There’s more than one way to administer a vaccine. The most common way, by far, is to administer an injection in a person’s arm. Other sites can also be used for the injection — for instance, researchers in Hong Kong recommend administering the vaccine (link) in the leg, which could yield the same efficacy and could reduce the risk of dangerous side effects on the heart.

But some vaccines may not use any injections at all.

Nasal vaccines are, as the name implies, vaccines administered through the nose, as opposed to an injection; they’re essentially a nasal spray. This approach is painless, involves fewer risks, and is particularly well-suited to airborne respiratory pathogens because we’re often in contact with them through our noses. This idea has a remarkably long history, with the Chinese Kangxi Emperor claiming to inoculate his entire family against smallpox by “blowing smallpox material up the nose”.

We’ve come a long way since the times of the emperor, and vaccines are much more refined and efficient — but nasal vaccines still haven’t truly become mainstream. But they could soon.

This type of vaccine could be extra effective against COVID-19, says Yale’s Akiko Iwasaki, the Waldemar Von Zedtwitz Professor of Immunobiology. In a new study, she and her colleagues found that intranasal vaccination provides broad protection against respiratory viruses in mice, while vaccines that use an injection did not.

“The best immune defense happens at the gate, guarding against viruses trying to enter,” said Iwasaki, senior author of the study.

It makes sense when you think about it. The nose hosts a mucous membrane that already serves as a defense line against pathogens. These tissues produce B cells, which then produce immunoglobulin A (IgA) antibodies. These are a special type of antibody that only works locally on the membrane found in the nose, stomach, and lungs (as opposed to regular vaccine antibodies, that act throughout the entire body).

The role of this mechanism is well known, but Iwasaki wanted to see whether these IgA antibodies also help offer vaccine immunity against respiratory diseases. They tested this idea on mice, administering a protein-based influenza vaccine through injections and also through the nose. They then exposed the mice to multiple strains of influenza viruses.

Results showed that the mice that received the nose vaccines had more protection against the influenza viruses than those that received injections. Essentially, the nasal vaccines protected the animals against a variety of strains, not just the ones they were vaccinated against.

Although it’s still early stages and we don’t know yet if the approach is safe and efficient in humans, Iwasaki believes there’s a good chance they could be used in conjunction with existing vaccines, potentially as boosters to reinforce the immune system against various strains. This could be excellent against influenza (which mutates quickly and already has several strains of concern) and, of course, COVID-19 — with the new Omicron variant and several others potentially lurking around the corner, having access to a robust vaccine that protects against many strains could be key to ending the pandemic. Still, there’s a long way to go from mouse studies to human studies, but the research team is confident that this approach can provide important benefits and is testing the approach on animal COVID-19 strains.

This isn’t the first study to suggest this approach could work for COVID-19. Just a month earlier, a team from Stanford University also published research on a nasal vaccine against the coronavirus.

“The gold standard for vaccination is through an intramuscular shot to the arm,” Massoud said. “But that’s really a roundabout way to achieve a barrier against a respiratory virus. We thought, theoretically, that administering protection at the site of infection could produce a more robust response,” said Tarik Massoud, MD, PhD and one of the study authors.

Massoud and his co-author, Ramasamy Paulmurugan, also only have a mouse study so far, but results seem promising. They use gold nanoparticles carrying harmless bits of virus-mimicking genetic material that teach the immune system to recognize the invader and mount a defense against them.

“So far, the results we’re seeing with the intranasal vaccine are incredibly encouraging,” said Paulmurugan.

Vaccines can help us gain the upper hand not just in the ongoing pandemic, but also in our long-term war against respiratory viruses. So far, we’ve always been one step behind, but versatile vaccines could help us finally gain the upper hand and be more prepared for the tough fights that will undoubtedly come.