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Foot and Mouth Virus:
Selected General Information The organism that causes Foot and Mouth Disease is classed by microbiologists as belonging to the large and diverse family of viruses called Picornaviruses (a family which includes the viruses which cause diseases as diverse as the common cold, hepatitis A and SVD). Picornaviruses are all extremely small viruses (just twenty millionths of a millimeter across) which do not have DNA as their genetic material, but the related RNA. Their small size means that they settle out of air very slowly, if at all, and can therefore be carried by wind for considerable distances until, typically, brought down by rain to coat grass, which is subsequently eaten by animals. They are also resistant to drying out, and can easily be carried on clothing or, indeed, by almost anything transported from an infected site. That the genes of FMDV are composed of RNA rather than DNA has two important consequences. Firstly, it makes the virus very susceptible to genetic change (mutation). Specifically, the virus does not possess any means of correcting for the damage to its genes which is commonly incurred as the virus multiplies in infected animals. This results in a rapid rate of genetic change which in turn means that the way the virus 'looks' to the immune system of infected animals is also constantly changing. Eventually such changes mean that vaccines cease to be effective. (Possession of an RNA 'genome' rather than DNA is the reason that vaccines against infections such as the common cold and HIV have proved so elusive.) This variation is currently reflected in the fact that in excess of seventeen major so-called "strains" and "sub-strains" of FMDV are currently recognized worldwide (see below). It was identification of the particular variant responsible for the present British outbreak of FMD that allowed its original source to be identified as material imported (almost certainly illegally) from possibly from Eastern Asia (where this particular strain of FMDV is now endemic). Problems associated with current vaccines are discussed in the section on vaccination. Newer vaccines currently being developed overcome some of the problems inherent with the only vaccines currently available in sufficient quantities to be used during the current outbreak. One particular approach, being pursued by the US Department of Agriculture's research laboratories, is to use a different virus genetically engineered to look like FMDV to the immune system of vaccinated animals. The particular organism being developed is a genetically modified adenovirus (one of a much studied and well understood group of viruses which infect the nose and throat). The adenovirus itself is disabled such that it cannot replicate and therefore does not cause any harm. It is however a live virus, and infects the cells of the animal it is administered to. When it does so it produces protein(s) from FMDV which subsequently give rise to immunity to FMDV in the vaccinated animal. Because the adenovirus has been engineered to carry some, but not all of the FMDV's genes, it makes only some FMDV proteins, and hence stimulates immunity only to these proteins. This is sufficient to confer immunity to the disease upon the animal, while leaving the absence of missing FMDV proteins as potential means of detecting animals which have been exposed to the true, infective and potentially pathogenic FMD virus. In this way, vaccinated animals can be distinguished from animals that have been exposed to the live virus. Such tests for parts of the FMD virus not contained within the immunizing adenovirus cannot distinguish between animals currently infected and animals which had previously been infected but but had recovered and subsequently freed themselves of the virus. A technique which can unambiguously distinguish between previously infected animals free of the disease and infectious animals still harbouring the live virus does exist but is currently only available as a research tool in specialist laboratories. Based on a routine laboratory technique known as PCR, development of such a test could potentially distinguish between vaccinated animals, infectious animals and animals which had previously been exposed to the virus but which are no longer infectious. Unfortunately, such vaccines and detection techniques will take too long to be developed, tested and implemented to be of any practical use during the current outbreak of FMD. The technical classification of the virus into particular strains, useful for diagnostic purposes, is in itself somewhat misleading. Each of these "strains" comprises an ever-changing number of "sub-strains", some of which are capable of evading the immune system, and hence evading the vaccines currently in use. New vaccines can (usually) be made against each sub-strain, but not until the sub-strain arises. Consequently, vaccination against FMDV can only be a continuous struggle in the battle to protect against this disease. (What actually constitutes a viral strain is partly the nature of its immunological identity, but mostly a matter of subjective opinion.) The second consequence of the genes of the virus being RNA rather than DNA is more encouraging. It results in their being more vulnerable than many organisms to their chemical environment, and hence to disinfection. In particular, the virus is sensitive to pH outside the range 6-10. Should a recommended disinfectant for some reason not be available, as a last resort (but only as a last resort) even a relatively mild solution of an alkali or acid (such as caustic soda, vinegar or citric acid) could be fallen back upon as a temporary 'fill in' - but only as a last resort. Hypochlorite (domestic 'chlorine' bleach) is also effective. However, organic solvents (such as alcohol or petroleum products) cannot be relied upon to kill picornaviruses. Recommended disinfectants should always be used whenever possible.
