‘Collaborate or die:’ Keys to next-gen inhalable vaccine device design from Aerogen’s R&D director

“We are just at the beginning of a very exciting era,” says Aerogen Director of R&D, Science and Emerging Technologies Ronan MacLoughlin.

Not too long from now, you might be able to skip the pharmacy or your doctor’s office for certain vaccinations and instead visit an automated dispensing station for immediate self-administration.

Instead of sticking yourself with a syringe, it’d be as easy as sipping from a cup. It might be less expensive than an intramuscular injection and even offer you better protection with fewer side effects.

“We’ve tried to make it as easy as possible in the sense that our vaccination station has a user interface and it gives you on-screen instructions,” Aerogen Director of R&D, Science and Emerging Technologies Ronan MacLoughlin said in an interview. “… Like you’re filling a cup at McDonald’s, it fills up with air, you take that, you exhale, you inhale one long, slow, deep breath, hold for four seconds and you’re done.”

“The only limit is the potential for cross contamination between patients,” he continued. “Through our fixturing and our vaccination station — for which we got our patents granted [in March], actually — we removed that risk.”

Aerogen is the nebulizer manufacturer that developed the world’s first approved inhalable COVID-19 vaccine with biopharmaceutical company CanSinoBIO, which has been used on more than 30 million patients since 2022. Delivering that vaccine via inhalation needs just one-fifth of the dose used for an intramuscular injection, which means pharmaceutical manufacturers can inoculate five times as many people.

“It’s going to open the floodgates for us, because we know that inhaled vaccines work,” MacLoughlin said.

There’s much left to learn about inhalable vaccines, but MacLoughlin said his team has invested years and more than $150 million to get a head start on the devices that will deliver these next-gen drugs.

“Given the school of hard knocks and the lessons we learned in our trials that didn’t do particularly well, as well as all the lessons that we’ve taken from device development at scale, drug-device-combination development and learning everything there is to know about aerosols and aerosol generation — we have 600 patents, and we have hundreds of clinical papers and bench studies that underpin our technology — we can now apply that to the vaccine space,” he said. “We’re unparalleled in that regard.”

Designing drug-delivery devices for next-gen vaccines

Inhalable vaccines have been studied for more than half a century, with research showing the potential for more efficient and effective inoculation. Until recently it’s just been easier and less expensive to administer vaccines orally or with an injection.

But fear of needles is estimated to cause a significant share of people to avoid intramuscular injections, and in the early days of the COVID-19 pandemic, manufacturing capacity and cold chain distribution limited the supply of vaccines approved in the U.S.

Taking the inhalable route, CanSinoBIO asked Aerogen for billions of its nebulizers at a price that wasn’t possible. Instead of developing a less expensive single-use nebulizer to deliver the new vaccine, Aerogen built a system to reuse the same nebulizer for hundreds or thousands of patients by dispensing the inhalable vaccine into a disposable plastic cup with a custom-designed lid.

“The reason we went with a cup is because it was globally available. We didn’t need to make that and we don’t want to make that. … We will sell you our delivery system, but the cups — here’s the instructions. Make them yourself,” MacLoughlin said. “… It’s not just any old sippy cup. There’s a lot of engineering, a lot of IP around this. We did a huge amount of work and generated a lot of data very quickly. I could make subtle changes to it and make it a terrible device.”

The smaller dose required for inhalable vaccines is another factor that lowers vaccination costs, not only for R&D but for scaled manufacturing and distribution.

“When you’re getting five times as much out of a single facility because you’re getting that protection when you inhale it at one-fifth the dose, that opens up a whole new route,” MacLoughlin said. “I’m heavily involved now with a number of vaccine companies working on inhaled clinical studies and development and moving toward inhaled vaccine studies, and they can now spend money on doing the necessary validations to get to that first-in-human as opposed to trying to make loads of it beforehand.”

Vibrating mesh nebulizers — as opposed to ultrasonic nebulizers — can nebulize and fully deliver doses as small as 5 microliters with specific droplet sizes for diseases where droplet size matters.

