It sounds like a dream: Prevent or reverse type 1 diabetes with a simple shot rather than face a lifetime of insulin injections. The idea of a vaccine for type 1 has been around for decades, but a truly effective treatment has remained just out of researchers’ grasp.
To better understand the search for a vaccine, it might help to remember what we know about how type 1 works in the first place. At its most basic, type 1—once known as juvenile diabetes because it tends to show up in childhood—is a matter of the body turning on itself.
The immune system is a vital part of our survival in a world filled with bacteria, viruses, and toxins that would like nothing more than to infect and even kill us. When specialized immune cells sense an invader, they attack, destroying the foreign cells.
In rare cases, the immune system goes haywire and mistakes the body’s own cells for invaders. Known as autoimmunity (in ancient Greek, “auto” meant “self”), these misguided assaults are responsible for a host of different diseases. Celiac disease, rheumatoid arthritis, lupus, and alopecia are all autoimmune afflictions.
Type 1 diabetes—which affects about 1.25 million Americans, and millions more around the world—is one of the best-known autoimmune diseases. It’s caused when the immune system mistakes beta cells, the specialized cells in the pancreas that produce insulin, for invaders. Over time, the immune system destroys the beta cells, and with them the body’s ability to produce insulin. Until the 1920s, when researchers discovered how to extract insulin from animal pancreases and inject it, type 1 diabetes was a death sentence.
A vaccine that would teach the immune system not to react to the beta cells would potentially prevent people from developing the disease, if they were given a vaccine early enough. Over the past few decades, researchers have identified molecular-level warning signs that the body is getting ready to mount its attack before the disease’s symptoms appear, making it possible to screen high-risk individuals and test preventive medicine (so far, none of these research studies have been especially promising). Another possibility is that a vaccine could halt or reverse beta cell decline in people who already have type 1, reducing their need for insulin injections.
Reversal of Fortune
Here’s how it might work: Immune cells that target a specific adversary, called antibodies, are the front line of the immune system’s defenses. Most vaccines work by encouraging the body to produce antibodies for specific diseases. When you get your flu shot, for example, a disabled version of the flu virus is injected. This gives the immune system the ability to fight off a future, active flu threat.
When it comes to a vaccine for type 1, the basic concept amounts to a simple reversal of how most vaccines work: Rather than training the immune system to seek out harmful invaders, the ideal type 1 vaccine would train the immune system to stand down. A vaccine would teach the immune system that beta cells are harmless and would discourage production of antibodies that target them.A
The idea of vaccination goes back centuries. At its root is a basic observation: For certain diseases, people who survived their initial illness never caught it again. Smallpox, for example, was once one of the world’s most deadly diseases: Epidemics swept across Europe once every decade or so.
Early doctors would blow dried smallpox scabs into a healthy person’s nose, giving them a mild form of the disease that was less likely to kill. But the procedure was still risky and seemed counterintuitive: Why give someone a disease to keep them from getting it?
Looking for a safer solution, a British doctor named Edward Jenner noticed that one group of people seemed naturally immune to smallpox: milkmaids. The common theme was that they were regularly exposed to cowpox, a close cousin to smallpox.
To test this, Jenner injected material from a milkmaid’s cowpox sore under the skin of a healthy 8-year-old boy. Later, he injected the boy with smallpox, to no effect. Though he didn’t understand exactly why, Jenner concluded that the cowpox had protected the boy and called the procedure “vaccination”—based on the Latin word “vacca,” or cow. The last known case of the disease was in 1977. Today smallpox is considered completely stamped out worldwide.
Type 1 Research Lab
As with most vaccines, type 1 vaccine research primarily focuses on how to prevent people from getting the disease in the first place. By that measure, the trial Denise Faustman, MD, PhD, is running at her Massachusetts General Hospital lab in Boston stands out. Her research is focused not on people about to develop full-blown type 1 diabetes but on people who have had the disease for five years or more.
Faustman and others think that a hormone called tumor necrosis factor (TNF) might have something to do with the immune attack on beta cells. The hormone is known to ramp up production of good T cells and reduce the production of “bad” ones that tend to target the body in autoimmune attacks. “We worked on the basic science of type 1 and realized they had a deficiency of TNF,” Faustman says.
