Meningitis: fresh hopes for its eradication
This essay was written by Gerry Klaus and was first published in the 1999 Mill Hill Essays.
Infant mortality is an excellent indicator of the state of a nation’s health. In the middle of the nineteenth century about one in five children in Britain died before the age of five. In 1951 this figure had fallen to less than one in thirty and by 1994 less than one in a hundred under-fives failed to survive. This spectacular, inexorable decrease in childhood mortality over the last century has occurred throughout the industrialised world, although sadly not in many developing countries, and is due to a multitude of causes: some of these are clearly socio-economic, such as improved nutrition, hygiene and housing. However, there is no doubt that improved healthcare has played a major role in this dramatic change, as it has in prolonging life expectancy amongst the elderly. A striking example of the effects of improved healthcare on childhood mortality is its impact on the incidence of fatal infectious diseases. In the middle of the last century infectious diseases accounted for sixty percent of deaths in children between the ages of one and fourteen. Deaths from infections in this age group fell from more than one thousand per million in 1911 to about eleven per million in 1991.
Most infant mortality resulting from infections occurs in the first year of life. The reason for this is that the cells of the body which fight infection, collectively called the immune system, are not fully developed in young infants, rendering them susceptible to a variety of microbes which are more or less innocuous to adults. The recognition of this fact was a major stimulus for the development of vaccines to a variety of childhood infections. These are now given routinely to babies – such as the combination DPT (diphtheria, pertussis and tetanus) and MMR (measles, mumps and rubella) vaccines, and the polio vaccine. Vaccines are, broadly speaking, either innocuous extracts of the infectious microbe, or an inactivated form of the microbe, which provoke immune responses that serve to curtail future infections with that organism. The introduction of mass vaccination to these childhood infections has had a huge impact on childrens’ health and has led essentially to complete eradication of some of these diseases in the Western world. In addition, many of the common causes of bacterial infections of children can be treated with antibiotics, which has also had a major influence on the incidence of serious infectious illness in this age group. One of the consequences of improvements in healthcare such as these is that we now live in a society where we no longer expect to suffer from infectious disease, or if we do, we expect it to be treatable. This is why the advent of AIDS has come as such as shock to the Western world, especially as it mainly affects young adults and babies. Indeed, any disease that kills young people, especially if it is potentially preventable, understandably evokes much anguish in parents of affected children. One such infectious disease is meningitis, which frequently hits the headlines in the national press. In 1998, for unknown reasons, the incidence of meningitis and septicaemia in Britain hit the highest level for fifty years. Meningitis can be caused by either viruses or bacteria. Viral meningitis is rarely life-threatening, but several types of bacteria can and still do, cause serious disease. The commonest bacteria that cause meningitis are Haemophilus influenzae type b (Hib), Streptococcus pneumoniae (called the pneumococcus, because it also causes pneumonia), and Neisseria meningitides (the meningococcus). H. influenzae used to be the major cause of meningitis in children, but the introduction of the Hib vaccine in the early part of this decade has led to the virtual eradication of this disease. In Britain, there are about two and a half thousand cases of bacterial meningitis each year, and about half of these are due to the meningococcus. About ten percent of normal, healthy individuals carry meningococci in their nose and throat, although the percentage of carriers amongst young adults is substantially higher than this: it is not known what causes the bacteria to enter the bloodstream and from there the central nervous system to cause disease. Those at greatest risk of meningitis are babies and young adults, especially students during their first year at college. The susceptibility of students seems to be related to communal living in shared accommodation, such as halls of residence and is now a major cause of concern amongst university health services.
Meningitis is caused by inflammation of the linings of the brain and spinal cord. The symptoms are variable and depend on the age of the individual. The first symptoms may simply be sickness, fever, tiredness and irritability and can resemble early signs of flu, or even be mistaken for a hangover!. Seizures occur in about a third of patients and the individual may complain of a stiff neck and exhibit a purplish rash. In babies many of these symptoms may not develop and the only signs of the infection may be irritability. The disease can progress very quickly: in the case of meningococcal infection about ten percent of cases are fatal and about a third of survivors suffer from permanent brain damage. Antibiotics can be highly effective against the bacteria which cause meningitis, but they have to be administered quickly, which poses problems, given the vague nature of early symptoms. In addition, the emergence of antibiotic-resistant strains of the bacteria has become an increasing problem. Clearly, the ideal solution for the control of meningitis would be through vaccination in early infancy.
The bacteria that cause meningitis are covered by protective coats made up of long chains of sugar molecules known as polysaccharides. These coats are important for the survival of the bacteria in the bloodstream. Following an infection, the immune system produces protective protein molecules called antibodies, which circulate in the bloodstream and stick to the coat polysaccharides. They cover the bacteria which are then recognised as foreign and destroyed by specialised cells of the immune system, thereby eliminating the infection. Different types of the bacteria carry different polysaccharides, so that infection with say meningococcus type B does not lead to immunity against the C strain of the organism, or vice versa. The first vaccines produced against agents like the pneumococcus and the meningococcus therefore contained mixtures of polysaccharides extracted from different organisms. These vaccines are quite effective in adults, but their effects are fairly short-lived, and they are completely ineffective in infants less than two years old. The immune system of infants is, for reasons that are not completely understood, incapable of producing good immune responses to polysaccharides. In contrast, infants can respond well to proteins of microorganisms, such as tetanus toxoid, one of the components of the DPT triple vaccine.
