The British government has rushed through a new vaccine for meningitis C and plans to offer it to every child and college student. There's not much we will know about side effects until it's too late.
On November 1 of last year, Liam Donaldson, the Department of Health's chief medical officer, announced the launching of a mass vaccination campaign against the group C strain of meningococcal meningitis. "By the end of nextyear," Donaldson confidently announced, "we hope to have confined this particular strain of meningitis largely to the history books."
Unusually for vaccine programmes in this country, which ordinarily copycats products and vaccine programmes formulated in other countries chiefly America this vaccine is true, blue British. Not only is the vaccine born and bred in Britain, but this is the only country to have launched a mass vaccination campaign against meningitis to date.
So confident were the powers that be about initial studies of the new, improved vaccine that they pushed forward the intended launch date by a year. At a time when the National Health Service was more strapped than ever for cash, Donaldson and Dr David Salisbury, the DoH's principle medical officer, managed to garner lb10 million to launch an ambitious scheme which would innoculate all of the nation's 14 million school children within a year.
The plan was to vaccinate the entire pool of children in stages, beginning with those most at risk teenagers aged 15 to 17, then babies under a year, who would receive the jab at the same time they were given the standard first collection of shots. Last month, supplies permitting, the government was to move on to children aged one to five, who would receive it with their MMR booster jabs. As yet more supplies became available, the rest of the population of children would be offered the jab, with the plan to reach the rest of Britain's children by the summer.
Although the new vaccine wasn't to be ready until November, the government paved the way for publicity about it in August by launching a vaccine drive for university students, who would receive the old A and C combined polysaccharide vaccine (see box, p 1). Although the old vaccine is considered less effective and shorter lasting than the new one, the idea, said a DoH spokesperson, was that at least the vaccine would see the nation's 480,000 freshmen students through their three year university tenure.
But behind the smiles at the DoH and all the self congratulatory back patting lies a rash decision and all the makings of a scandal not dissimilar to that of the measles campaign of 1994. At that time, all the nation's school children were pressed into receiving a booster measles jab, supposedly to ward off a predicted measles epidemic. The epidemic never arrived, but at least several hundred families are currently suing vaccine manufacturers over apparent brain damage, paralysis and even death suffered by their children allegedly due to the measles booster.
With the new meningitis vaccine, the press has whipped up a fury over the limited supplies of the old vaccine, which were inadequate to meet the demands of the university students. In focusing on the shortage, journalists have missed the real scandal here, which has to do with expediency and, inevitably, politics. In the wholly laudable desire to staunch the increasing number of meningitis cases on the part of all involved, an alliance with no checks and balances has been forged between a government wishing to be regarded as heroic and a private company, with its need to turn a profit. In the process, our entire population of children are being exploited as a giant, convenient pool of guinea pigs.
Not an epidemic
Much has been made of meningitis as a random killer of children, and there is no doubt that it is horrendous and frightening in its rapid, potentially fatal onset. But just how much actual risk does your child face?
Although the plan is to give all children the vaccine, rather than simply individual groups at high risk, children between five and fifteen are at virtually no risk of contracting meningitis C. In the five year period between 1994 and 1999, group C meningococcal disease killed approximately 20 babies under one, 21 babies aged one, 18 two year olds, approximately 15 three year olds, a handful of four, five and six year olds, and almost no other children under adolescence.
After babies are a year old, they develop active immunity by being exposed to a non pathogenic form of meningococcus.
Casualties did not pick up again until the age of fifteen through twenty, the so called highest cluster. In this age category, meningitis killed some 12 fifteen year olds, approximately 30 sixteen year olds, 12 seventeen year olds, about 18 eighteen year olds, about 18 nineteen year olds, and 10 twenty year olds over five years. So, in total, the disease killed approximately 200 young children, or an average of 40 children a year (70 a year in 1999).
While no one wishes to denigrate the tragic loss of these lives, in strictly epidemiological terms, the death rate of this form of meningitis is small potatoes.
It rates well behind many accidents as conditions which account for appreciable numbers of childhood deaths. For instance, your baby is five times more likely to drown in his bathtub and 86 times more likely to die of cot death than die from meningitis C. Six times as many children and young adults get knocked over and killed by cars than die of meningitis C. British traffic deaths of all varieties among children representing the highest fatalities among this age group in all of Europe claim the lives of 1,309 children and young adults every year more than 32 times the rate of meningitis deaths.
