Science for Health
Over the past two or three years worries have been raised in the media about the safety of vaccines against measles, mumps and rubella (MMR). The belief that MMR vaccines cause Crohn's diseases and autism has been put forward together with the claim that 'safer' vaccines are available but are being kept from the public. The result has been to cause alarm and confusion among parents who have to decide whether to have their children immunised. The scientific studies that have given rise to the concern either claim to show that children who have been immunised have a higher chance of getting Crohn's disease or becoming autistic than those who have not, or report that measles virus can be found in pieces of diseased intestine from patients with Crohn's disease or autism. Scientifically the discussion boils down to whether the studies are convincing or not and, if the story is true, does it have other implications which can be tested. In terms of public health, however, the truth or otherwise of the claims is more highly charged.
Measles is one of the five common virus infections that cause childhood misery, other examples being mumps, chicken pox, and German measles (rubella). Generally measles is an unpleasant and alarming disease because of the extremely high temperatures that it produces, but in a small number of cases in developed countries such as the United Kingdom it can also have serious consequences.
f there were no vaccination every child in the country would get infected with measles giving an average of about six hundred thousand cases per year. It is estimated that between fifty and one hundred would die as a result either of infection of the brain, (encephalitis) or from pneumonia. Up to ten years later a few more would die of the effects of measles virus lingering in the brain rather than being cleared from the body by the immune system as in most cases. Delayed death is due to the invariably fatal disease called sub acute sclerosing pan encephalitis, or SSPE for short. In developing countries, in contrast, measles is a massive killer, for reasons that are still not entirely clear.
Cases of measles vary a lot in how severe they are. It is also clear that once a child has had measles they will not get it again. (They may get other rashes, but they will not be due to measles). The principle of making a vaccine is therefore to grow a measles virus which gives an infection which is so mild that it gives no disease but does give protection, and give it to children before they have a chance to get infected with a nastier strain. There have occasionally been items in the press on 'measles parties', where children are sent round to play with infected friends to catch measles and get it over with. Measles vaccines, to me, sound like a very similar but rather better idea in so far as the child is deliberately exposed to measles virus, as at a measles party, but it is a very mild version.
Crohn's disease is a serious as well as a long-running illness. It involves inflammation of the gut and can occur throughout the length of the intestinal tract although it is most common in the small or large intestine. Because these are the regions where most absorption of food and water takes place, the symptoms can involve diarrhoea and stunted growth. About one or two in twenty cases lead to cancer of the intestine, although surgical removal of the affected part or treatment with steroids can help.
Inflammation is a response of the immune system where a diseased or damaged area of the body attracts white blood cells, which usually deal with the problem. Crohn's disease involves chronic inflammation in which the invasion with white blood cells continues indefinitely and the most obvious cause would be chronic infection or chronic damage. Medical scientists have looked for an infection causing Crohn's disease for a long time, and at different times a number of common viruses and a variety of bacteria have been suggested as possibilities. In 1992 attention alighted on measles virus, and then measles vaccine.
If this idea is correct the benefit of measles vaccine would have to be carefully examined. It could be that in some parts of the world where the death rate is high it could be justified, while in the UK with only a potential fifty to one hundred deaths per year from measles, Crohn's disease might be the bigger threat. If the notion is not true, children could be discouraged from vaccination for no reason and measles epidemics which have currently disappeared from the UK, will resume. Measles is not a trivial disease even though everyone contracts it if they do not have the vaccine; without vaccine children will die of the infection and this should not be forgotten.
While the first reports in this area were that measles caused Crohn's disease, at a later stage it was considered that measles vaccines were more effective than the natural virus in this respect and later still that measles vaccines in combination with mumps and rubella vaccines were the worst of all. The 'safer' vaccine referred to in the media is therefore the single measles vaccine rather than MMR. As measles vaccines are just weakened or attenuated measles viruses, the idea that both natural infection and the vaccine can cause Crohn's disease is biologically reasonable. The way in which this was thought to happen was as follows. Measles virus is known to be able to linger on in some infected people as in the disease SSPE referred to above. Moreover, it is known to have strange effects on the immune system, and it likes to grow on mucosal surfaces, broadly defined as anything wet and more or less exposed, such as the inside of the mouth, or the lungs. As many measles deaths in the tropics are from diarrhoea, another possible mucosal surface is the lining of the intestine, although it must be said that measles is not regarded as a virus of the intestine by most virologists. If the virus could linger in the gut, as it lingers in the brains of victims of SSPE, and disturb the immune system of the infected person, chronic inflammation and Crohn's disease could result. As a possible explanation this is not a bad start, although it does not explain how measles mumps and rubella vaccine can cause autism.