An important property of a successful vaccine is its capacity to induce so-called immunological memory: this leads to a rapid, strong immune response in a vaccinated person if they are exposed to the infectious agent in the future, or if they are given a ‘booster’ dose of the vaccine. Immunological memory induced by a good vaccine can persist for many years. In general, microbial proteins produce excellent immunological memory, whereas polysaccharides do not. The strategy adopted in attempts to produce more effective vaccines against bacterial meningitis were based entirely on the results of experiments performed in mice. The immune responses of mice to bacterial polysaccharides are remarkably similar to those of humans, and scientists could study them in detail under carefully controlled laboratory conditions. The results of these experiments indicated that attaching polysaccharides to so-called ‘carrier’ proteins greatly improves the immune response to the polysaccharide and also induces long-term immune memory. This led researchers to investigate the possibility of enhancing the effectiveness of meningitis vaccines by attaching the bacterial polysaccharides to a microbial protein, producing a so-called conjugate vaccine. The first conjugate vaccine against meningitis, the Hib vaccine, was included in the childhood vaccination programme in the UK in the early part of this decade, and has led to almost complete eradication of meningitis caused by H. influenzae. Needless to say, the success of this approach stimulated the development of similar conjugate vaccines to the other causative agents of bacterial meningitis.
The announcement by the Secretary for Health in July 1999 of the release of a new vaccine for type C meningococcus was therefore greeted with great enthusiasm in the press. This strain of meningococcus accounts for forty percent of meningococcal infections in the United Kingdom. The remainder are caused by the B strain, and the Public Health Laboratory Service is in the process of conducting trials of a conjugate vaccine against this strain, with encouraging results. In both instances, the conjugate vaccines are highly effective in babies and also induce immune memory responses. Immunisation of babies and teenagers against type C meningococcus began in October this year, and over the first year some fifteen million individuals will be vaccinated. Babies will receive the vaccine together with DPT at the age of two, three and four months. In fact, the new vaccine was first given to two hundred and fifty children in Coalville, Derbyshire in August, following an outbreak of meningitis C in the village. Because of the limited supplies of the new vaccine, first year students enrolling in college in the autumn of 1999 were strongly advised to get themselves vaccinated with the existing non-conjugate polysaccharide vaccine, which gives about eighty percent protection.
Health authorities have welcomed the arrival of this new vaccine with enthusiasm, since it heralds the eradication of one of the major causes of meningococcal meningitis in Britain. However, some parent groups have been somewhat more cautious, believing that the addition of yet another vaccine to the considerable number already given to infants could overburden their immature immune system. In truth, there is no scientific evidence that the current vaccination programme produces any such deleterious effects. Nevertheless, there have been several vaccine ‘scares’ in recent years. The most recent one resulted from a study, involving a very small number of children, which linked the mumps vaccine with the development of autism, or bowel disease in children. Subsequently, more extensive studies contradicted this claim, but in the meantime the percentage of infants receiving the MMR vaccine had dropped from ninety to seventy-five percent. This sort of panic amongst parents raises the spectre that some of the killer diseases of childhood, which have essentially been eradicated as a result of mass vaccination, might reappear.
So what does the future hold for the control of bacterial meningitis? As I mentioned previously, trials of a conjugate vaccine against the B type of meningococcus are already underway. If the encouraging early results of these are sustained, then this vaccine should become generally available within a few years. If the percentage of children who become vaccinated with the C and B type vaccines reaches sufficiently high levels, this will reduce the percentage of people who carry the bacterium, and this could well lead to eradication of meningococcal disease in Britain.
The remaining cause of bacterial meningitis, the pneumococcus, also poses very serious problems. In the United States the pneumococcus is the major cause of meningitis and in developing countries pneumococcal infections are the principal cause of death in children under two years old. Pneumococcal pneumonia is also a significant cause of death in elderly people, particularly those living in institutions. There are at least ninety different types of pneumococci, and infection with one type does not induce immunity to the others. Polysaccharide vaccines against the most important types have been available since the end of World War Two. Ironically, their use was abandoned for some time when antibiotics became available which were highly effective against pneumococcal infections. The vaccines were subsequently reintroduced, since a significant percentage of pneumococci have become resistant to common antibiotics, such as penicillin. The available vaccines against pneumococci suffer from the same shortcomings as those of the original meningococcal vaccines: in particular, they are ineffective in children under the age of two. So, researchers have also attempted to develop protein-conjugate vaccines against this bacterium. The logistical problems of this approach are formidable, since it is reckoned that the vaccine would have to induce immunity against at least twenty-three types of pneumococci. There are therefore concerns about the sheer amount of the ‘carrier’ protein that would have to be administered to say, infants, which could have unknown effects on the developing immune system. In addition, different types of pneumococcus are found in different parts of the world, so that a vaccine made for the population of the United States of America may not be effective in for example African children. Clearly considerably more research needs to be done before this infectious disease can be effectively controlled.
In conclusion, the introduction of the meningitis C conjugate vaccine into Britain opens up another chapter in the fight against this deadly disease. It raises the distinct possibility that meningitis may join the long list of infectious diseases which have more or less been eradicated in the western world.