If there were an average of 50 childhood deaths from meningitis C in 1998 and there are 14 million British children, generally speaking, your child's chances of catching this disease at the moment are one in 200,000, with slightly higher risks in babyhood and late teens. However, it is the tragic swiftness of the disease's deadly progress and the existence of so called local clusters that placed the disease on the front pages. Media coverage, more than the actual prevalence of the disease, accounts for its high profile and also for the irrational fear instilled in the public mind about it.
No one would wish to put a price tag on the heads of these dead children. But one must question the wisdom of throwing such heavy economic resources at a disease with such relatively small fatalities, rather than simply concentrating on groups at high risk: those without spleens, with chronic underlying illness, and in crowded or impoverished conditions.
Heikki Peltola, professor of infectious diseases and pediatrician at the University of Helsinki and the Hospital for Children and Adolescents, confirmed that although the UK has a higher per capita incidence of this disease than other countries do, including his native Finland, "The question was whether the incidence of this diease was high enough to merit mass immunisation. In no country is there an epidemic of this disease". As he wrote recently in an article about meningitis vaccination (Drugs, 1998; 55: 347-66): "Generally speaking, the incidence of meningococcal disease is too low to indicate vaccinations for the whole population, or even children, but some risk groups and epidemics are important exceptions."
A deadlier form of meningitis
The British government has touted Neisseria meningitidis group C as the most deadly bacterium causing meningococcal disease, which affected 1,530 people in Britain last year and claims the lives of one tenth of those who contract it.
But not according to the DoH's own "factsheet". Group C meningococcal disease, which began appearing only a decade ago, accounts for only 40 per cent of cases of meningitis contracted in Britain and elsewhere. Between 1994-9, meningitis B killed nearly 70 infants under one. This incidence represents more than three times the number of deaths of meningitis C among this age group during the same period. Strain B also killed twice as many one year olds as did strain C. In all, meningitis B killed approximately 170 children under six which represents the same number of deaths from meningitis C among all age groups combined. Although meningitis C is the major cause of meningococcal death among teenagers, accounting for 80 per cent of deaths (meningitis B only claimed the lives of about 24 teenagers and young adults), the B version is far more deadly to babies and small children, representing at least two thirds of all meningococcal deaths in this age group.
David Hall, corporate affairs manager for Wyeth, who developed the new vaccine, says that so far, producing a vaccine for the B strain has proved elusive. "B has structural differences, having to do with one of antigens on the polysaccharide protein code," he says. "For some reason, that makes it difficult to come up with a workable vaccine."
Dr Richard Nicholson, editor of the Bulletin of Medical Ethics, is concerned that even if this vaccine proves 100 per cent effective, it will protect against only a minority of meningococcal cases. Nevertheless, its existence could cause the public to become complacent about watching for warning signs of the disease caused by the other strains.
Immunity for life?
This vaccine will offer teenagers "almost 100 per cent immunity for life", wrote the Times, and the DoH confirms that besides babies, who will get three doses, a single dose is sufficient in all other children. In the very first edition of What Doctors Don't Tell You, we quoted then health minister Edwina Currie claiming that the new triple measles, mumps, rubella (MMR) vaccine would offer "life long protection with a single jab". Five years later, the British government launched the countrywide booster campaign, after massive epidemics of measles among previously vaccinated youngsters in America proved that the MMR does not, after all, give you protection for life.
If the meningitis vaccine works similarly and most vaccines appear to wane over a decade then teenagers and young adults vaccinated as babies and toddlers will experience waning immunity just at a point where they are most vulnerable to the disease.
Besides not knowing how long this vaccine will last, no one is sure how many shots and of which variety will confer long term protection.
In one study of 114 infants from West Gloucestershire, babies were randomly divided into groups receiving either a 2 mcg or 10 mcg dose of meningococcal C vaccine. Then, half the infants received the old A and C polysaccharide vaccine at 15-20 months. (The others were to receive this booster at age 4.)
