By Thania Benios
In the 19th and early 20th centuries, diphtheria, measles, and mumps were frightening household names. Each year in the United States, these illnesses struck hundreds of thousands of people, and claimed up to tens of thousands of lives. Children were especially vulnerable to the bacteria and viruses that led to such staggering loss of life. Today, however, these infectious diseases are all but forgotten, thanks to one of medicine’s most powerful and cost-effective weapons: vaccines.
The Juvenile Diabetes Research Foundation is now trying to leverage the power of vaccines to prevent another disease: type 1 diabetes, which causes the immune system to turn against the normal, healthy insulin-producing beta cells of the pancreas. This autoimmune attack progresses silently for a time but eventually leads to a drastic shortage of insulin, a hormone that is needed for cells to use blood sugar for energy. The loss of the beta cells results in high blood sugar levels, which is why people with the disease must inject insulin multiple times every day to stay alive and to stave off complications such as eye disease and kidney failure.
New insights into the workings of the immune system and how it interacts with beta cells have given scientists an unprecedented vantage point from which to develop a diabetes vaccine. JDRF’s vaccine research portfolio now supports two dozen preclinical research programs and four clinical trials, with projects ranging from delivering diabetes vaccines in genetically-modified lettuce, to packaging diabetes vaccines in nanoparticles and delivering diabetes vaccines as a component of dying cells.
“When we looked at the field three to four years ago, we decided that developing a diabetes vaccine was a direction we needed to go,” says Richard Insel, M.D., chief scientific officer at JDRF. “We have begun to fund both early-stage discovery research and later-stage translational research to support the discovery and development of many different diabetes vaccine candidates with distinct mechanisms of action, hoping that one or more of these will prove successful.”
Type 1 diabetes begins when the immune system mistakesthe beta cell as a foreign invader and destroys it in a misguided attack that reflects a loss of immune tolerance for the body’s own cells. A diabetes vaccine would help restore this tolerance by re-educating the immune system to recognize the beta cell as a natural part of the body. “Inducing immune tolerance is the holy grail of immune therapies,” says Insel. “Vaccines not only have the potential to restore immune tolerance, but also to prevent it from being lost in the first place.”
Over the past two years, JDRF has prioritized the development of beta cell antigen-specific tolerogenic diabetes vaccines. These are vaccines which specifically target one or more of the beta cell proteins recognized via the specific autoimmune process associated with type 1 diabetes. Antigen-specific vaccines work like traditional vaccines developed for infectious diseases like the measles, but in reverse. Instead of teaching the immune system to attack an unwanted invader that it may or may never encounter, the vaccine teaches the immune system not to attack something it encounters every day: the body’s own cells.
So far, researchers have identified four molecules within beta cellsGAD65, ZnT8, IA-2 and insulin—that the immune system attacks in type 1 diabetes. It is thought that, at first, the immune system targets just one of these molecules. However, as the disease progresses, the immune system can start to attack all four. Ideally, a vaccine could be given at the earliest stages of the disease, before the autoimmune process progresses or before it even starts. “If we can get ahead of it,” says Insel, “we may be able to prevent the immune attack from becoming too aggressive and destroying too many beta cells to cause insulin dependence and overt diabetes.”
Because the attack of the immune system in type 1 diabetes may affect varying molecules or a number of molecules within beta cells, a vaccine that works for some people may not work for others, explains Bart Roep, Ph.D., an immunologist and a professor at Leiden University in the Netherlands, who is an advisor for several clinical trials that are testing antigen-specific vaccines. “We know that different antigens are recognized by different individuals, so a vaccine that targets a very specific antigen may only work for a subset of people,” says Roep. “The hope is that we can get a vaccine that can work for everybody using a one-size-fits-all strategy, but this remains difficult because type 1 diabetes is such a heterogeneous disease.”
If the development of such a one-size-fits-all vaccine proves successful—in terms of both efficacy and safety— it could be given preemptively to all children early in life, and would essentially be a “cure” for children at risk for developing the disease. For those who already have type 1 diabetes, a vaccine could be used in combination with other therapies, such as beta cell regeneration or transplantation. By fixing the root cause of type 1 diabetes and rebalancing the immune system, a diabetes vaccine would teach the immune system to not attack the newly acquired beta cells and eliminate or control beta cell-specific autoimmunity long-term.
