Using a completely new approach, a German biotech startup is hoping to produce the first successful vaccine to treat Helicobacter pylori infections, the major cause of stomach ulcer and gastric cancer.
Vaccination against H. pylori could also help fight the global problem of rising antibiotic resistance, according to Markus Gerhard, professor of medical microbiology and immunology at Technische Universität München (TUM) and founder of ImevaX GmbH.
Having recently secured funding to test their promising vaccine candidate in humans, the start-up aims to have a therapeutic H. pylori vaccine on the market within 10 years.
Why the old approach hasn’t worked
Each year, more than half a million people die from gastric cancer. The major culprit behind the disease is H. pylori, a bacterium that colonises the stomach of more than 50 per cent of the world’s population. In 20 per cent of those infected, it leads to stomach ulcer and may progress to cancer.
To treat H. pylori infections, doctors currently use a combination of different antibiotics. However, these come with serious side-effects and also contribute to antibiotic resistance. That’s why researchers have tried for years – so far without success – to develop an effective vaccine against H. pylori.
Why is it proving so difficult? According to Gerhard, most earlier attempts have relied on ‘traditional’ vaccination approaches without a thorough understanding of the special relationship between H. pylori and its human host, which scientists have only recently begun to unravel.
“In adults, the immune system has adapted to this chronic infection for decades, and the bacterium has adapted to its host for 100,000 years. It’s a long and well established co-evolution at the immunological level that we have to overcome. So we can’t compare the situation with prophylactic vaccination,” he explains.
Staging a counterattack in new ‘battlefield’
Contrasting with prophylactic vaccines to prevent a future infection, for instance with the measles or flu virus, therapeutic vaccines enlist the body’s immune system to fight an existing infection. “There is barely any therapeutic vaccine in development or on the market for infectious diseases, so it’s a completely new field we’re entering,” Gerhard says. In fact, it’s a battlefield, involving an arms race between the bacterium and its host.
Gerhard’s team has discovered that H. pylori secretes a unique protein that blocks a crucial element – the T-cell response – of the host’s immune defence. The researchers have taken this ‘immune evasion mechanism’, which the bacterium uses to colonise the stomach and cause infections, and turned it against the bacterium itself.
“We purified this protein and showed that when we use it for immunisation, we can induce an immune response in the host that blocks and thereby disables the bacterium’s immune evasion protein. That again allows a sufficient T-cell response against the infection,” Gerhard explains.
The researchers used an inactivated form of this protein, gamma-glutamyl transpeptidase, as a key component in their novel vaccine – specifically designed to defeat the immune-evasion strategies of H. pylori. Many experts in the field have recently called for such ‘rational design’ to overcome the bacterium’s defence mechanisms in order to succeed in the quest for an effective vaccine.
Testing the vaccine
Testing the vaccine in mice, the ImevaX team was able to achieve so-called sterilising immunity in typically 80 per cent of the test population. So far, very few experimental H. pylori vaccines have achieved sterilising immunity, meaning a complete eradication of the bacterium from the host.
And while Gerhard says he is “pretty confident” that their new approach will also produce promising results in humans, he is very cautious about predicting the outcome. “We know that the mouse model – which is the established animal model for H. pylori research – can be very predictive but in many cases it is not,” he says.
That’s why ImevaX, with support from their scientific advisors and investors, concluded that they need to optimise the vaccine in human clinical trials. Having ascertained the safety of the vaccine in animals, they are now in the process of acquiring the regulatory documentation required to start tests in humans.
With €5.9 million in funding from Germany’s Federal Ministry of Education and Research and an even larger amount from venture capitalists, the plan is to start a phase I trial in early 2016. This clinical trial will primarily assess the safety but also to some extent the efficacy of the vaccine in healthy volunteers.
“When we have the phase I data, we will aim for a second financing round to cover the cost for phase II, which will be an extended efficacy trial in infected patients,” Gerhard says.
Tackling a growing medical need
Insufficient funding and lukewarm support from the health industry are among the many hurdles researchers are facing when trying to develop a H. pylori vaccine. “Some of the big pharmaceutical companies that we talked to didn’t see a medical need here,” Gerhard says, before pointing out the major reason why a vaccine is indeed needed: “The bacterial resistance against the three antibiotics used for treating H. pylori is as high as 60 or 70 per cent in some countries.”
The problem lies in the fact that these antibiotics are also used to treat many other common infections – and the fact that two effective antibiotics in combination are needed to successfully eradicate H. pylori. So if, for instance, you are treated with one of these antibiotics for a throat infection, the H. pylori colonising your stomach will become resistant to that particular drug. This way, the bacterium can eventually develop resistance against all three antibiotics.
“That’s a development we see everywhere and it’s starting to be a severe problem, especially in countries where you can get all these antibiotics over the counter,” Gerhard says.
“In Germany today, we may still find a rescue therapy to treat most H.pylori infections. In other countries, for instance Japan, they really have a demand for a vaccine right now, because they have high gastric cancer incidence and high antibiotic resistance.
“In Western Europe, we might end up in this situation in 10 years.” If their clinical trials demonstrate the results Gerhard and his team are hoping for, ImevaX could have a vaccine on the market by then.
By Lillian Sando