Among those getting the lower initial dose, bactericidal antibody titres rose at five months but fell by 14 months to not much higher than they were originally (1: 4 to 1:1057 to 1: 19). With those receiving the 10 mcg dose, antibody responses were significantly higher at five months than in the 2 mcg group, but were lower after boosting with the plain polysaccharide vaccine than with the lower dose group.
This appears to mean that 1) the government believes that boosters will be necessary at some point and is probably already planning for them and 2) nobody really knows which combination of vaccines higher or lower doses for initial shot and follow up boosters is really going to work, or whether using the old polysaccharide vaccine actually lowers your immunity, as it appears to in one study (J Infect Dis, 1999; 179: 1569-72).
The researchers say in the conclusion of their report that "total antibody levels required for protection against serogroup C disease are not known (italics ours).
In another study, also by the PHLS (J Infect Dis, 1996; 174; 1360-3) of a conjugate meningococcal combination A and C product, antibodies also fell rapidly 12 to 14 months later, even after three doses.
Because the antibody levels fell so rapidly, the PHLS addressed itself to what it says is the good news the presence of immunologic "memory". The Hib vaccination, they claim, offers long term protection despite the fact that antibody levels fall rapidly with that vaccine as well. As the Hib vaccine has only been around for a handful of years, time will tell whether that theory is correct.
According to Wyeth's David Hall, the old "polysaccharide" vaccine works at best 75 per cent of the time on older children and wears off after a few years. It does not work in babies and toddlers. The new "conjugated" variety, called Meningitec, has produced immunological "memory" cells in babies and toddlers by being piggybacked onto the diphtheria toxoid, which produces a sort of red alert immune system response (see box, p 1). The existence of these memory cells, he says, means that it's likely the vaccine will last longer, but nobody knows for sure. "We know that this is a sign of long lasting immunity," says Hall, "but until you embark on a mass vaccination programme, you're never going to prove it."
Lucky for Wyeth, then, to be located in Britain. Several years ago, the DoH and its government sidekick, Public Health Laboratory Service, which studies, monitors and formulates immunisation policy, approached Wyeth and other vaccine companies, asking them to step up research into a meningitis C vaccine and even offering to help research it.
When Wyeth got to the finish line first with a product, the PHLS basically took over its testing. Many of the larger trials were conducted by the PHLS.
"One way we were able to bring forward our launch date was because we worked together in collaboration with the DoH," says Hall. Rather than our company having to set up trials, the PHLS did much of the studies for us."
In other words, Wyeth was able to fasttrack this drug through the usual drug approval procedure, which ordinarily requires a drug company to set up its own trials. The government is then supposed to act as an independent judge, approving them on the basis of safety and effectiveness. In this instance, defendant, prosecution, judge and jury were all effectively on the same team.
A further wrinkle on might be labelled a conflict of interest has to do with the monitoring system of the Public Health Laboratory Service. In 1994, the PHLS devised a surveillance system for monitoring side effects of vaccines. This was first tested out with the all country measles booster scheme, leading the cynical to wonder whether the mass measles campaign was manufactured in order to test out the effectiveness of the new system.
By working with the PHLS, the third party in the collaboration, Wyeth ensured not only that its studies had the most positive spin possible, but also that the product would be given a blessing to be test marketed on a mass basis through this new surveillance system. As Hall says, no one would know the effectiveness of the vaccine until it was mass marketed. In effect, the government is carrying out the best post market testing that Wyeth could ever have dreamt of.
Illness from the jab
The vaccine is highly safe, says the DoH, or "harmless", as Heikki Peltola put it. That is an assertion that no one can make about any vaccine, let along a brand new one that is neither tried nor tested. Although the meningitis C vaccine was tested on 6000 British children, and more than 21,000 people outside the UK, these were short term tests, lasting at most a few weeks, and many of the trials remain unpublished that is, unavailable to anyone outside of Wyeth or the government.
In the largest of the three published trials shown to WDDTY, all conducted partly or entirely by the Public Health Laboratory Service among 114 infants vaccinated at two, three or four months, side effects were only recorded for seven days by parents and a health nurse (J Infect Dis, 1999; 179: 1569-72). Any symptoms outside this window of time probably would not have been associated with the vaccine. Nevertheless, within the small cohort of babies, 26 of those receiving the lower dose and 53 of those receiving the higher dose had systemic symptoms within the first 24 hours from one of three shots.