A Targeted Attack
In the past, the best tools to blunt the immune attack on beta cells were drugs that suppressed every component of the immune system. Although these immune-suppressing therapies have enjoyed success in certain clinical settings, such as transplantation, they weaken the body’s ability to fight infections and tumors and may produce other unwanted side effects.
The goal in diabetes vaccine research is to develop a therapy with a more tailored and targeted approach. Rather than suppress the entire immune system, an antigen-specific vaccine aims to eliminate or paralyze only the destructive T cells that specifically hone in on and destroy beta cells. Several promising vaccine candidates are currently being developed that not only selectively target and destroy these destructive T cells, but also ramp up the regulatory T cells—cells in the immune system that keep destructive T cells in check. Since these vaccines aim to re-educate the immune system rather than suppress it, their effects can be longer lasting and potentially safer than general immunomodulatory therapies.
There are various ways to design a vaccine that can carry out a targeted attack and induce immune tolerance. For example, researchers are working with different vaccine components, along with beta cell autoantigens, and are trying out different ways to formulate or package the vaccine. Researchers are also tinkering with the ways the vaccines can be delivered, such as via injection versus ingestion. Each strategy uniquely attempts to rebalance both the destructive and protective immune responses.
Vaccines can be delivered by multiple routes: in the nose, by way of the gastrointestinal tract, systemically through the skin, or directly into the bloodstream. “There are many ways to gain access to the immune system and not all of them are created equal,” says Teodora Staeva, Ph.D., scientific program director of immune therapies at JDRF. “When the immune system recognizes something that has come through the nose or mouth, it applies different rules for whether it should be attacked or ignored than when it comes in through the blood. Therefore, approaches have to be designed based on the planned delivery route.”
If any of these approaches prove successful, it may be possible to use the specific vaccine technology or platform to treat a number of autoimmune disorders: not only type 1 diabetes, but also multiple sclerosis and rheumatoid arthritis, for example. On a commercial level, this could be a very attractive strategy, says Stephen Miller, Ph.D., the director of the Interdepartmental Immunobiology Center at Northwestern University. A vaccine developed for one autoimmune disorder can be used for another by switching out the autoantigen–which is the antigen that is specific for causing the disease—and using the same generic vaccine platform.
A Robust Pipeline
Last year, Pere Santamaria, M.D., Ph.D., chair of the Julia McFarlane Diabetes Research Centre in University of Calgary’s Faculty of Medicine, and his team developed a vaccine that was able to blunt most of the destructive T cells responsible for attacking and destroying beta cells in mice at risk for type 1 diabetes. In these mice, the vaccine was shown to prevent or slow down the onset of type 1 diabetes, and even reverse diabetes without compromising the entire immune system. The team has developed a company named Parvus Therapeutics, Inc. that is working to advance the research to clinical vaccine trials in humans.
Designed with a nanoparticle-based technology, Santamaria’s vaccine works by eliminating these highly destructive T cells while generating more of the protective regulatory T cells—a “one-two punch” approach that tilts the immune system toward immune tolerance. “Throughout evolution, Mother Nature has figured out a very elegant way of training our immune system to kill outside invaders, yet keep it from attacking the body’s own cells,” says Santamaria, who was awarded a JDRF Scholar Award in 2007 to develop an antigen-specific diabetes vaccine. “Our vaccine simply takes the immune system of someone with type 1 diabetes and shapes it into one that Mother Nature intended.”
Selecta Biosciences, Inc., a biotechnology pharmaceutical startup, is also trying to develop a nanoparticle-based vaccine. Recently, JDRF announced that it will provide milestone-based financial support and expertise toward the development of Selecta’s tolerogenic vaccine technology. Once initial proof-of-principle experiments are successful, the research collaboration between JDRF and Selecta may be extended to help identify a clinical candidate to target type 1 diabetes.
