respiratory tract,” Roberts says.

One of the major remaining unknowns about an intranasal vaccine is how well it will mount a lasting immune response. Russell says that the mucosal immune must constantly contend with our microbiota and the everything we eat and inhale in ways that the rest of the body does not. Thus, it’s possible that the mucosal system’s memory of, and response to, the virus may diminish more quickly than the systemic immune response will.

Roberts predicts AdCOVID will be available in early 2022. In regions of the world where many people have been vaccinated, it may serve as a sort of seasonal re-vaccination. Roberts says that, like the flu, Covid-19 may become a seasonal illness. For people with a systemic immune response, either from intramuscular vaccination or natural infection, the intranasal vaccine could act as a booster to support their mucosal immunity and protect against variants.

As pharmaceutical companies develop second generation vaccines and think about vaccine boosters, Tal says they have renewed opportunity to devise ways to boost mucosal immunity.

“Obviously, we've got to get out of the current situation we find ourselves in, but also provide a better preparedness to deal with the virus becoming endemic in the human population,” Russell adds. “It seems very likely that we will not totally eliminate this virus, we're going to have to live with it forever in [the] future.”