This section assumes some basic, but not detailed, knowledge of immunology and genetics.
Early vaccines against viral diseases consisted of either killed intact viral particles, or fragments of virus. However, while often simple to develop, for a number of reasons these tend to be limited in their effectiveness. The most powerful modern vaccines consist of live virus particles that do not cause symptoms of disease. Only one naturally occurring live viral vaccine has been exploited (against smallpox in humans). All others have been constructed in the laboratory from the disease-causing virus itself by the introduction of mutations into its genome. If one were to adopt a policy of vaccination, one would, ideally, like to exploit a live vaccine, rather than use a killed virus (which is what the "traditional" FMD vaccines are). Live vaccines can infect and replicate, but have been incapacitated by specific mutations so as to produce no symptoms of disease, and therefore cause the animal no harm. However, live vaccines to FMDV carry a risk, related to the very high mutation rate that this virus has. The risk is that the incapacitating mutations will 'revert', regenerating the virulent disease-causing agent. A well known example of a such a vaccine is the live but incapacitated polio virus, the Sabin vaccine, which carries 57 separate mutations. Each of these mutations would have to 'revert' for the virus to regain its ancestral virulence. Even given a mutation rate of one in 1000 (see below) the chances of this, even over many replication cycles, is very small with the Sabin vaccine - Sabin hardly ever reverts to virulence. However, hardly ever is not never - it did revert causing a polio epidemic in Sweden, and killed (Salk) vaccine was returned to in many countries. Interestingly, one reason polio has largely disappeared in some areas (the USA in particular) is that the live but 'attenuated' Sabin vaccine has replaced the 'wild-type' virus in its some of its natural reservoirs (water supplies). Subsequent harmlessly infection thereby protected people although they had never been knowingly vaccinated. This may be of relevance to the adoption of such a vaccine to combat FMD (see below). As discussed above, FMDV is an RNA virus. It therefore replicates its genome by means of an RNA-dependent RNA polymerase. Unlike DNA polymerases, these do not have any error checking-editing mechanism. As a result, the mutation rate of FMDV reflects only the base-pairing energies (equilibrium constants) of the nucleotide base pairs forming during replication. For every few thousand 'correct' base pairs that form, a mismatch occurs, resulting in a mutation. A daughter viral genome, of around 10,000 bases in length, will be consequently be expected to carry several mutations. (An additional consequence of this high mutation rate are that, a multiple dose of viral particles is normally needed for infection, reflecting the fact that many viral particles are inviable due to the presence of a 'lethal' mutation. That the virus is continually changing also means that it is constantly and rapidly evading the immune system of the animals it infects.) Such a high mutation rate (a million times higher than in man, for example) makes protection against reversion of incapacitating mutations introduced into a live vaccine particularly challenging. The construction of live vaccines, particularly to RNA viruses, is non-trivial. The Sabin vaccine (also an RNA virus) took many years to develop, although current genetic technology not available in the 1960s somewhat simplifies this process. Live FMDV vaccines now exist, but with nothing like Sabin's in-built protection. Because live vaccines infect their host and replicate themselves, albeit without causing disease, they can become and remain endemic in a vaccinated herd - with the accompanying possibility of reversion to virulence and the subsequent emergence of a spontaneous epidemic, without the necessity of the introduction of the virus from an external source.
