Since the early days of the coronavirus pandemic, a niche subset of experimental vaccines has offered the world a tantalizing promise: a sustained slowdown in the spread of disease. Formulated to spritz protection into the body via the nose or the mouth—the same portals of entry most accessible to the virus itself—mucosal vaccines could head SARS-CoV-2 off at the pass, stamping out infection to a degree that their injectable counterparts might never hope to achieve.

Now, nearly three years into the pandemic, mucosal vaccines are popping up all over the map. In September, India authorized one delivered as drops into the nostrils; around the same time, mainland China green-lit an inhalable immunization, and later on, a nasal-spray vaccine, now both being rolled out amid a massive case wave. Two more mucosal recipes have been quietly bopping around in Russia and Iran for many months. Some of the world’s largest and most populous countries now have access to the technology—and yet it isn’t clear how well that’s working out. “Nothing has been published; no data has been made available,” says Mike Diamond, a virologist and an immunologist at Washington University in St. Louis, whose own approach to mucosal vaccines has been licensed for use in India via a company called Bharat. If mucosal vaccines are delivering on their promise, we don’t know it yet; we don’t know if they will ever deliver.

The allure of a mucosal vaccine is all about geography. Injectable shots are great at coaxing out immune defenses in the blood, where they’re able to cut down on the risk of severe disease and death. But they aren’t as good at marshaling a protective response in the upper airway. When viral invaders throng the nose, blood-borne defenses have to scamper to the site of infection at a bit of a delay, leaving an opening for pathogen to creep in—it’s like stationing guards next to a bank’s central vault, only to have them rush to the entrance every time a robber trips an external alarm. Mucosal vaccines, meanwhile, would presumably be working at the door.

That same logic drives the effectiveness of the powerful oral polio vaccine, which bolsters defenses in its target virus’s preferred environment—the gut. Just one mucosal vaccine exists to combat a pathogen that enters through the nose: a nasal spray made up of weakened flu viruses, a version of which is branded as FluMist. The up-the-nose spritz is reasonably protective in kids, in some cases even outperforming its injected counterparts (though not always). But FluMist is much less potent for adults: The immunity they accumulate from a lifetime of influenza infections can wipe out the vaccine before it has time to lay down new protection. When it comes to cooking up a mucosal vaccine for a respiratory virus, “we don’t have a great template to follow,” says Deepta Bhattacharya, an immunologist at the University of Arizona.

To circumvent the FluMist problem, some researchers have instead concocted viral-vector-based vaccines—the same group of immunizations to which the Johnson & Johnson and AstraZeneca COVID shots belong. China’s two mucosal vaccines fall into this category; so does India’s nose-drop concoction, as well as a nasal version of Russia’s Sputnik V shot. Other researchers are cooking up vaccines that contain ready-made molecules of the coronavirus’s spike protein, more akin to the shot from Novavax. Among them are Iran’s mucosal COVID vaccine and a newer, still-in-development candidate from the immunologist Akiko Iwasaki and her colleagues at Yale. The Yale group is also testing an mRNA-based nasal recipe. And the company Vaxart has been tinkering with a COVID-vaccine pill that could be swallowed to provoke immune cells in the gut, which would then deploy fighters throughout the body’s mucosal surfaces, up thro