Friday, 13 December 2013

BCG vaccination limits the development of MS

Ristori G, Romano S, Cannoni S, Visconti A, Tinelli E, Mendozzi L, Cecconi P, Lanzillo R, Quarantelli M, Buttinelli C, Gasperini C, Frontoni M, Coarelli G, Caputo D, Bresciamorra V, Vanacore N, Pozzilli C, Salvetti M. Effects of Bacille Calmette-Guerin after the first demyelinating event in the CNS. Neurology. 2013 Dec. [Epub ahead of print]


OBJECTIVE:To evaluate Bacille Calmette-Guérin (BCG) effects after clinically isolated syndromes (CIS).
METHODS: In a double-blind, placebo-controlled trial, participants were randomly assigned to receive BCG or placebo and monitored monthly with brain MRI (6 scans). Both groups then entered a preplanned phase with IM interferon-β-1a for 12 months. From month 18 onward, the patients took the disease-modifying therapies (DMTs) that their neurologist considered indicated in an open-label extension phase lasting up to 60 months.
RESULTS:Of 82 randomized subjects, 73 completed the study (33 vaccinated and 40 placebo). During the initial 6 months, the number of cumulative lesions was significantly lower in vaccinated people. The relative risks were 0.541 (95% confidence interval [CI] 0.308-0.956; p = 0.03) for gadolinium-enhancing lesions (the primary endpoint), 0.364 (95% CI 0.207-0.639; p = 0.001) for new and enlarging T2-hyperintense lesions, and 0.149 (95% CI 0.046-0.416; p = 0.001) for new T1-hypointense lesions. The number of total T1-hypointense lesions was lower in the BCG group at months 6, 12, and 18: mean changes from baseline were -0.09 ± 0.72 vs 0.75 ± 1.81 (p = 0.01), 0.0 ± 0.83 vs 0.88 ± 2.21 (p = 0.08), and -0.21 ± 1.03 vs 1.00 ± 2.49 (p = 0.02). After 60 months, the cumulative probability of clinically definite multiple sclerosis was lower in the BCG + DMT arm (hazard ratio = 0.52, 95% CI 0.27-0.99; p < 0.05), and more vaccinated people remained DMT-free (odds ratio = 0.20, 95% CI 0.04-0.93; p = 0.04).
CONCLUSIONS: Early BCG may benefit CIS and affect its long-term course.
CLASSIFICATION OF EVIDENCE: BCG, as compared to placebo, was associated with significantly reduced development of gadolinium-enhancing lesions in people with CIS for a 6-month period before starting immunomodulating therapy (Class I evidence).

In this study people treated with beta interferon had a better outcome if they were vaccinated with BCG

BCG is Bacillus Calmette Guerin and is a live vaccine and if you have had it you will likely have a noticeable scar on your arm. This was given to school children when I was a young mouseling. It is now not routine in the UK any more and probably not in Italy as the aim of vaccination is to give you life long protection.

The vaccine which contains cow loving bacteria called Mycobacterium bovis, aims to give you protective immunity against tuberculosis caused by Mycobacterium tuberculosis. 

In the West exposure to mycobacteria may not be at a young age, but in areas where Leprosy caused by Mycobacterium leprae is common then this may not be the case, especially as people my blow millions of bacteria from their noses if they have lepromatous leprosy and vaccination with BCG may be less effective in some places 
Giving Freunds complete adjuvant which contains killed Mycobacteria does not necessarily stop EAE from being developed. As far as I know M.bovis is not a reservoir host of mice, otherwise we would be shooting mice and not badgers. Therefore the bacteria probably gets destroyed or encapsulated by specialised macrophages called epithelioid cells. 

It has been reported that BCG causes a dose-dependent inhibition of EAE. Giving killed mycobacteria such as in Freunds adjuvant that is used to induce EAE can influence subsequent immunity and Freunds adjuvant can stop NOD mice getting diabetes but it does not stop EAE from being developed. This current study seems to translate the mouse experience. In the mouse study the implication was that having an inflammatory response elsewhere than the CNS, will suck in CNS-reactive cells into the site of peripheral inflammation so they can’t get into the brain to cause havoc. 

