Goodbye syringe? Measles and rubella patch demonstrates its worth in Gambia vaccine trial

Jul 04, 2023

Painless, easier to administer and more thermostable than traditional vaccines, microarray patches are being touted as the future of vaccination in low-income and pandemic settings.

To the untrained eye, it looks like a small round sticking plaster – the sort you might be given after a routine blood test. Pressed onto the skin, the patch feels rough, but not uncomfortable; as if someone had pressed a piece of Velcro against you. "People don't describe it as being painful, and they will certainly overwhelmingly prefer it over an injection," said Prof Mark Prausnitz, director of the Center for Drug Design, Development and Delivery at Georgia Institute of Technology in Atlanta, US.

Welcome to the future of vaccination, where these lifesaving interventions are delivered painlessly, without the need for syringes or perhaps even trained medical professionals. This week, Micron Biomedical, which Prausnitz co-founded, announced positive Phase 1/2 data from the first-ever clinical trial of a vaccine patch in children – including infants as young as nine months old.

The study, which evaluated the impact of delivering the standard measles-rubella (MR) vaccine in this way, found that the vaccine was safe and well tolerated, with no allergic reactions or related serious adverse events. Immune responses triggered by the vaccine were similar, regardless of whether it was delivered via a patch or traditional subcutaneous injection – while more than 90% of parents whose children were enrolled in the trial said that patches were a better way to give vaccines to children.

"These are exciting results which show, for the first time, the potential for microarray patches to safely and effectively deliver vaccines to children," says Prof Ed Clarke, Head of Infant Immunology at Medical Research Council, The Gambia, who led the study.

The results were presented at the 7th International Conference on Microneedles in Seattle, US on 17 May 2023.

Trials for vaccine patches against COVID-19, seasonal influenza and hepatitis B are also ongoing, while patches against HPV, typhoid and rotavirus are in preclinical development.

Studded with microscopic projections that deliver vaccine to the top layers of the skin, vaccine microarray patches could overcome many of the logistical challenges hindering vaccination efforts. Whereas liquid vaccines require constant refrigeration to remain effective, as well as trained professionals to inject and then safely dispose of the syringes, patches are designed to be more thermostable, easier to transport, and can be applied with minimal training. Some evidence even suggests they may stimulate a stronger immune response than traditional vaccines, potentially at a lower dose – meaning vaccine supplies could stretch further.

"This technology has revolutionary potential for extending the reach of vaccines in low resource settings and during pandemics," said David Hoey, president and CEO of Vaxxas, a biotechnology company based in Brisbane, Australia, which currently has patches against measles and rubella, COVID-19 and seasonal influenza in human trials.

Weighing between 3.5 and 10 kilograms (7.5 and 22 pounds), and with a surface area of 1.5 to 2 square metres, our skin is the heaviest and largest of our organs. It is also our main interface with the outside world, so many immune cells are stationed within its layers to keep us safe.

Among them are dendritic cells – potent antigen-presenting cells that direct the responses of T-cells in the lymph nodes. T-cells are a major target of vaccines, because they can remember antigens that they have previously encountered. But although humans have been applying salves and potions to the skin for millennia, it wasn't until the 20th century that scientists began to deliver drugs through it.

In 1979, the world's first transdermal patch began to be marketed for the treatment of motion sickness. It was designed to deliver a sustained dose of the drug Scopolamine through the skin. Others followed, but because the skin is such an effective barrier, only certain types of molecules can be delivered this way. Because of this, scientists began to search for alternative methods.

Prausnitz began his career investigating the use of electric currents to temporarily disrupt the skin's structure to aid drug delivery, but doing so came with side effects such as twitching and pain, because it also stimulated underlying nerves.

This is when he first hit upon the idea of a microneedle: "The needle is very powerful; it can penetrate and deposit a drug or a vaccine very effectively, but it also has limitations in terms of the expertise needed to use it, to safely dispose of it and so on," said Prausnitz. "But the barrier layer in the skin is thinner than the thickness of a hair, so you don't necessarily need a big needle; a small needle could, in principle, do the job."

Yet, manufacturing microneedles wasn't straightforward. "A real issue was that the people in the microfabrication world weren't really involved with drug delivery and medical applications, while the people who knew about pharmaceuticals and drug delivery didn't know how to make microneedles," Prausnitz said.

Moving to Georgia Institute of Technology in Atlanta, US, in 1995, he began working with microfabrication experts who drew on techniques developed in the computer chip industry to manufacture projections that were tiny enough to achieve the goal of delivering vaccines into the skin.

The next challenge was finding ways to incorporate active ingredients into these microneedle patches. Whereas traditional vaccines tend to be formulated as liquids and stored in glass vials, vaccine patches must either be coated in a dried vaccine formulation, or the ingredients integrated into projections that dissolve upon contact with the skin.

"The formulation not only has to be compatible with the vaccine, it must also be compatible with the microneedle. You need something that is mechanically strong, which is a new constraint for us," said Prausnitz. "Achieving this has been a lot of work and is very much customised for each vaccine. Each one needs its own formulation to incorporate it into the patch, get the right dose and stabilise it at least sufficiently to be stable under refrigeration – and ideally without refrigeration."