Looking for a safe and effective way to raise TNF levels in people with type 1, Faustman noticed that a familiar drug encourages the body to produce more of the hormone. It’s known as Bacillus Calmette-Guerin, or BCG, and was developed by French researchers in the 1920s as a vaccine for tuberculosis. Since then, it’s been administered 4 billion times. It’s no longer used in the United States or Europe because TB is so rare in the developed world, but last year 100 million newborns in the developing world were given BCG. “It’s generic and affordable,” Faustman says. “And safety? We’ve got it nailed.”
Studies in Turkey provided a hint that BCG could play a protective role: Repeated doses of BCG seemed to prevent the onset of type 1. In an early BCG trial in Massachusetts, patients who got standard doses of the tuberculosis vaccine showed increased levels of TNF, which seemed to eliminate the T cells responsible for attacking insulin-producing beta cells. “BCG is definitely modulating the immune system,” Faustman says.
Even better, having more TNF seemed to relieve some of the pressure the immune system was putting on the surviving beta cells. While it didn’t restore full function, it did have a measurable effect on insulin production and resulted in lower blood glucose. “Preserving or restoring even a little beta cell function might be beneficial,” Faustman says.
The big question now is how and when BCG is most effective. Over the next five years, she’ll be working with 150 people divided into three groups. One group will get a placebo, while the other two will get six BCG injections in different amounts and on different schedules. At the end of the trial, Faustman will compare the three groups to see if BCG worked.
If it did, the next step would be to figure out what doses worked best—and to make the treatment more widely available.
Faustman’s lab gets calls every day from people wondering if they should be giving their kids BCG now. The answer is no, for several reasons: Faustman’s original BCG trial involved only six participants, so results from her larger study are needed before the approach is deemed effective. And there’s no way to know what dose to use until more research is done.
On top of that, since BCG is no longer used as a vaccine in the United States, it’s not available in a Food and Drug Administration–approved form. Giving kids BCG off-label without more information on proper dosage “is a bit like giving insulin without a blood sugar measurement,” she says. “Not a good idea.”
The Taste Test
Ezio Bonifacio, PhD, and Anette Ziegler, MD, are a husband-and-wife diabetes research team based in Germany. They have decades of experience between them investigating the onset of type 1 diabetes. The couple has helped develop techniques to assess diabetes risk based on the presence of specific autoantibodies, components of the immune system that target insulin and beta cells.
Knowing a child is at risk isn’t enough, though. Now they’re working on a vaccine. “We need to find ways to lower the chance that genetically at-risk children develop bad immunity,” says Bonifacio, a professor at the Center for Regenerative Therapies in Dresden, Germany.
That’s because once the immune system reaction begins, it may be too late to reverse the disease. “Once the autoimmunity starts, it’s going to go to diabetes,” Bonifacio says. “We think the immune system hasn’t learned beforehand to stay away from the beta cells and insulin.”
Their goal: identify kids at risk for type 1 diabetes and literally feed them insulin in an effort to short-circuit the disease. The idea has a lot in common with recent research into allergies, particularly peanut allergies.
Doctors once thought that babies and toddlers should be kept away from peanuts to prevent allergies. Based on a series of studies in Israel, however, it looks as though that was the wrong approach. Kids raised in a peanut-free environment were at least 10 times more likely to develop peanut allergies later in life than kids who were exposed to peanut products from a very young age. “For a long time, we thought you’ve got to avoid exposure. But in fact you have to be exposed, and in the right context,” Bonifacio says.
That may be thanks to something called “oral tolerance,” the idea that the immune system is unlikely to respond aggressively to things it first encounters in the mouth or digestive system. The vast majority of the foods we eat provoke no reaction from the body. “We’re allergic to a very, very small number of things we eat,” Bonifacio says.
Bonifacio and Ziegler hope that introducing the immune system to insulin orally will teach it that insulin is harmless before there is an assault on the beta cells. “If you constantly expose the immune system to things in a friendly environment, it learns it shouldn’t go bad,” Bonifacio says.
To do that, they’re feeding insulin to 44 infants and toddlers at high risk for developing type 1 as part of a study called Pre-POINT Early. Their parents are given capsules to mix into their food once a day for a year; half of the kids get a placebo and the other half get insulin.
A previous study called the Diabetes Prevention Trial of Type 1 Diabetes (DPT-1) tried a similar technique in relatives of people with diabetes who had already developed autoantibodies against their beta cells. The trial showed no appreciable results overall, although there were hints of protection in a small group of participants. In comparison, the German Pre-POINT studies are treating children before they show any signs of autoimmunity and use much higher doses of insulin, in some cases nearly 10 times what the children in the DPT-1 trial were given.