Now we have the TH1 and TH2 brigade of immunologists who believe TH1/TH17 bad, TH2 good (someone said “TH17 who cares” recently so are they falling from favour?). They are aiming to promote TH2 responses by hook or by crook, although as we know anti-CNS antibody responses are not good for MSers is this what we want?. Maybe it is TH1/TH2 =Bad?. 

However, people (neuros) are attempting to drive TH2 responses by giving people parasites like hook worms, This study in contrast is supplying another parasite in this case a bacteria that is associated with driving a TH1-like response and they are suggesting benefit, so are the worm trials doomed? However in this context they are implying infection = BAD so we are not bothered about the subtle variations of TH1 and TH2. 

This was a suck-it and see experiment where the neuros state they do not know how it works, so they have struck lucky and translated earlier animal studies, the look-see approach however is riddled with failure. 

CISers are becoming gold dust. Because in some places you can do placebo controlled trials and if you hit early and hard you have the chance to stop MS in its tracks. We have seen recently studies with beta interferons offering potential benefit, potentially BCG in combination with beta interferon and also recently cladribine had a staggeringly good effect. At some stage, preferably now, NICE needs to wake up and promote treatment options to CISers could benefit most from the “Early and highly effective approach”. Also the question is do you need to have beta interferon also. BCG is a relatively innocuous vaccine. Larger studies will need to confirm or refute this. 

One suspects that medical records could be probed to examine influence of BCG vaccination and MS prevalence as BCG was standard vaccine to most people in the UK. We are however MS central and so it clearly is not curative when given in adolescence. The people in this study were tested before vaccination to ensure they did not have pre existing immunity as it could cause an adverse allergic (type 4-delayed hypersensitivity) reaction. 

Please note this study concerns whether you will convert and become diagnosed with MS, it provides no indication of what happens to established MS although that may also be influenced based on past studies.

Also remember this is a live vaccine that is destroyed by the immune response and there could be consequences if the bacteria is given to immunosuppressed people

5 comments:

  1. Isn't it a problem that a lot of CISers are diagnosed as having transverse myelitis, and told to go away, it will get better of it's own accord. So losing a golden opportunity to treat early and hard.
    (I know my son was, no treatment, not even steroids, even though the MRI showed inflammation in the brain and spinal cord)

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    1. I do think that as well as in treatment, there needs to be a shift in improved diagnosis. UK neurologists appear to be extremely conservative when it comes to diagnosis/treatment. The early treatment provided in other countries puts the UK to shame. I know this is also a consequence of tradition, but it's now also due to NICE which often acts as a rationing body (though I don't necessarily disagree with them trying to get drug prices down, given the ridiculous cost of MS drugs that don't come close to curing people)

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  2. I am not at all convinced by this life-long protection thing, as thanks to my father being diagnosed (thankfully very early on, due to an x-ray for broken ribs) with TB at age 19 (1956), my sister, brother and I all had the TB vaccination at 6 weeks old. We all expected to prove positive for antibodies at age 15, yet each of us ‘failed’ the skin test and had to be re-vaccinated! Living as I do in east London, I am very concerned at the re-emergence of a disease we had effectively eradicated from these shores.

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  3. Life long proection that is the aim of vaccination, sometimes you need boosters

    Father aged 19 brother, sister and you...must have started family early.

    Anyway 6 weeks old is very young and your immune system may have not fully formed but sometimes vaccines do not work.

    The skin test is the mantoux test. The response is probably not antibody mediated but is T cell driven this is why you have to wait to see if you get response as this is what is called a delayed type hypersensitivity.

    I have BCG in my teens I remember the injection site bursting. I don't know if I respond as I have had a Freunds adjuvant needle stick a few times and have not responded or I cleaned the injection site pretty well. On the other hand MD2 had a corker of a reaction requiring surgery to remove the injection site.

    The particular concern about Tb is that there are drug-resistant forms

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  4. it seems not the first time that BCG comes out to be beneficial in MS; see also article:

    Use of Bacille Calmette-Guèrin (BCG) in multiple sclerosis

    Source: Neurology, October 22, 1999

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