The roaring success of Covid vaccines – in countries able to obtain them – has led to deaths and severe disease from the infection plummeting even as the virus evolved to sidestep immunity and rip through populations more swiftly.
But while the rapid development of Covid shots ranks as the finest achievement of the pandemic, scientists are not done yet. In a small number of labs around the world, teams are taking on a problem that cannot be ignored: that the virus remains rampant in the face of mass immunity.
The problem has arisen because existing Covid vaccines are better at preparing the immune system to fight the virus inside the body than stopping it at the gates. So even though immunity has largely “defanged“Covid, countries still face waves of infection that hospitalize vulnerable people, keep staff off work, and leave an uncertain proportion of people with long Covid.
Hopes to halt the spread of infection are riding on the development of vaccines that are delivered by a spray up the nose rather than a shot in the arm. They aim to produce strong immune protection in the nose and throat, where most Covid infections gain a foothold. Beyond their potential to block infections, intranasal sprays may be more acceptable to people who are not keen on needles.
“If you think of your body as a castle, an intramuscular vaccination is really protecting the inner areas of your castle so once invaders come in, that immunity protects against them taking the throne,” said Dr Sean Liu, medical director of the Covid clinical trials unit at the Icahn School of Medicine at Mount Sinai in New York City.
“But if you train your immune system to work at the gates of the castle, then the invaders not only have trouble getting in, but they may have trouble spreading inside.”
Liu is running an early-stage trial on an intranasal Covid vaccine made in a similar way to seasonal flu vaccines, meaning it could be churned out by the same facilities and dramatically improve global access to Covid vaccines.
More than a dozen clinical trials of intranasal Covid vaccines are under way, but the process is not without its challenges. For an intranasal vaccine to work, it should produce a robust and lasting immune response in the nasal mucosa, the moist membrane that lines the inside of the nose. It helps, too, if people do not swallow or sneeze it out, which can make reliable dosing difficult.
The widely used Pfizer and Moderna vaccines do not immediately lend themselves to intranasal delivery. Both vaccines use tiny, fatty nanoparticles to smuggle the genetic instructions (RNA) for the coronavirus spike protein into cells which prime the immune system.
“In theory, RNA vaccines could work, but nobody has worked out how to deliver them as an effective intranasal spray,” said Prof Robin Shattock, head of mucosal infection and immunity at Imperial College London.
“The lipid nanoparticles are quite delicate and work beautifully when you inject them into the body, but it’s more of an engineering problem to work out how to deliver them into the nose, get them across the mucus, and into the cells.”
So far, only one intranasal vaccine has found a wide market, namely AstraZeneca’s influenza spray, marketed as Flumist in the US and – mindful of potential misunderstandings in Germany – Fluenz in Europe. The vaccine uses a weakened influenza virus, which can get into the cells of the nasal lining and provoke an immune reaction. It not only protects the individual against flu, but helps to reduce community infections, a feat scientists want to repeat with Covid.
An early-stage trial of an intranasal version of the Oxford/AstraZeneca vaccine is expected to publish results soon. The Oxford vaccine is based on a weakened adenovirus, which may be able to induce an immune response in the nose. But all researchers face hurdles with intranasal vaccines, including measuring the strength of the immune response, knowing how protective it will be, and how long it might last. If an intranasal vaccine provides strong protection against infection, but only for a few months, it may work best as an autumn booster, topping up Covid jabs that provide more enduring “systemic” protection against severe disease.
“I think you’d want the systemic vaccine as well because it’s so important for protecting against severe disease,” said Prof Peter Openshaw, a member of the government’s New and Emerging Respiratory Virus Threats Advisory Group (Nervtag). “I wouldn’t want to just rely on a purely mucosal immunization unless it can also generate a decent systemic response.”
Dr Sandy Douglas, a pharmaceutical physician who works on the Oxford vaccine, does not expect any intranasal Covid vaccines to be available this year. “Nobody should put off having their intramuscular vaccine to wait for a nasal spray,” he said.
“But as a midterm prospect, this is one of the most important questions in vaccinology, not just for Covid, but for the next pandemic,” he added. “How do we make vaccines that are good at completely stopping infection with respiratory viruses? We need to solve that problem as soon as we possibly can. It may be that it takes a significant amount of effort and investment, but I’d say it’s absolutely worth it. We can see how big the advantage would be if we had vaccines that completely stopped infection.”