“Influenza binds to sialic acid receptors — α2-6, α2-3, and α2-8 receptors — in your airways: α2-6 is primarily in your upper airways and some in the alveolar region, and α2-3 is really only in the lower airways, the alveolar region. So if you have an influenza that preferentially binds to α2-3, there’s no point in delivering to the upper airways. You have to get it into lower areas to bind and elicit that immune response,” he said. “That’s if it’s receptor-bound. For something like tuberculosis, you’re looking to see T cell response and need to get it to where those T cells are. Depending on a huge number of different factors, that could be upper, lower or just everywhere.”

There are pediatric design considerations as well. Researchers are studying the best route for RSV vaccinations in babies, which primarily breathe through their nose.

“No matter what droplet size you put in there, their nose is going to filter out the bigger droplets, and all that’s going to get into their lungs is the small droplets,” MacLoughlin said. “So if you can start small, you bypass the losses in the upper airways and get down into the lungs.”

Inhalable vaccines have potential applications beyond respiratory diseases. Vaccines inhaled and delivered to respiratory mucus can confer immunity to mucosal surfaces elsewhere in the body, like the GI tract.

“Diabetes, cancer, the number of diseases that are vaccine-preventable or -treatable is ginormous,” MacLoughlin said. “The inhaled route may not be suitable for them all. However, they all have potential. And the beauty of it is you can get away with a very small dose. … We know that you can get infected with influenza with as few as 10 individual viral particles being inhaled. So in theory, you could get away with as few as 10 vaccine particles to give you that protection.”

“We are just at the beginning of a very exciting era,” he continued. “We now know what can be done, we know it can be done at scale, we know the technology exists where if we come up with this wonder vaccine it can actually be delivered.”

Related: Nasal vaccine device design and regulatory need-to-knows

‘Collaborate or die’

MacLoughlin recounted helping a team working on a pneumococcal vaccine after their trials told them an inhalable drug wouldn’t work — or so they thought. He asked what device they used and if they had one handy, and when he turned it on he almost immediately felt the heat it generated.

“What they’d used in the clinical trial cooked the vaccine. … There’s so many learnings that that vaccine developers haven’t had to think about. I think now we’re having these conversations more and more that we’ll certainly be in a position where we’ll see a lot more momentum in the next couple of years. … Maybe you’re looking for disease mitigation or injury mitigation or maybe just looking for transmission reduction. There’s so many levers that we can pull, and we’re still trying to figure out what the levers do.”

More than ever, device and drug developers will need to consider human factors. MacLoughlin pointed to Mexico’s inhalable measles vaccine campaign in the 1980s.

“It was a thundering success, an amazing success,” he said. “All these kids got full protection. The device, however, was not fit for purpose [because] this particular device needed an air compressor that was really only ever found at car mechanics. … What you’re looking for is reliable, reproducible delivery of whatever it is in the real-world setting.”

That might mean systems powered by solar or hand cranks for areas without reliable electricity, equipment that can be easily assembled out of low-cost materials like cardboard, or automation that minimizes the risk of a doctor or patient incorrectly administering the vaccine.

“You need to maintain flexibility because not everywhere is in the First World, not everywhere has power, not everybody can read,” he said. “Your usability, your user and human factors come into it in a huge way [to ensure] your product is ultimately going to be used.”

Five years after the COVID-19 pandemic started, MacLoughlin recalls device development insights from unusual places, like a wind turbine manufacturer that wanted to manufacture a basic ventilator when they were in short supply.

“Those guys had a completely different view on things and some of the assumptions and thinking that they brought to their project, we were able to apply to other projects,” he said.

Even his own son, Eoin, contributed to inhalable vaccine research when he was just 5 years old by designing a simple mask for testing inhalable drugs on pigs.

“Pig models are very, very good for humans because we share a very similar immune response and airway geometries — way better than mice and ferrets and rats and golden hamsters and all that, which are valuable but not as good,” MacLoughlin said. “Eoin designed a face mask that’s been used in hundreds of trials now for pigs, teasing out the understanding of how inhaled vaccines work or don’t work.”

“The lesson from that is you don’t need to be a genius, you don’t need to be any more than 5 years old,” he continued. “You just need to be able to sit down and logically think through something and be willing to accept feedback. Collaborate or die.”

Related: This simple, needle-free COVID vaccination device might stop transmission