Even so, recent achievements suggest that these challenges aren't insurmountable. Micron Biomedical grew out of the technology Prausnitz and his colleagues developed at Georgia Tech. Based in Atlanta, US, is one of two companies that currently have vaccine patches in clinical trials, the other being Vaxxas.

In 2017, Micron published a study in The Lancet, investigating the safety, immunogenicity, and acceptability of delivering a seasonal influenza vaccine using a dissolvable microneedle patch versus intramuscular injection. It suggested that the immune response was similar. The most common reported side-effects were mild tenderness and redness or itchiness around where the patch had been applied. "I think that gave people a lot of confidence that you could make a vaccine microneedle patch and that it could really work," Prausnitz said. "I'm hopeful that the measles and rubella vaccine trial is going to move the field forward even more."

Launched in 2021, the trial set out to investigate the safety, tolerability, and immunogenicity of delivering the standard measles and rubella vaccine using Micron's technology, compared with standard subcutaneous injection, in 45 adults, 120 toddlers and 120 infants. "Generally, parents were very positive about the ability to vaccinate their young infants without a needle," said Steven Damon, Micron's Chief Executive Officer.

Measles and rubella vaccination is a prime example of an intervention that could significantly benefit from a vaccine patch-based approach. Even though a safe, affordable and highly effective vaccine is available, in 2018, there were more than 140,000 measles deaths globally. "Mostly, it is a matter of people being in locations where they don't have access to health care resources and as a result, they don't get vaccinated," said Prausnitz. "If we can have a vaccine that doesn't require a nurse to administer it, [and] can get it at least partially out of the cold chain so that we can get it to locations that may not have reliable electricity and refrigeration, we are hopeful that this could bring the vaccine to many more kids."

Vaccine patches could also be useful in the event of another pandemic. One of the biggest roadblocks to getting COVID-19 vaccines to everyone who needed them quickly was having enough doses. But several studies have now suggested that vaccine patches can induce comparable immune responses to injected vaccines – only using less antigen. For instance, according to a study published in PLoS Medicine in 2020, an influenza vaccine delivered using Vaxxas' technology required only a sixth of the dose of the injected vaccine to elicit a similar response. Smaller doses could mean limited vaccine stocks are able to stretch further. Another advantage is that rollout of vaccine patches wouldn't rely on ancillary supplies such as vials and syringes, which also experienced stock-outs during the COVID-19 pandemic.

In February 2023, Vaxxas launched a phase 1 study of a related influenza vaccine delivered using the same technology in 150 adults. Separately, it recently published data suggesting equivalent performance when its vaccine patches were administered by a trained professional or self-administered.

"If you can self-administer, you could potentially use services like the US Post to deliver a vaccine dose to every household," Hoey said. Doing so might further hasten the rollout of vaccines, as well as avoiding the need to attend crowded vaccination centres, where people risk getting infected.

As highlighted during the COVID-19 pandemic, cold chain, or even ultra cold chain storage was a big barrier to delivery of COVID-19 vaccines in certain countries. Vaxxas' influenza vaccine remained stable when stored at 40°C (104°F) for at least 12 months: "It would never need to see a fridge," said Hoey.

Stabilising influenza virus antigens on a vaccine patch is one thing, but mRNA-based vaccines are expected to play a major role in the early response to future pandemics – as they did during COVID-19 – because they can be designed and manufactured faster than traditional vaccines. The downside is they need to be stored at ultra-cold temperatures, limiting their use.

To try to overcome this obstacle, the Coalition for Epidemic Preparedness Innovations (CEPI) is providing Vaxxas with up to US$ 4.3 million to advance development of microarray patches for mRNA-based vaccines.

According to Hoey, they have already managed to tweak the lipid nanoparticles that encapsulate the mRNA molecules in a way that makes them "much more friendly for thermal stability". However, "I think we're probably more excited about the next generation of constructs – ones that will either be derivatives of lipids, or completely different from lipids," he said.

Even then, it is unlikely that vaccine patches will entirely replace syringe-based vaccines, at least in the short term. "There's been a lot of a lot of money put into designing those vaccines, building the manufacturing facilities and distribution channels, and a lot of experience with their safety and efficacy," says Prausnitz. "There has to be a pretty compelling reason to take a vaccine that's already being successfully used, and to invest and take some risks in changing it."

For measles and rubella, that argument has been largely won. The seasonal flu vaccine could be another strong contender. Unlike most vaccines, it is usually offered as an annual shot, meaning people must repeatedly make the effort to go out and get it. They might be more motivated to do so if that vaccine was painless, and they could administer it themselves. Although injections are among the most common medical procedures, fear of needles is common – and a recent study estimated that some 16% of adults avoid influenza vaccination because of it.

Hoey is more optimistic about the longer-term prospects for syringe-free vaccines. "In high income countries, perhaps 15 to 20 years from now, I think all vaccines are going to be given by patch," he says. Assuming they really do require lower doses of vaccine ingredients, and can be manufactured efficiently, it may be more profitable for companies to put their vaccine on a patch rather than in a syringe, he explains. "Once you are in the market, you also have patient preference. Scientifically, it's smarter, but the driver will end up being economics."

Few people look forward to getting jabbed with a needle, or comforting a screaming baby who has just been vaccinated – although most still go ahead with it for the health benefits it brings. But if vaccine patches really do prove to be as safe and effective as injected vaccines, would anyone really mourn the death of the syringe?