Vaccine against type 1 diabetes 'shows promise'
News of a successful trial of a vaccine for type 1 diabetes has been covered by BBC News, who reported that, "It may be possible to reverse type 1 diabetes by training a patient's own immune system to stop attacking their body."
Type 1 diabetes is a condition where the body's immune system destroys the insulin-producing beta cells of the pancreas. This means people with the condition require lifelong insulin treatment.
It's possible to block the effects of the immune system by using immunosuppressants, but this would make people more vulnerable to infections. An ideal type 1 diabetes treatment would block the immune cells attacking the pancreas while leaving the rest of the immune system untouched. New research suggests that this could be possible.
A trial of a new vaccine compared its effects against placebo in just 80 people. The vaccine improved the function of the insulin-producing beta cells of the pancreas, but its effects seemed temporary as beta cell functioning declined soon after the regular vaccine injections were stopped. This suggests that regular vaccine injections might be required for it to work long-term, but this was not tested directly.
There are thought to be many different substances that are recognised by, and possibly trigger, immune cells to attack the beta cells of the pancreas. This vaccine is quite specific in preventing just one such pathway. This means the vaccine may lead to an improvement in symptoms, but not a complete cure for the condition.
Nonetheless, these are positive results and are likely to spur on larger and longer term studies. If all goes well, it could provide the basis for a new treatment approach for type 1 diabetes.
Where did the story come from?
The study was carried out by researchers from Europe, the US and Australia, and was funded by Bayhill Therapeutics, a biopharmaceutical company that focuses on research into treatments for autoimmune diseases such as type 1 diabetes.
The study was published in the peer-reviewed journal Science Translational Medicine.
The BBC News coverage was generally well balanced. It highlighted the importance of this breakthrough while also warning that it was, in the words of the lead researcher, "early days … clinical use is still some time away".
What kind of research was this?
This was a randomised control trial testing the ability of a new vaccine to stop or improve the function of the insulin-producing beta cells of the pancreas, which are destroyed in people with type 1 diabetes.
Type 1 diabetes is an autoimmune disorder whereby the body launches an inflammatory attack that destroys beta cells in the pancreas. The beta cells are responsible for producing insulin, which has a crucial role in regulating blood sugar levels. The disease usually develops during the teenage years, and people with the condition need lifelong insulin.
For decades researchers have been trying to develop vaccines for type 1 diabetes. Efforts have mainly focused on suppressing the inflammatory response that destroys the beta cells.
However, efforts to date have not been very targeted and have suppressed the immune system more generally. This leaves patients more susceptible to infectious diseases.
Scientists' key task is to try to suppress the specific part of the immune response that destroys the beta cells but leaves the rest of the immune system functioning normally.
Insulin is made in stages. It is first made and secreted from the beta cells as an immature form called pre-proinsulin. The body then processes it into proinsulin, and finally into insulin.
The researchers' approach to the problem was to inject patients with a ring of DNA (called a plasmid) that contained the DNA code for making proinsulin. Researchers discovered from previous research in mice that injecting a similar proinsulin-containing plasmid could prevent and reverse the destruction of the beta cells by CD8+ T cells (the immune cells responsible for targeting and destroying the beta cells).
By artificially introducing the proinsulin molecule through the vaccine, the researchers suggested the immune system would become more tolerant to it. Consequently, the immune system would be less likely to react to the naturally occurring proinsulin and the beta cells that produce it.
What did the research involve?
The researchers studied 80 adults over the age of 18 who had been diagnosed with type 1 diabetes in the previous five years. They were randomly selected to receive intramuscular injections of the proinsulin-containing plasmid (BHT-3021, the vaccine) or a plasmid without the active proinsulin component, which acted as a control treatment.
Twice as many people were given the "vaccine" compared with the control. Injections were given weekly for 12 weeks, after which patients were monitored for safety and immune responses by doctors who did not know the treatment allocation (blinded).
