Most vaccines throughout history have been jabbed into the upper arm, often to great success. But when protecting people against pathogens that invade the airway — like the coronavirus — an intramuscular shot isn’t necessarily the best strategy, some experts say.
“When we take apart and present pathogens in a way that the immune system doesn’t naturally see them, it’s not as ideal,” said Avery August, an immunologist at Cornell University. “You run the risk of not generating the right immune response.”
Many microbes, including the coronavirus, enter the body through the mucosa — wet, squishy tissues that line the nose, mouth, lungs and digestive tract — triggering a unique immune response from cells and molecules there. Intramuscular vaccines generally do a poor job of eliciting this mucosal response, and must instead rely on immune cells mobilized from elsewhere in the body flocking to the site of infection.
Given the potency and rapid spread of the coronavirus, some say it makes sense to develop vaccines for the airway as well as the more standard jabs. “Knowing how potent mucosal responses can be against a viral pathogen, it would be ideal to be thinking about mucosal vaccines,” said Akiko Iwasaki, an immunologist at Yale University.
Several research groups, including teams in the United States, Canada and the Netherlands, are working on nasal coronavirus vaccines. And a few companies, including the American biotech Vaxart, are starting to cook up oral formulations, which deliver their contents to another mucus-rich surface: the spongy lining of the gut.
The hope is that mucosal vaccines will do all that their intramuscular competitors can and more, mounting a multipronged attack on the coronavirus from the moment it tries to breach the body’s barriers, said Deepta Bhattacharya, an immunologist at the University of Arizona.
Under ideal circumstances, both types of vaccines would marshal a response in the blood. B cells, for example, would churn out antibodies — including a particularly potent disease-fighter called IgG — to roam the body in search of invaders to dispatch. Other cells, called T cells, would either help B cells produce antibodies or seek out and destroy infected cells.
But vaccines spritzed through the nose or mouth would also tap into another set of immune cells that hang around mucosal tissues. The B cells that reside here can make another type of antibody, called IgA, that plays a large role in bringing gut and airway pathogens to heel. And T cells in this neighborhood can memorize the features of specific pathogens, then spend the rest of their lives patrolling the places they first encountered them.
These mucosal immune responses seem to underlie the success of the oral polio vaccine, which contains a weakened form of polio virus and has helped most of the world eradicate polio. When it debuted in the 1960s, the vaccine was considered, in many ways, an enormous improvement over its injected predecessor because it targeted the body’s immune response in the gut, where the virus thrives. Many people who took the oral vaccine seemed to quash infections even before they felt symptoms — or passed the germ on to others.
“It was a fabulous vaccine to stop the transmission of polio,” said Dr. Anna Durbin, a vaccine expert at Johns Hopkins University. “It helped induce herd immunity,” she said, referring to the threshold of the population that needs to be immune to a pathogen to keep it from spreading.
Vaccines given through muscle are great for prompting the body to churn out antibodies in the bloodstream, like IgG. If a pathogen shows up, hordes of these on-call molecules will rush to meet it.
For many respiratory infections, that’s good enough.
“The majority of respiratory vaccines, like the measles vaccine, are given intramuscularly, and it works,” Dr. Iwasaki said. “If enough antibodies reach the right mucosal surface, it doesn’t really matter how they were induced.”
Still, relying on that strategy alone can be risky — a bit like shoring up a bank’s security at every entrance except for the one a thief would most likely hit. Sentinels roving throughout the building could subdue the interloper after they trip the alarm. But by that point, some damage has probably already been done.
“It’s mainly a timing issue,” Dr. Bhattacharya said. “If you have circulating cells and molecules, they’ll eventually find the infection. But you’d rather have a more immediate response.”
Without a strong mucosal response, injected vaccines may be less likely to produce so-called sterilizing immunity, a phenomenon in which a pathogen is purged from the body before it’s able to infect cells, Dr. Durbin said. Vaccinated people might be protected from severe disease, but could still be infected, experience mild symptoms and occasionally pass small quantities of the germ onto others.
Reliably rousing mucosal immunity isn’t easy, however — and vaccines that specifically target them come with their own drawbacks. Although FluMist, a nasal spray vaccine containing weakened flu viruses, has been shown to be more effective than flu shots in young children, its performance is more lackluster in adults. And the oral polio vaccine has been linked to a very small number of cases of polio after the weakened virus in the product mutated.
Designing a mucosal vaccine with less risky ingredients, such as inactivated viruses or genetic material, could circumvent that issue. But these more innocuous formulations could be too weak to stimulate a long-lasting immune response.
“You want the vaccine to be strong enough to get in and do what it needs to do, but it can’t cause a lot of symptoms,” Dr. Durbin said. “It’s a really difficult balance.”
Much of mucosal immunity also remains mysterious to researchers. “A lot of what we know about the rest of the immune system kind of goes out the window when we’re talking about a mucosal site,” said Dr. Frances Eun-Hyung Lee, a physician and immunologist at the Emory Vaccine Center. There are also fewer tried-and-true technologies for developing nasal and oral vaccines, compared with injectables.
All these factors can introduce speed bumps in the vaccine-development timeline, as researchers work to ensure both safety and effectiveness, Dr. August said. That means mucosal recipes might not be among the first generation of coronavirus vaccines. But perhaps that’s all the more reason to invest in them earlier, he said.