Three nasal spritzes, now in advanced trials, could trigger stronger immunity than shots in the arm

By Marla Broadfoot

The relentless evolution of the COVID-causing coronavirus has taken a bit of the shine off the vaccines developed during the first year of the pandemic. Versions of the virus that now dominate circulation—Omicron and its subvariants—are more transmissible and adept at evading the body’s immune defenses than its original form. The current shots to the arm can still prevent serious illness, but their ability to ward off infection completely has been diminished. And part of the reason may be the location of the jabs, which some scientists now want to change.

To block infections entirely, scientists want to deliver inoculations to the site where the virus first makes contact: the nose. People could simply spray the vaccines up their nostrils at home, making the preparation much easier to administer. There are eight of these nasal vaccines in clinical development now and three in phase 3 clinical trials, where they are being tested in large groups of people. But making these vaccines has proven to be slow going because of the challenges of creating formulations for this unfamiliar route that are both safe and effective.

What could be most important about nasal vaccines is their ability to awaken a powerful bodily defender known as mucosal immunity, something largely untapped by the standard shots. The mucosal system relies on specialized cells and antibodies within the mucus-rich lining of the nose and other parts of our airways, as well as the gut. These elements move fast and arrive first, stopping the virus, SARS-CoV-2, before it can create a deep infection. “We are dealing with a different threat than we were in 2020,” says Akiko Iwasaki, an immunologist at Yale University. “If we want to contain the spread of the virus, the only way to do that is through mucosal immunity.”

Iwasaki is leading one of several research groups in the U.S. and elsewhere that are working on nasal vaccines. Some of the sprays encapsulate the coronavirus’ spike proteins—the prominent molecule that the virus uses to bind to human cells—into tiny droplets that can be puffed into the sinuses. Others add the gene for the spike to harmless versions of common viruses, such as adenoviruses, and use the defanged virus to deliver the gene into nasal tissue. Still others rely on synthetically bioengineered SARS-CoV-2 converted into a weakened form known as a live attenuated vaccine.

The more familiar shots in the arm create a type of immune response known as systemic immunity, which produces what are called immunoglobulin G (IgG) antibodies. They circulate throughout the bloodstream and patrol for the virus. Nasal sprays assemble a separate set of antibodies known as immunoglobulin A (IgA). These populate the spongy mucosal tissues of the nose, mouth and throat, where the COVID-causing coronavirus first lands. Iwasaki likens mucosal vaccines to putting a guard at the front door, as opposed to waiting until the invader is already inside to attack.

While conventional injectable vaccines are generally poor at inducing protective mucosal immunity, nasal vaccines have been shown to do a good job of triggering both mucosal and systemic responses. Last year researchers at the National Institutes of Health conducted a side-by-side comparison of intranasal and intramuscular delivery of the Oxford-AstraZeneca vaccine. They found that hamsters that had received the vaccine through the nose had higher levels of antibodies against SARS-CoV-2 in their blood than those who received it through the muscle. The University of Oxford is now testing intranasal vaccination in a phase 1 trial, which will assess the safety of the vaccine in a small number of people.

Developing a nasal vaccine is tricky, however, because scientists know relatively little about the machinations of mucosal immunity. “While the human immune system is a black box, the mucosal immune system is probably the blackest of the black boxes,” says epidemiologist Wayne Koff, CEO and founder of the Human Vaccines Project, a public-private partnership aimed at accelerating vaccine development. What scientists do know is making them tread cautiously. Because of the nose’s proximity to the brain, substances squirted up the nasal passages could raise the risk of neurological complications. In the early 2000s, a nasal flu vaccine licensed and used in Switzerland was linked to Bell’s palsy, a temporary facial paralysis. “Since then, people have become a little bit nervous about a nasal vaccine,” Iwasaki says.

And although a spray seems like an easier delivery method than a shot, in practice, that is not the case. With intramuscular injections, a needle delivers the vaccine ingredients directly into the muscle, where they quickly encounter resident immune cells. Sprays, in contrast, must make their way into the nasal cavity without being sneezed out. Then those ingredients have to breach a thick barrier gel of mucus and activate the immune cells locked within. Not all do. One company, Altimmune, stopped development of its COVID nasal vaccine AdCOVID after disappointing early trial results.

Weakened or attenuated viruses can get through the barrier to infect cells, so some vaccine developers are turning to them. Two companies, Meissa Vaccines and Codagenix, have used synthetic biology to build an attenuated version of the novel coronavirus containing hundreds of genetic changes that drastically reduce its ability to replicate. In a recent news release, the Codagenix team reported promising results of their vaccine, CoviLiv, in a phase 1 trial. The spray induced a strong immune response against proteins shared by different variants of SARS-CoV-2, including the recent Omicron subvariant BA.2. That is because the vaccine trains the immune system to recognize all the viral proteins, not just the spike. Presenting all components of the virus makes the vaccine less vulnerable to the whims of evolution that might alter a few proteins beyond recognition. “The beauty of live attenuated vaccines is that they can provide broad long-term immunity in a very resistant context,” says J. Robert Coleman, a virologist and the company’s co-founder. CoviLiv is moving on to advanced testing in people as part of the World Health Organization–sponsored Solidarity Trial Vaccines, a giant randomized controlled trial of several new COVID vaccines.

For each of the candidates that have made it into clinical trials, there are several more in preclinical development. In research with mice at Yale, Iwasaki has devised a nasal spray that works as a booster to the standard intramuscular shot. The strategy, which she calls “Prime and Spike,” starts with an injection of an mRNA or other COVID vaccine based on the spike protein, and this triggers an initial immune response. Then researchers spray a mix with similar spike proteins directly into the nose, converting that first reaction into mucosal immunity. In a preprint study not yet published in a peer-reviewed scientific journal, her team found that their one-two-punch protected mice from severe COVID while also significantly reducing the amount of SARS-CoV-2 in the nose and lungs.

When the researchers added spike proteins from the coronavirus that created a global outbreak in 2003—SARS-CoV-1—to their spray, they found that it induced a broad spectrum of antibodies. The combination has the potential to defend against new coronavirus strains or variants “There is a big push for a universal coronavirus vaccine,“ Iwasaki says. “We can get there, and as a bonus we can provide mucosal immunity.” She has licensed the technology to Xanadu Bio, a company she co-founded, and is currently seeking funding to launch human trials.

With no needles or syringes, nasal inoculations could reach a lot more people, and that could prove to be a big advantage. Koff, however, thinks the real deciding factor will be whether tests prove these vaccines stop infections and illness, and those results will be more important than ease of use. “At the end of the day, efficacy is going to trump everything,” he says.

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