Herd Immunity & Endemic Virus There are certain immunological considerations that might lead one to prefer to vaccinate against foot and mouth, rather than eliminate the disease. Endemic viruses, whether resulting from vaccination with live vaccine or through infection by the 'wild-type' pathogen itself, can result in the infected herd developing partial immunity, showing itself as either an absence of symptoms of the disease, or a far milder infection than one would expect in uninfected and unvaccinated animals. This is know to happen for many endemic infectious diseases. The reasoning goes as follows. A future mother has had the disease previously and has recovered. She therefore has antibodies in her bloodstream against the pathogen. She becomes pregnant. Mother's antibodies of the immunoglobulin-G class pass to the foetus across the placenta, and subsequently, following birth, mother's milk contains antibodies against the virus. The baby thereby receives the mother's antibody and hence some protection against the pathogen. (The placenta and the infant's stomach have special receptors to take up the mother's antibodies) If the infant is then infected by the micro-organism early in life, preferably while still receiving mother's milk, it will either not show symptoms of the disease, or the disease symptoms will be milder, and recovery quicker, than otherwise expected. Infant is partially or fully protected from micro-organism by mother's own immunity. However, while protected by the mother's antibodies but also infected by the pathogen, the baby is developing its own T and B-cells specific for the pathogen. For this lifetime immunity to be imparted, a protected baby has to become infected with the organism. This is why the pathogen has to be endemic in the herd for this to work. The effect is referred to as 'herd immunity'. Spontaneous outbreaks of disease will usually still occur from time to time, but most often with reduced severity. These outbreaks result from the pathogen mutating to a novel form, not so strongly recognised by the immune system. If this should happen, both mother and child will perhaps become develop symptoms of the disease, but will normally not be as ill as if they had been immunologically naïve with respect to the virus. This is because their antibodies, together with their T and B cell receptors, will retain some degree of cross-reactivity to the newly mutated pathogenic strain. Illness therefore will not usually be as serious as in an immunologically naïve individual, and recovery will be much quicker. The B and T memory cells will react with the new form of the virus, albeit to a somewhat reduced extent, and as they proliferate they mutate to become specific for the new strain. Another way to think of this is that the individual already immune to one strain of the pathogen is halfway on the road to recovery from the infection by the new strain, even before infection with the new strain occurs. The continuous chase between the immune system 'needing to overtake' the virus, and the virus 'needing to pass' the immune system is an example of what Leigh van Valen has called the Red Queen effect. (In 'Through the Looking Glass', the Red Queen tells Alice that one has to run as fast as one can just to stay in the same place.) A familiar example of this effect occurring repeatedly is yearly appearance of new strains of influenza in human populations. Each time a new strain appears - people get ill, but unless their immune system is alreadyweak they usually recover quickly. However, when in the past populations that had not been exposed to influenza encountered the virus for the first time, which happened to the indigenous peoples of the Americas in the sixteenth century, millions died. The system is not 'foolproof'. Occasionally, a mutant crops up with little cross-reactivity to its parental type and herd immunity fails. Then this mechanism fails and people/animals die, as in the 1919 influenza pandemic, which killed more Europeans than the 1914-18 war. A second immunological effect, mediated by HLA-type, is also involved in viral immunity and virulence. As well as lacking antibodies or immune system cells necessary to combat the influenza virus, native North Americans also lacked the type I MHCs that the Old World inhabitants had evolved over centuries as another way the immune systems resist pathogens, in this example, influenza. The effect is common to all mammals continually, but more importantly continuously exposed to a viral pathogen. This is a second (in this case evolutionary) reason why an endemic virus becomes far less virulent than a virus encountered by an immunologically naïve population. A strong argument has also been made, and now accepted by the many geneticists and immunologist, that resistance to pathogen infection may be the most important advantage to sexual reproduction - sex shuffles HLA combinations, hence 'experiments' with the HLA-mediated aspects of pathogen resistance. If this is correct, inbred herds would be expected to be more disease prone, and show more severe symptoms when a disease is contracted, and this is just what is found. In short, an initially very serious pathogen becomes progressively less pathogenic provided it becomes, and remains, endemic within a population. A strong argument can be made, therefore, for wishing to establish foot and mouth disease within national herds and flocks, rather than eliminating it completely. Elimination of the disease inevitably leaves national herds and flocks susceptible to serious illness on the inevitable re-arrival of the disease generations in the future, when herd immunity has been lost.
Links For general information, including the progress of the current epidemic and the steps being taken to combat it, as well as practical advise on such things as effective disinfectants, refer to the relevant section of the Ministry of Agriculture Fisheries and Food Web site (from June 2001, The Department of the Environment, Food and Rural Affairs) at www.defra.gov.uk. Some of the general information about FMD at this site is, however, somewhat selective in its presentation and could be a little misleading.
For more detailed information (particularly technical information) there are a great many links accessible from The Institute for Animal Health (Pirbright Laboratory) which is the designated World Reference Laboratory for Foot-and-Mouth Disease. Their Foot-and-Mouth Web site is at
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