The relentless evolution of the COVID-causing coronavirus has taken away some of the brilliance of vaccines developed in the first year of the pandemic. Versions of the virus that now dominate the circulation—Omicron and its sub-variants are more portable and adept at avoiding the body’s immune defenses from their original form. Current injections in the arm can still prevent serious illness, but their ability to completely repel the infection is reduced. And part of the reason may be the location of the strikes, which some scientists now want to change.

To completely block infections, scientists want to deliver inoculations to the site where the virus first comes into contact: the nose. People can simply spray the vaccines in their nostrils at home, which makes the product much easier to administer. There are currently eight of these nasal vaccines in clinical development and three in phase 3 clinical trials, where they are tested in large groups of people. But making these vaccines has been slow due to the challenges of creating formulations for this unknown pathway that are both safe and effective.

What may be most important about nasal vaccines is their ability to awaken a powerful body protector known as mucosal immunity, something that is largely unused by standard vaccines. The mucosal system relies on specialized cells and antibodies in the mucus-rich mucosa of the nose and other parts of our airways and intestines. These elements move quickly and arrive first, stopping the SARS-CoV-2 virus before it can create a deep infection. “We are dealing with a different threat than the one in 2020,” said Akiko Iwazaki, an immunologist at Yale University. “If we want to limit the spread of the virus, the only way to do that is through mucosal immunity.”

Iwazaki leads one of several research groups in the United States and elsewhere working on nasal vaccines. Some sprays encapsulate the spiny proteins of the coronavirus – the prominent molecule the virus uses to bind to human cells – in small droplets that can swell in the sinuses. Others add the spike gene to harmless versions of common viruses, such as adenoviruses, and use the decolorized virus to deliver the gene to nasal tissue. Others rely on synthetically bioengineered SARS-CoV-2, a weakened form known as a live attenuated vaccine.

The more familiar blows to the hand create a type of immune response known as systemic immunity, which produces so-called immunoglobulin G (IgG) antibodies. They circulate in the bloodstream and patrol the virus. Nasal sprays collect a separate set of antibodies known as immunoglobulin A (IgA). They colonize the spongy tissues of the mucous membranes of the nose, mouth and throat, where the coronavirus that causes COVID first enters. Iwasaki likens mucosal vaccines to guarding the front door, as opposed to waiting while the invader is inside to attack.

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

However, the development of a nasal vaccine is difficult 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 black boxes,” said epidemiologist Wayne Coffe, CEO and founder of Human vaccine project, a public-private partnership aimed at accelerating vaccine development. What scientists know is to make them tread cautiously. Due to the proximity of the nose to the brain, substances sprayed into the nasal passages can increase the risk of neurological complications. In the early 2000s, a nasal flu vaccine was licensed and used in Switzerland associated with Bell’s palsy, temporary paralysis of the face. “Since then, people have become a little nervous about the nasal vaccine,” Iwazaki said.

And although the spray seems to be an easier method of delivery than the injection, in practice it is not. In intramuscular injections, a needle delivers the components of the vaccine directly to the muscle, where they quickly collide with resident immune cells. In contrast, sprays must make their way into the nasal cavity without sneezing. These ingredients must then break through a thick barrier gel of mucus and activate the immune cells locked inside. Not everyone does. One company, Altimmune, stopped development of his nasal vaccine for COVID AdCOVID after disappointing results from early studies.

Weakened or attenuated viruses can cross the barrier to infecting cells, so some vaccine developers are turning to them. Two companies, Meissa Vaccines and Codagenix, have used synthetic biology to create an attenuated version of the new 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 elicited a strong immune response against proteins shared by various variants of SARS-CoV-2, including the recent subvariant of Omicron BA.2. This is because the vaccine trains the immune system to recognize all viral proteins, not just the peak. The introduction of all the components of the virus makes the vaccine less vulnerable to the vagaries of evolution, which can change several proteins beyond recognition. “The beauty of live attenuated vaccines is that they can provide broad long-term immunity in a very sustainable context,” says J. Robert Coleman, virologist and co-founder of the company. CoviLiv moves to expanded human testing as part of the World Health Organization-sponsored Solidarity trial vaccinesa giant randomized controlled trial of several new vaccines against COVID.

For each of the candidates who have been included in clinical trials, there are several more in preclinical development. In a study with mice at Yale, Iwazaki developed a nasal spray that acts as an enhancer of standard intramuscular injection. The strategy, which she calls “Prime and Spike,” begins with an injection of mRNA or another COVID vaccine based on thorn protein, and this triggers an initial immune response. The researchers then sprayed a mixture of similar protein spikes directly into the nose, turning this first reaction into mucosal immunity. In a pre-press study not yet published in a peer-reviewed scientific journal, her team found that their one or two strokes protected mice from heavy COVID while significantly reducing the amount of SARS-CoV-2 in the nose and lungs.

When researchers added spikes to proteins from the coronavirus that created the global epidemic in 2003, SARS-CoV-1, to their spray, they found that it caused a wide range of antibodies. The combination has the potential to protect against new strains or variants of the coronavirus, “There is a big boost for a universal coronavirus vaccine,” Iwasaki said. “We can get there and as a bonus we can provide mucosal immunity.” She has licensed the technology to Xanadu Bio, a co-founding company, and is currently seeking funding to launch human trials.

Without needles or syringes, nasal inoculations could reach many more people, and this can be a great advantage. However, Koff believes that the real deciding factor will be whether tests prove that these vaccines stop infections and diseases, and these results will be more important than ease of use. “At the end of the day, efficiency will prevail,” he said.

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