frequently given answers
The work towards a Crohn's Vaccine began in 1997 and has fallen naturally into 3 stages. These are summarised in the Chart below together with the amount of money raised, where it came from, what it was used for and what it achieved.
The vast majority of the money has come, and continues to come, from Crohn’s disease people and their families together with small private Trusts often with links to people affected by the disease. Without this, neither the anti-MAP vaccine nor the new MAP test would exist. Long experience has shown that conventional grant applications in our field will almost invariably be rejected. Far from being over, the fundraising and investment has to continue and intensify for a bit longer until the Crohn’s vaccine, together with its companion diagnostic, are proven by us to be safe and effective in humans. We can then make it available to Crohn’s people as far as our resources allow, while at the same time getting it entrusted to industry for assured delivery into the clinic.
So, we still have the last bit to do. But now the end is in sight. Hidden within the Chart is the huge generosity of very many people. Also hidden, is the fantastic work of our fundraisers starting with Nickie and Tom Colville and their family and friends whose early contributions were so pivotal. We now need our growing band of supporters all over the world to unite and help us finish this. If you would like to help, visit our fundraising page to find out more and do please get in touch.
Why has it taken so long?
Making a new treatment and prevention for a disease, particularly where a cause has not been recognised, and getting it to the people who need it does take time. Then there are inevitably setbacks along the way which cause delays and have to be overcome. For the vaccine there were three main ones.
Yes there are treatments for MAP! Crohn’s Disease can be treated with anti-MAP antibiotic therapy. The protocol for this combination therapy includes Rifabutin, Clarithromycin and often a 3rd agent, Clofazimine. These are DIFFERENT antibiotics from those such as ciprofloxacin or metronidazole which mainly kill the overgrowth of other gut bacteria rather than having significant action against MAP itself.
Side effects of anti-MAP antibiotics can limit their use in some people. But in those who can take them, many will benefit from treatment and profound remissions can occur, even in those with severe disease. In some cases, major surgery has been avoided.
What is the success rate of anti-MAP triple therapy? In ordinary terms, of 5 people who can take it, 2 will get a complete remission, 2 will get a partial remission and one will not respond, probably because the MAP in that person is already resistant.
A review of the published scientific literature reveals 7 clinical trials which have investigated the effects of anti-MAP therapy in Crohn’s Disease, with clinical remission rates ranging from 44-89%1. Of these, the ‘landmark study’ is considered to be that conducted by Selby et al.2 in Australia in 2007; it is the only large randomized controlled trial and hence the most well-known. The failure of this study to show a long-term benefit of anti-MAP therapy in Crohn’s Disease is regarded by many as the ‘final nail in the coffin’ for the MAP/Crohn’s hypothesis and is a major reason for the reluctance of some Gastroenterologists to recommend this treatment to their patients. However, the trial has since been widely criticized, both in terms of the protocol used and the subsequent analysis 1,3,4, such that it cannot be relied upon as having any clinical significance. Major flaws include the following:
Despite these flaws, the trial still demonstrated a remission rate of 66% (of 102 patients with Crohn’s Disease) at 16 weeks (p<0.02).
A fresh start has been badly needed for a long time, but there is new hope on the horizon that the true potential of this treatment may finally be revealed. In the USA, a large multi-centered randomized-controlled trial is currently underway entitled ‘Efficacy and Safety of Anti-MAP Therapy in Adult Crohn’s Disease (MAPUS)’. The anti-MAP therapy being used in this trial is a fixed-dose combination of Rifabutin, Clarithromycin and Clofazimine combined into a new 3-in-1 pill called RHB-104: http://clinicaltrials.gov/ct2/show/NCT01951326?term=crohn%27s+disease+redhill&rank=1Are there any side effects?
Overall, anti-MAP therapy is well tolerated by the majority of patients. But as with most medicines, there are potential side effects which may be experienced by some people. Common side effects include a ‘tanned’ appearance and aching joints. More rarely, patients may experience a rash or the more serious, but reversible, condition ‘uveitis’ (inflammation of a part of the eyes) which would require treatment to be stopped. Very occasionally treatment may exacerbate disorders such as depression. Treatment should only be undertaken with close medical supervision.Why do some people with Crohn’s not improve with anti-MAP therapy?
Whilst antibiotic treatments can be a real help, they are not always a long-term solution, due to the ever-present threat of developing resistance and the ability of MAP (like other similar organisms) to go into ‘hibernation’ or latency in which state they are very difficult to kill with drugs. We need to follow the lead of our US counterparts and invest in the development of the promising anti-MAP Vaccine.
Immunosuppressants used to treat Crohn’s Disease include Azathioprine, Methotrexate and 6-Mercaptopurine as well as the newer ‘biological’ or ‘anti-TNF’ agents Infliximab (Remicade) and Adalimumab (Humira). If these were given to someone with an infection like tuberculosis, they would make the disease worse. Hence checking for latent (inactive) TB is an essential precaution before giving biological agents. So it’s not unreasonable to presume that the same would happen with immunosuppressants and MAP. But as so often with MAP, it turns out to be the opposite of what you would expect...
In the case of Azathioprine, Methotrexate and 6-Mercaptopurine, independent research by 2 groups in the USA has shown that all three of these drugs have a direct anti-MAP action1,2. They do not kill MAP but they do retard its growth and activity. Some of the benefit from these drugs is probably due to this slow anti-MAP action and is one of the reasons they take 2-3 months to work in Crohn’s disease.
TNF-alpha (tumour necrosis factor alpha) is a protein produced by cells of the immune system, to help fight infections by temporarily increasing inflammation in the affected area. The anti-TNF agents work by binding to TNF-alpha anchored on the surface of inflammatory cells involved in the Crohn’s disease inflammation. This results in the death of some of the inflammatory cells, many of which will be harbouring MAP bacteria which are likely to be killed at the same time. For this reason, treatment with anti-TNF drugs has a significant anti-MAP action too
It is also the case that a lot of the actual damage to the gut wall in Crohn’s Disease is due to the immune dysregulation caused by MAP, which immunosuppressants help to reduce.
You might expect that occupations resulting in frequent exposure to MAP-infected animals, such as dairy farmers and vets, would be associated with a higher risk of Crohn’s Disease, but in fact, data from the US show that these occupations are associated with a significantly reduced death rate from Inflammatory Bowel Disease1. Children exposed to farm animals, particularly cattle, in early life also subsequently have a lower incidence of CD2, and in many countries Crohn's Disease is more common in towns and cities than in the countryside.
The explanation of this apparent paradox lies in the fact that Mycobacterium avium subspecies paratuberculosis (MAP) can exist in (and switch between) two forms:
As with almost everything to do with MAP, the truth is more complicated than it first appears and what actually happens turns out to be the opposite of what you would expect.
© 2018 Professor John Hermon-Taylor. All rights reserved.