Although "systemic symptoms" were not defined, they presumably mean that the children were generally ill after the jab. According to this report, more than one fifth of the jabs 79 out of a total of 344 jabs made babies in the vaccine groups ill. Seven of the low dose group and eight of the high dose group more than 13 per cent developed a fever higher than 38 degrees centigrade. Five of the babies had persistent crying for more than one hour in the first day after the vaccine. Nine babies had erythema (reddening of the skin) of more than 2.5 cm and eight had swelling of more than 2.5 cm.
These latter side effects which consisted of mainly swelling at the injection site were noted to be less than those caused by the Hib vaccine, leading to the often quoted remark that this vaccine produces fewer reactions than other ones.
In its data sheet, Wyeth reports that systemic reactions usually include crying, irritability, drowsiness, impaired sleeping, anorexia, diarrhoea and vomiting, all conditions that are "common" after vaccination. Nevertheless, the company points out, "there was no evidence that these were related to Meningitec, rather than concomitant vaccines, particularly DTP vaccines" as most of these have been given at the same time.
Those reactions the company admits "may possibly be related to the vaccine" include headache and myalgia in adults and irritability and drowsiness in younger children.
One baby was hospitalised for a viral illness following the second vaccination, although the PHLS maintains that this illness was not attributable to the vaccine. One baby given the old A and C polysaccharide jab developed a generalized rash, "mild" facial swelling, cough and coryzal (acute rhinitis) symptoms within five hours after vaccination, although these symptoms resolved within two days after oral antihistamines were given. This baby had no evidence of antibodies to A or C meningococcus in other words, the vaccine didn't work on him. The researchers again concluded that these adverse events, despite happening within hours of the jab, were "not vaccine related".
In one independent case study, a 25 year old woman developed acute disseminated post vaccinal encephalomyelitis (ADEM) after being vaccinated with the old combination group A and C polysaccharide vaccine (Arq Neuropsiquiatr, 1997; 55: 632-5). The symptoms only disappeared and the lesions on the myelin sheath of her nervous system finally resolved after treatment with high doses of intravenous steroids. As the researchers noted, although most cases of ADEM have been related to other vaccinations or conditions, this case report indicates that it may also be related to exposure to A and C polysaccharide protein vaccines and meningococcal vaccine. Whether ADEM becomes a new condition in children once the meningitis C vaccine is widely disseminated is anyone's guess.
In an adult study of another meningitic C vaccine which had been conjugated with the tetanus toxoid, half the 30 subjects reported tenderness at the injection site and half erythema, 13 or nearly half reported pain, two reported headache, and one myalgia.
One patient had a fever higher than 38 degrees C five to seven days after vaccination, but this again was discounted because the researchers said it was associated with a viral illness" (Vaccine; 1999; 18: 641-6).
As David Hall says, we won't really know the long term effects until the product is out in the mass market. Indeed, we won't be sure of anything until virtually every child in Britain has been given the jab.
"There is no evidence that multiple vaccines overload a child's immune system," says the DoH factsheet. But we don't know the effect of this vaccine on other vaccines given at the same time, as this wasn't really tested for, since multiple vaccines are always presumed to be safe before proven dangerous.
Including the meningitis C vaccine on the standard schedule of infant vaccinations now increases to six the number of vaccines given simultaneously to infants at two months of age.
In the British infant study, the researchers admitted that "increased amounts of carrier protein may interfere with immunologic priming with other conjugate vaccines. This should not affect protection induced by this vaccine but may be important in combination conjugate vaccines using the same carrier proteins." This means that the new vaccine may interfere with other conjugate vaccines like the Hib vaccine although, again, we won't know until we suck it and see.
No doubt the government was motivated by nothing but good intentions in rushing through this new vaccine. But the history of vaccination shows that it is always wise to err on the side of caution. In the US, a vaccine for pneumococcal meningitis under development, also produced by Wyeth, was carefully tested for four years on a sample population of 38,000 children in northern California before being released to the public at large.
In the UK, however, as with the measles epidemic, the DoH is rashly attempting wholesale herd immunity with an untested product, rather than carefully weighing up the risks and benefits of a new, potentially dangerous jab on individual children. One day the government may learn to lead with its head as well as its heart.