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People might tolerate a needle if it means getting a life-saving vaccine — but odds are, swallowing a pill sounds better. “People can say they don't care about shots and whatnot,” says Harvinder Singh Gill, an immunoengineering scientist at Texas Tech University. “But if given the option, I'm sure everyone will say, hey, why would I take a shot if I can eat the vaccine, right?”
The potentially universal appeal of an edible vaccine has a small number of researchers like Gill pursuing the option. Teams of scientists are designing pods and stickers that would free people from skin pricks. An oral vaccine would eliminate the anxieties people have about needle injections and would let people enjoy the benefits of a primed immune system from the comfort of their own couch: Just bring the pill home with you and take as directed. As dreamy as that future sounds, edible vaccines will only become a reality if researchers outsmart the corrosive, defensive and destructive environment called our digestive tract.
The Gut Is Too Good at Its Job
To most people, an edible or oral vaccine sounds appealing just with the words "needle-free." As much as 10 percent of the population could have enough fear and anxiety around needles as to prevent them from having a calm interaction. But even after the vaccines are swallowed, the benefits of ingestible options could keep coming. Ideally, this vaccination style builds a defense against the virus in our mucus — the part of the body many pathogens interact with first. When we get sick with the seasonal flu or COVID-19, the thick goop coating our nose, throat, mouth and stomach deploys its own class of antibodies against the virus, targeting the invader and keeping it from interacting with our cells.
Vaccines administered into our arms don’t prioritize pushing those mucus antibodies into action. Also, researchers typically evaluate how effective vaccines are by searching for a different kind of antibody that circulates through a range of body fluids. While those antibodies float around in mucus too, the versions specific to our gut-lining goop are what some researchers call the “hallmark” of a solid mucus immune defense. Vaccines that target mucus-like nasal sprays reliably bulk up the mucus-only antibody as well as the version found elsewhere in the body. “If we are successful in making an oral vaccine, we should be able to get the mucosal immune response and the systemic immune response — both,” Gill says.
As Gill says, there are some serious benefits of having ingestible vaccines, provided developers make them happen. But there’s a lot about the gut that makes delivering a vaccine via this route challenging. For one, our digestive tract, well, digests. “Our gastrointestinal tracts have evolved to digest food,” says Giovanni Traverso, a gastroenterologist with Harvard Medical School and an engineer at MIT.
Strong acids and digestive agents called enzymes act together to break down proteins and any DNA in what we eat. Vaccines are made of the same materials. “The body doesn't care whether you want this particular protein to be destroyed or not,” Gill says. “It's going to do its job very effectively.”
If the vaccine can make it through enzymes and acids unscathed, the next challenge is breaking into the cells that line our gut to kick off the immune response. Mucus — the goopy blockade normally so useful for defending cells from pathogens — becomes a physical barrier the vaccine has to get through. Also, the cells of our intestines resist accepting any larger molecules. It’s their job to accept nutrients in their simplest, smallest form, not entire, clunky proteins.
So far, vaccines against only four different pathogens have cleared these hurdles and come in digestible forms: cholera, polio, rotavirus, and typhoid. All four rely on a killed or partially broken version of the pathogen to provide immunity. Viruses have the equipment necessary to push their way into cells — that’s how they infect people — and can manage their usual tricks in the digestive tract too, Gill says, which is why they work in edible vaccines. Rarely, the semi-damaged virus in these vaccines is still whole enough to accidentally infect the recipient and make them sick. Though the risk of this outcome is small, it motivates oral vaccine developers to find other technologies that deliver immunity through the gut.
The Trojan Horse
Both Traverso and Gill have taken on that design challenge and hope to introduce the perfect vaccine package: One that survives (or dodges) our digestive system to deliver the immunity-creating molecules into our cells.
Gill and his lab are focusing on swallowable, vaccine-filled pollen grains. For those with a ragweed allergy, don’t worry — the team cleans out the allergy-inducing molecules inside the pollen. What’s left is the harmless shell, Gill says, that also happens to stick to mucus and could linger in the digestive tract, giving cells a better chance of scooping them up. “That’s the concept we are using in the lab,” he says. “To use clean pollen shells, fill them up and almost use them like Trojan horses to deliver the vaccines.” Feeding the pollen to mice has shown that the shells last in their small intestines for at least a full day.
While Traverso and his team aren’t plucking their ingestible drug packages from nature, one option is inspired by wildlife: A tiny, rolling capsule with a flat bottom that, like a tortoise, ultimately orients itself right-side down in the stomach. After the capsule settles and injects the contents — which for now, is insulin — it passes through the rest of the digestive system. The lab is also investigating delivery options that stop short of dealing with the entire gut and just stick to the mouth, literally. Small patches full of microneedles that adhere to the roof of the mouth could dodge the issues with typical injections but avoid interactions with destructive digestive juices.
The concepts Traverso and his team are working on only deliver insulin right now. Vaccines aren’t the only needle-based health care that could benefit from a redesign — hormones and other medications also require injections that people might prefer to avoid. But the team has already worked through mouse and pig models with some of their insulin delivery techniques and is looking towards human trials, and a few of the designs might be modified to also deliver vaccines one day, Traverso says.
Moving on to later phases of development means talking about manufacturing and other logistical questions, conversations Traverso and his team are having with new colleagues. Because these kinds of ingestible or oral drugs are relatively new, Traverso says there isn’t much information available about consumer acceptance.
Pharmaceutical companies, however, might prove challenging to win over. When it comes to vaccines at least, the industry has a regular, reliable way of delivering the protective agents to recipients. If someone is trying to convince manufacturers to stray and produce a vaccine people can swallow, the proposal better transform what companies can currently provide, Gill says. An edible vaccine for a disease which currently has no vaccine might be enough — if someone can do that, “I think they will be golden,” Gill says. “They can win it.” Otherwise, developing an ingestible vaccine that’s as effective as or even slightly cheaper to produce than syringe varieties might not be compelling enough for companies.
However, a unique vaccine approach isn’t destined to languish in research labs forever. Katalin Karikó, the researcher who thought that vaccines could rely on snippets of genetic code and coax cells into making virus proteins, spent decades getting rejected. Now, two of the vaccines helping end the pandemic rely on her once “out there” idea.