Researchers evaluated four dose levels of the BHT-3021 vaccine:
- 0.3mg
- 1.0mg
- 3.0mg
- 6.0 mg
The researchers then measured a molecule called C-peptide, which is part of the proinsulin molecule. The molecule is often used in medicine to assess beta cell function and assess how well the cells are secreting insulin.
They also measured levels of the so-called proinsulin-reactive CD8+ T cells, which were thought to be responsible for targeting and destroying the insulin-producing beta cells.
The combination of these measurements should have provided an accurate reflection of how well participants were responding to treatment.
What were the basic results?
Two key findings emerged. In those given the vaccine, C-peptide levels improved relative to placebo at all doses during or shortly after the 12-week treatment period.
The biggest difference was at 1mg dose after 15 weeks. At this point, C-peptide levels were 19.5% higher than the start of the study in those given the vaccine, whereas C-peptide levels in those given placebo had reduced by 8.8%.
This difference was statistically significant. However, the increase in C-peptide only occurred during active vaccine treatment and shortly after.
The treatment period was 12 weeks and yielded increases in C-peptide effects up to around week 15 in two of the treatment groups (1.0 and 3.0mg). But once treatment was stopped, C-peptide levels started to decrease, and continued declining until the end of the study (two years after vaccination).
This was still in contrast to the levels of C-peptide in the placebo group, which showed a steady decline from day one. This suggests that if the vaccine did prove safe and effective, regular injections might still be required.
The second finding was that proinsulin-reactive CD8+ T cells (but not T cells against other molecules) declined in those given the vaccine. This meant that the number of immune cells attacking the beta cells had decreased in the vaccine group, but only those specifically reacting to proinsulin.
An independent safety assessment indicated there were no obvious side effects related to the vaccine.
How did the researchers interpret the results?
The two results taken together led the researchers to conclude that, "a plasmid encoding proinsulin reduces the frequency of CD8+ T cells reactive to proinsulin while preserving C-peptide over the course of dosing".
In effect, this means it targets the specific immune response caused by the reaction to proinsulin, and leaves the rest of the immune response alone.
Conclusion
This early-stage study of 80 adults shows that a new vaccine shows promise in improving the function of the insulin-producing beta cells of the pancreas in adults with type 1 diabetes.
This vaccine specifically reduces the immune response mediated through proinsulin, but there are other molecules the T cells use to target the beta cells for destruction in people with type 1 diabetes, such as:
- glutamic acid decarboxylase (GAD)
- tyrosine phosphatase-like insulinoma antigen (IA2, also called ICA512)
- zinc transporter ZnT8
- islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)
The researchers highlight that antibodies to GAD, IA2 or insulin are present in 95% of pre-diabetic or new-onset type 1 diabetes patients. In fact, 80% of patients are positive for two or more of these antibodies, and 25% are positive for all three antibodies.
So, this vaccine seems unlikely to be able to stop all beta cell destruction or restore all function, because the problem occurs through several routes. However, it does show promise at limiting the proinsulin element of the problem. This may stimulate development of other vaccines that work in a similar way but target the alternative routes.
It was also not made clear what impact the changes in C-peptide had in the people with diabetes themselves. For example, we don't know whether it had any effect on their insulin requirement or allowed better control over their blood sugar. These questions are important and remain unanswered for now.
The vaccine is in an early developmental stage and the dose may undergo more refinement. Similarly, as the effect seems to wear off when treatment stops, the vaccine developers will need to investigate the potential safety implications of the long-term use of the vaccine, or alternatively find a way of increasing the longevity of the effects.
The finding of no adverse events from using the drug is positive but needs to be seen in studies involving more people to be confirmed. Also, as type 1 diabetes tends to develop in the teenage years, the vaccine will need to be tested on younger people at some point.
This seems to be in the pipeline, as Reuters news agency has reported plans to design a longer term study recruiting around 200 younger people with type 1 diabetes in an effort to slow or stop disease progression before too much damage has been done.
