What happened to the coeliac disease vaccine?

Coeliac disease is more common than we think: 1 in 100 people have the condition, and increasing rates of diagnosis mean its prevalence has risen significantly in the past 50 years. Sufferers and doctors had high hopes for a vaccine in clinical trials, but sadly it didn't pan out...

I met Violet for the first time a year ago, at the corner coffee shop. She was discussing with the waitress about the exact composition of the croissant in front of her. “Can’t wait for this to be over,” she told me. “I’m so excited about the news! Soon I will be able to enjoy all cakes and pastries without any worrying!” When I asked Violet why, she told me. “They found a cure for people like me. I've read about a vaccine. I’m so excited”.  I was impressed: in front of me someone whose life was going to be changed thanks to science.

Violet is a smiling young woman with plenty of energy and a positive attitude to life. But she wasn’t always like that. She started to have stomach cramps when she was 10. She knew that was something to do with the food, not with her. Every time she ate, Violet felt something was wrong in her body. Everyone around her, including doctors, disagreed, assuming it was all in her mind. “It was like a circle, the more I was ill, the more I was stressed and grumpy, and the more I was ill.” she told me. Her family were going through a tough time; both her brother and her father had died a few years apart, and they thought she was reacting to stress. “Doctors were saying that my stomach cramps were due to my emotions and mental stress. I did therapy for a long time, but the pain was always there.” After years of suffering, finally, one doctor suggested further analyses. “I was 25 when I was told that I had coeliac disease, and I was happy. I could finally give a name to it and start eating without worrying. My teenage years were hell, but I could start to live again.”

BREAD

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Coeliac disease is a life-long autoimmune disease caused by a reaction to the gluten present in some cereal products. In practical terms, what being coeliac means is that, after eating your favourite sandwich, you may spend the next few hours in pain. Symptoms can be initially ‘mild’ - you feel the urges to run to the nearest toilet with diarrhoea, stomach cramps and vomiting. But years of undiagnosed or misdiagnosed disease can lead to more severe disease, and your entire life is dogged by constant feelings of fatigue, itchy rashes, oedema, anaemia and weight loss. But why?

The cells of our immune system work as an army: they patrol the body and have different abilities that allow them to fight various enemies. Some cells, called T cells, are equipped with small radars that enable them to scan the chemicals we encounter and decide if it’s a friend or a foe. If something is recognised as dangerous, such as a virus or bacterium, it triggers an attack on the invader. However, sometimes immune cells mistake something innocuous for an enemy and trigger an attack on the body’s own tissues and organs. In coeliac patients, the benign gluten in wheat, rye, and barley fools the immune system into sensing danger where there us none. When foods containing gluten are consumed, the immune system reacts. This usually happens in the walls of the small intestine where the immune system encounters the constituents of the foods we consume. The result is inflammation and the loss of the ridges and folds - called villi - that normally endow the small intestine with the large surface area it needs to absorp nutrients efficiently. Without these villi, the gut can pick up only a fraction of the calories it normally can, contributing to the symptoms.

There is no cure for this disease. Instead, to keep it under control, coeliac patients adhere rigidly to a gluten-free diet (GFD) for life. If they do so, the intestine recovers and remains healthy. But this lifestyle is a tough one to subscribe to. Gluten is virtually everywhere, and avoiding it is challenging. As Violet says, “if you are very well organised it is doable,” but it is a pain. A gluten-free diet is burdensome and restrictive in social situations. Younger patients see it as a stigma and often they fail to adhere to the strict diet to fear of not being accepted from the group.

Cure coeliac disease with a simple vaccine?

Although the gluten-free diet has been the only long-term effective solution for coeliac disease, researchers are actively seeking potential alternatives. These include approaches to re-educate the immune system that gluten is not an enemy. This was the goal of one trial vaccine called Nexvax2, developed by researchers in Australian and USA. Nexvax2 used gluten fragments to train the cells of our immune system. The fragments are injected at increased doses so that the immune system can slowly learn to recognise gluten as a friend rather than an enemy. In this way, new gluten ingestion would not result in an attack on the intestine cells. 

The phase I trial was a success. NexVax2 was found to be safe and tolerable at therapeutically-relevant doses. Based on these results, the vaccine was granted fast-track status by the FDA to start a phase II trial to test whether the vaccine was capable of producing a clinical benefit in coeliac patients. A few months into the phase II trial I spoke with Dr Ken Truitt from ImmusanT Inc., the pharmaceutical company based in Boston that lead the human study. At the time, he explained to me “we are doing one step at the time: the first step is to show that the drug works. Now I can only speculate that one day, if this works for some patients, it might be possible to drop the GFD completely; but I cannot tell you more.” Nexvax2 was considered a chronic treatment. It was never meant to be a cure: coeliac people are not going to stop being coeliac. Moreover, Dr Truitt said that they expected that it would only act as a therapy to help coeliac people to feel better in case of accidental exposure to gluten, and to prevent further damages to the body.

The coeliac community eagerly awaited the phase II trial’s results, hoping that this vaccine would significantly change their everyday life. However, as Dr Truitt said, drug discovery takes time, and, unfortunately, there are many more failure then victories: Less than a year after the trial started, ImmusanT halted the study, explaining that the results were not as positive as expected. What they told the patients involved in the study was that results from vaccinated people exposed to gluten versus those exposed to the placebo didn’t show a significant difference. NexVax2 was not protective in the way they were hoping. “While we did not achieve the desired outcome, we believe the study will generate valuable data that will help inform the field on improving treatment for patients with coeliac disease,” was the final company statement.

Still lots to learn

Disappointing as NexVax2's demise was for Violet and thousands of other coeliac patients around the world, not all was lost. As Truitt poins out, the lessons learnt from the phase I and phase II trials would be “important in establishing clinical proof-of-concept for a treatment that would provide benefit beyond that of the gluten-free diet.” NexVax2 trials have, in fact, helped researchers to test new diagnostic tools and make further steps towards a cure. And even though drug discoveries take time, and the final product to change coeliac people’s life is not yet on the market, we might not be so far from it. Next time I see Violet, she has heard about the failure of the trial. “Well, it’s annoying. But it’s a disease you can live with. Now gluten-free diet is fashionable, so I’m very trendy after all!” She is a strong, cheery woman, but not everyone has the same approach to life and the disease.