In contrast, Miller, at Northwestern University, packages his vaccine on cells that are in the process of dying to mimic how the immune system learns to tolerate dead cells in the body. Like Santamaria’s vaccine, Miller’s vaccine works by ramping up the production of these protective regulatory T cells, but rather than eliminate destructive T cells, Miller’s team has found a way to paralyze them. “In order for a destructive T cell to become ‘activated,’ it needs two signals,” explains Miller. “By using dying cells as carriers for the vaccine, we found a way to deliver signal one without signal two.” That is, without the second signal, the T cells that specifically target the insulin-producing cells in the pancreas do not have the proper resources to hone in on the beta cells and carry out their mission.
While Miller and Santamaria are packaging their vaccines on cells and in nanoparticles in an attempt to tweak and direct the immune defenses, Mark Peakman, M.D., Ph.D., professor of clinical immunology at King’s College and the director of the JDRF Diabetes Genes, Autoimmunity and Prevention Center in London, relies instead on a protein fragment, or peptide vaccine, that is injected directly into the body. “The way you inject vaccines influences which cells you primarily target,” says Peakman. “Injecting these vaccines without a carrier favors an immune response that helps boost the numbers of regulatory T cells.”
Henry Daniell, Ph.D., a molecular biologist and chair of the board of trustees at the University of Central Florida, is packaging a vaccine in bio-engineered lettuce, freeze drying it, and forming it into a pill. “The cell walls of plants can’t be broken down by enzymes in the body, but they can be pierced by bacteria in the gut,” says Daniell, who has been funded by JDRF to see if his vaccine induced immune tolerance and now is being funded for dosage studies. Tiny holes allow the vaccine to exit the lettuce and enter the gut. By attaching the vaccine to a protein from the cholera bacteria, Daniell’s vaccine can preferentially induce immune tolerance.
Two years ago, JDRF also funded Michael Czech, Ph.D., a professor of biochemistry and molecular pharmacology at the University of Massachusetts Medical Center, and his team to develop a technology that could load hollowed yeast cells with gene-silencing molecules called RNAis. Immune cells in the body called antigen-presenting cells take up these yeast-encapsulated RNAis. The RNAi molecules silence the antigen-presenting cells, preventing them from signaling the destructing T-cells to carry out their mission, and paralyzing the immune systems attack on beta cells..
Several vaccine trials are also aiming to determine how the immune system recognizes insulin, an autoantigen in type 1 diabetes, by delivering insulin directly to the body. JDRF is currently conducting two Phase II clinical trials to determine whether administering an insulin vaccine through the mouth or nose makes a difference in preventing the onset of type 1 diabetes. One of these JDRF-funded initiatives, called pre-POINT, is looking at whether orally-administered insulin, at four different doses, can prevent the immune system from attacking insulin in children who are at high genetic risk for developing type 1 diabetes. The other initiative, called INITII, is looking at whether insulin administered intranasally can prevent the onset of the disease in people whose immune system has already started attacking the insulin molecule.
In the INITII trial, the participants are on their way to developing type 1 diabetes, explains Insel, but they still have enough beta cells and insulin to maintain healthy glucose levels in the blood. “At this stage of the disease, it’s all about saving the beta cells,” says Insel. “Saving the beta cells and preventing the individual from developing type 1 diabetes.”
JDRF continues to prioritize research in vaccine development to prevent type 1 diabetes by supporting clinical studies in individuals who have already shown signs of the autoimmune attack that precipitates type 1 diabetes, as well as in those who are at risk for the disease—and that research should be applicable to all stages of the disease.
Although many vaccine candidates are being developed, it is not clear exactly how these vaccines exert their effect to rebalance the immune system. That’s why in the past two years, JDRF has launched several programs to identify biomarkers, changes in the body that scientists can measure and use to determine whether—or how well—a vaccine is working. Having accurate biomarkers early in clinical development is critical to developing vaccines and would accelerate this area of research. “Biomarkers could dramatically change the time scale with which vaccines are developed and tested,” says immunologist Bart Roep, Ph.D. “Instead of waiting two or three years to see whether a therapy is working, a biomarker could tell us in weeks or months whether a vaccine has put the body on a path toward immune tolerance.”