There are two main types of study which can be used to see whether an idea like this has some truth in it or is reasonable but wrong. One involves examining groups of people to see if Crohn's disease and measles or measles vaccines go together. The other involves examining pieces of inflamed intestine from Crohn's disease to see if there is any measles virus present. The first approach is termed epidemiology and while it can be extremely effective in linking disease with causes, to the uninitiated, including the author, it can seem fraught with possible error. For example, the incidence of Crohn's disease has roughly doubled every ten years since 1950; measles vaccine was first introduced in 1968 when this steady upward trend was already well established. It could therefore be that the cause has nothing to do with measles vaccine but is something else that the UK population has been changing since the Second World War, (such as its diet for example, which might be thought a reasonable factor in an intestinal disease). Alternatively the apparently smooth upward curve may not be real and there could be an initial upward surge for one reason, followed by a second surge for another. It can be difficult to be sure that a person with Crohn's disease has been vaccinated. Studies in other areas have shown that the recollection of patients, parents or doctors are all unreliable and that only documentary records are credible. Moreover as the study would involve comparing the frequency of the disease in vaccinated and unvaccinated individuals, it is necessary to make sure that the two groups are comparable in all respects other than vaccination. This could involve age, sex, how rich they are, or the region of the country they live in.
Finally Crohn's disease is not that common; in 1985 there were about ten cases for every one hundred thousand people in the country. Unless a huge number of people are studied, or there are very large differences between the groups, a single case in one group or the other can make all the difference to what appears to be going on. Epidemiological studies must be carefully designed and interpreted and require a very special expertise. All the studies which claim to demonstrate a link between Crohn's disease and measles have been widely examined by the scientific community, and all are flawed. One study specifically designed to look at possible links, where there were good records of vaccination, failed to show any connection at all. Based on the work to date there is no reason to say that there is a connection between measles, particularly measles vaccine and Crohn's disease. The only scientific group who would disagree with this conclusion is the one which proposed the link in the first place.
The position with autism is even worse. Autism is usually diagnosed in the second year of life. For some time a favoured theory was that the birth of a second child into the family (which often happens about two years after the first) was so upsetting that autism resulted. MMR vaccine is given in the second year of life and if the child is diagnosed soon after, a parent would have to be super rational if not unfeeling to think the two were unlinked, and probably to feel both guilty and angry at having exposed their child to a 'risk'. However, the fact is that many things happen for the first time in the second year of life, and it is difficult to distinguish between something that has caused autism and something that happened at about the same time by coincidence. Autism occurred before MMR vaccine was introduced and it would be surprising if it did not occur after. To find out if there really is an effect needs a large carefully designed study, but again with the exception of the group that first described a link, it is agreed that there is no scientific reason to believe that there is a connection based on knowledge that is available now.
Virology is the study of viruses, and could give a clearer cut answer to the involvement of measles virus in disease. The same scientific group who proposed a link between Crohn's disease or autism and MMR vaccine has also reported that measles virus can be found in pieces of inflamed intestine taken from Crohn's disease patients. Viruses can be detected by infecting cells in the laboratory, or the components of the virus can be detected by using the right technique. Antibodies are 'sticky' proteins made by the body's immune system to recognise and attach to specific foreign molecules such as virus proteins. They can therefore be used to identify when the proteins are present, although it must be recognised that because the antibodies are supposed to be sticky, they may stick to other proteins as well. It is also possible to make nucleic acids which will stick specifically to the nucleic acids of particular viruses, nucleic acids being the blue print of viruses that defines them. Finally there are structures that viruses make when their proteins get together with their nucleic acids, and these structures can be seen by electron microscopy; it is also possible to improve matters by using antibodies together with electron microscopy to confirm that the structures are in fact pieces of a virus. All of these things have been done with pieces of tissues from the diseased intestine of patients with Crohn's disease, and all have been found to give positive results, suggesting that measles virus is there in most cases. However, there is a difficulty with all of these methods. Antibodies, being sticky by definition tend to stick to the wrong thing as well as the right one, and great care must be taken to make sure that the right conclusion is drawn. The same applies to nucleic acids, and electron microscopy is notorious (among non-electron microscopists at least) for producing beautiful but totally misleading pictures. The conclusions that measles virus is present in Crohn's tissue may therefore be entirely wrong.
The beauty of these studies is that they make a very specific prediction which can be tested. In all cases tissue from the brain disease SSPE, caused by the lingering presence of measles virus was used as an example of cells where it was known that the virus was present. The amount of measles in the SSPE tissue looked similar to the amount in the Crohn's tissue. The only way in which a virus can make a virus protein or a virus structure is to start with nucleic acid, which it translates into more virus with the help of the cell it is in. The polymerase chain reaction involves starting with a nucleic acid and copying it using the right enzymes, then copying the copies, and copying these copies and so on until there is a large amount of nucleic acid amplified from a small amount of starting material. If measles virus is present in Crohn's disease it should be possible to detect measles virus nucleic acid by this method. No measles virus nucleic acid has been detected in a variety of laboratories, including the one first reporting the presence of measles virus in the tissues. Moreover it is possible to measure the rough amount of measles virus nucleic acid present in Crohn's tissue and compare it to the amount present in SSPE, and the amount (if there is any at all) must be at least fifty thousand fold less. This is hard to square with the other studies and the simplest explanation is that they are the result of proteins and nucleic acids sticking where they should not.
There is no evidence currently available that stands up to examination that measles virus is present in tissues from Crohn's disease. There is no epidemiological evidence currently available that convinces scientific groups other than those who first put the theory forward that links measles and Crohn's disease. Science has to be broad minded if it is to get anywhere, and if evidence appeared that suggested anything different it would be looked at. At the moment the scientific consensus is that there is nothing in it.
This essay was published in the Mill Hill Essays 1998
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