Why we need nasal-spray vaccines

The first vaccines against COVID-19 were developed in record time, and have been mighty effective, saving countless lives. But since their deployment, we have been chasing new variants around the globe, trying to boost immunity against a shape-shifting virus now capable of evading the body’s immune system.

And so once again the world finds itself reckoning with a global surge of highly transmissible Omicron variants“that is occurring, in large part, because of our inability to block infections” and slow the spread of COVID-19, write California-based cardiologist Dr Eric Topol of the Scripps Research Institute, and Yale University immunologist Professor Akiko Iwasaki, in a perspective article published in July in the journal Science.

As good as existing vaccines are at protecting against severe illness and death, we need something more. Topol and Iwasaki argue that if we could break the chain of transmission with vaccines better able to block infections, that would put us in a far better position to possibly contain the virus, reduce infections and by extension, maybe ease the growing burden of long COVID.

If we could break the chain of transmission with vaccines better able to block infections, that would put us in a far better position to possibly contain the virus.

The prospect of achieving this with nasal-spray vaccines is high, no needle or syringe required. But many hurdles still need to be cleared, not least working out how to measure the hard-to-elicit immune response intranasal vaccines are attempting to induce.

Called mucosal immunity, it’s a localised, frontline immune response found in the slippery mucosa that lines the nose, mouth, respiratory tract and lungs, as well as the gut and urogenital mucosa.

Adept at shielding the body from inhaled or ingested pathogens and everyday allergens, the mucosal immune system generates the vast majority of the body’s immune cells, called in from nearby lymph nodes. However, mucosal immunity is fleeting and not as potent as its systemic counterpart.

Still, the allure of nasal-spray vaccines is that they could raise antibodies to stop a respiratory virus at its port of entry and where it first takes hold: in the nasal passage. Trigger an already-primed mucosal immune response, and it can hopefully quash the virus before it replicates enough to cause an infection in the lungs.

“It has been a big wake-up call,” says Professor Kanta Subbarao, an immunologist at the Peter Doherty Institute of Infection and Immunity in Melbourne, of the way Omicron variants have thwarted current, injectable vaccines. “We’re now recognizing the potential significance of mucosal immunity in reducing transmission.”

Trigger an already-primed mucosal immune response, and it can hopefully quash the virus before it replicates enough to cause an infection in the lungs.

There have been decades-long efforts to develop intranasal vaccines for other respiratory viruses such as influenza and respiratory syncytial virus (RSV). But only a small handful of nasal-spray vaccines have been developed before, and used to varying success – with lesser than expected efficacy in some countries once administered outside clinical trials.

That’s not for lack of effort. The challenges with readying the mucosal immune system with vaccines are many and varied, explains Subbarao. The mucosal immune response is “hard to elicit, it’s hard to measure and another challenge is figuring out how to get a lasting, durable response” when antibodies in the respiratory tract mucosa don’t stick around nearly as long as they do in blood, she says.

Despite a renewed interest in nasal vaccines during the pandemic, the ability to measure mucosal immunity lags behind approaches routinely used to measure systemic immunity: neutralising antibodies and immune cells that circulate in the blood. “We know what to measure in the blood; it’s less clear in nasal secretions,” says Subbarao.

Scientists are making some headway, beginning to tease out signals of mucosal immunity to COVID-19, in nasal secretions and fluid samples whisked away from the lower respiratory tract, which harbour immune cells. But they still need to better define markers of protection in the mucosal immune response, Subbarao says.

Only a small handful of nasal-spray vaccines have been developed before, and used to varying success.

Building on this, steady but substantive progress has been made in testing newly developed COVID-19 intranasal vaccines in clinical trials. Four out of 12 candidates are currently in late-stage, phase III human trials, with some trialling intranasal vaccines as boosters.  

But as for how nasal-spray vaccines might bolster immune systems already primed with two doses of an in-arm mRNA vaccine, “That’s where we currently have a void in evidence,” says Associate Professor Paul Griffin, an infectious disease physician at the University of Queensland.

Recent data hints at what may be possible. An animal study of twice-vaccinated mice, led by Iwasaki and pre-printed ahead of peer review, shows that boosting with an intranasal vaccine could raise antibodies and muster immune cells in mucosal tissues where mRNA vaccines alone can’t. Other data from mice shows this so-called ‘prime and spike’ strategy could even confer protection against Omicron variants.

Four out of 12 intranasal COVID vaccine candidates are currently in late-stage, phase III human trials.

Researchers are using a number of clever techniques to induce stronger mucosal responses with vaccines. That includes delivering a weakened virus which mimics a natural infection only in the upper airways but not the lungs; or a viral vector carrying instructions for the SARS-CoV-2 spike protein that can replicate only once, but enough to stimulate a much larger mucosal immune response.

“There certainly have been a number of promising developments that should mean some of the challenges that we’ve encountered previously [with intranasal vaccines] are hopefully able to be overcome,” says Griffin.

Read more on intranasal and other vaccines: Next-generation COVID-19 vaccines are on their way

Based on what is known from influenza and depending on the formulation, though, it might be tricky to find the sweet spot in terms of developing an intranasal vaccine that is as effective in older adults, who have already been exposed to the virus, as it is in children, says Subbarao.

Mucosal immunity wanes with age, much like systemic immunity. And a recent study found that compared to adults, cells from the lining of children’s noses produced a heightened anti-viral response to early strains of SARS-CoV-2 – so intranasal vaccine candidates, if approved, may turn out to be more effective in children, much like how the FluMist nasal-spray vaccine for influenza is now used to vaccinate kids in the UK.

Scientists are also running into real difficulty recruiting participants for clinical trials, with enthusiasm to volunteer waning as the approved vaccines and booster shots are rolled out.

Mucosal immunity wanes with age, much like systemic immunity.

Griffin, who has been involved in a number of clinical trials testing all sorts of COVID-19 vaccines – from nasal-spray and oral vaccines to intramuscular shots – says scientists, funders and manufacturers should continue to be aggressive in developing new vaccines, with nasal-spray vaccines poised to be a key part of our arsenal against COVID-19.

However, intranasal vaccines are not the whole story or a silver bullet, Griffin says. Oral-drop vaccines may too elicit a mucosal immune response, in the gastrointestinal tract. Variant-proof pan-coronavirus vaccines are also in the works, and the first Omicron-specific booster shot has just been approved in the UK – nine months after the variant emerged.

Developing new vaccines also doesn’t detract from how safe and effective existing vaccine are, in providing lasting protection against the worst of the disease, says Griffin. “But they certainly don’t protect from infection to a high enough degree to really alter the trajectory of this pandemic.”

Scientists are running into real difficulty recruiting participants for clinical trials, with enthusiasm to volunteer waning as the approved vaccines and booster shots are rolled out.

As time ticks on, the concern is for the growing burden of long COVID, which could be somewhat alleviated if people aren’t getting infected and reinfected. “I think that’s something that, despite where we are in the pandemic, so many people still are under appreciating,” says Griffin. Although there are many unknowns about what causes long COVID, fewer infections would undoubtedly ease the toll on health systems.

Whichever type of vaccines become available, and even with the ones we’ve got, Griffin says improving vaccine coverage in as many parts of the world as possible is vital, to protect many more people from severe disease and squash new variants.

Curbing the spread of infections with public health interventions such as masks and protecting immunocompromised people with anti-viral drugs would also go a long way to reigning in the virus, he adds. “We need to do better with the tools we have.”