In a 2009 to 2013 pilot study of 25 kids, they showed that oral insulin doesn’t enter the bloodstream so it doesn’t cause hypoglycemia. The new study will look at the same phenomenon in a larger sample. “We need to validate the safety and have evidence that the immune system sees this in a nice, healthy way,” Bonifacio says.
If their oral insulin approach works, the next step is to set up a reliable screening process and test the procedure for a longer period—four years, plus four years of follow-up. They hope to have conclusive evidence that oral insulin is a workable vaccine within 10 years.
The Inflammation Angle
University College London researcher Mark Peakman, PhD, is approaching the vaccine problem from a different angle. He’s interested in inflammation, the irritation that accompanies an immune response like the one unleashed in type 1 diabetes. It may play a role in tipping the balance from “at risk” to type 1 diabetes. “I expected patients to have an inflammatory response that drives the disease,” he says.
Peakman noticed that occasionally one of his patients would show up with an immune response accompanied by anti-inflammatory reactions, as though the immune system was trying to put a fire out rather than light it. The patients who had this response still developed type 1 diabetes, but on average their onset was eight years later than people with the classic inflammation.
Intrigued, Peakman made beta cell fragments in a lab, realistic enough to trigger a reaction but stripped of components that might signal a more severe inflammatory response. In a trial study, he injected the beta cell fragments into people with recently diagnosed type 1 diabetes. The hope is that the fragments will get the immune system used to beta cells and coax the immune system out of attack mode. “It’s about desensitization, like we do in allergy,” he says.
In a slightly larger study, Peakman is working with 24 patients, divided into three groups: One group gets a placebo, and the other two are given the beta-cell fragments repeatedly in differing doses. The study participants have all recently been diagnosed with type 1, and all have some beta cell function left—which means they are still able to make some of the insulin their body needs.
The hope is that this approach can slow or stop beta cell decline. And because they already have type 1, the participants are good test subjects. “In terms of risk-benefit, they’ve already lost a lot of their beta cells,” Peakman says. Although the study has the potential to hasten beta cell failure, it’s not causing it.
Peakman has been encouraged by the initial results. “The numbers are very small, but we see interesting signs” that beta cell function is returning, he says.
After decades of research, the promise of a type 1 vaccine remains just that—a promise. Whether research is directed at restoring some beta cell function to people who have had type 1 for years or heading off the disease’s onset altogether, the potential is intriguing. But even the most optimistic researchers say it will take lots more work—both in the lab and in the clinic—before that promise is a reality.
For people who have been living with diabetes for a while, promises of a vaccine may sound familiar. That’s because researchers have been searching for one for decades. Every so often, an exciting announcement is followed by disappointment.
In 2003, vaccine expert Nikolai Petrovsky, PhD, a professor at Australia’s Flinders University, counted vaccines among the most promising strategies to prevent type 1 diabetes. Fast-forward 13 years, and Petrovsky says that promise hasn’t been fulfilled.
“Reviewing the literature, it’s hard to see where things have moved forward,” he says. In study after study, encouraging initial results have fizzled when tested on a broader scale, or the ability to avoid insulin injections have been very short lived. “The obsession with finding an immediate cure has diverted resources from attempts to get to the bottom of the science underlying type 1 development,” he says.
Petrovsky argues that when type 1 vaccine attempts don’t work out, they waste research funding. They’re often heavily hyped, and when they fail, they dash the hopes of people with diabetes. An even bigger risk is that an approach that could lead to a cure might be abandoned prematurely because it doesn’t show results fast enough, or because the vaccine doses are too small to be effective. “When these studies fail, researchers don’t get a second chance,” Petrovsky says. “Funders just jump on the next bandwagon.”
But Ezio Bonifacio, PhD, a professor at the Center for Regenerative Therapies in Dresden, Germany, is one of many researchers who say an incomplete picture of how type 1 works shouldn’t prevent people from working on vaccines.
And even Petrovsky remains cautiously optimistic, despite his disappointment that the field has not moved forward faster. He says a successful type 1 vaccine is probably achievable—but it might take another 15 to 20 years. “My team has not given up hope and continues to quietly pursue a type 1 vaccine, while being careful not to make unrealistic promises to our patients that any cure is imminent,” he says.