Meningococcal epidemic - fighting a killer

Plans to vaccinate everyone aged under 20 against meningococcal disease depend on the success of a trial starting in Auckland shortly. ANDREW LAXON reports.

In a few months volunteers should start walking through the doors of the University of Auckland medical school, rolling up their sleeves and giving blood samples.


The 90 human guinea pigs will then be given an injection against meningococcal meningitis, the disease that has killed 184 New Zealanders, many of them children, in the past decade.


Thirty will get a new vaccine, developed specifically for New Zealand. Thirty will get a variation on this vaccine, and the rest will get the Norwegian vaccine, which served as model for our version.


The 18-to-50-year-olds taking part in this clinical trial - possibly Auckland Hospital doctors and nurses if other Aucklanders are reluctant to come forward by May - will take away a diary to record any reactions, such as a sore arm or a temperature.


Six weeks later, they will be back for another dose and another blood test to see if the vaccine is working. In six more weeks, they will return for their final dose and blood test (all sent to Government laboratories for evaluation, with checks by international experts).


Then scientists will start to know whether the $100 million experiment to stop New Zealand's worst infectious disease is working.


For Professor Diana Lennon, the childhood infectious diseases specialist running the trial, an even more important test will come in the next phase.


If the vaccine works on adults, she hopes to start trials among 100 to 150 older schoolchildren this year, before moving on to the same numbers of toddlers and babies. She describes this as the absolute "stop-go" point of the trial - children under 5 with poorly developed immune systems are the disease's biggest victims.


If the second phase works, the vaccine will gradually be introduced into high-risk areas such as South Auckland. If it brings the disease rate down with no severe side-effects, the vaccine will be used to immunise a million New Zealanders under the age of 20.


After that, meningococcal B vaccine could become part of the child immunisation schedule given at six weeks, three months and five months (with shots against hepatitis B, diphtheria and measles, mumps and rubella) within the next five years.


All this involves a lot of "ifs", but the scale of meningococcal disease has given the search for a vaccine a sense of urgency. Since 1991 New Zealand has suffered 184 deaths and the epidemic is expected to last another decade, with 4000 more cases and 200 more deaths.


One in every 100 Maori and Pacific Island children under 5 can expect to catch meningococcal disease, which is strongly linked to poverty.


Although no one knows exactly what causes it to spread, Auckland researchers have shown that the risk here increases with household overcrowding. Overseas research has suggested a link with passive smoking, but not enough to account for all the cases.


As a result, public health specialists regard an effective vaccine as the best hope of fighting meningococcal meningitis. The problem is that finding one for the New Zealand strain has been challenging scientists for decades.


All vaccines work by giving the body a tame version of the real disease which gradually builds up the body's natural defences. The trick in developing a new vaccine is to find the substance in the bug carrying the disease which will provoke human antibodies into a hostile reaction.


Although the presence of antibodies does not guarantee a successful vaccine, it is considered a reliable guide. Scientists scrutinising the blood tests in the Auckland clinical trial will therefore be looking for a certain level of antibodies - Professor Lennon says the exact "pass rate" is still to be determined - to see if the vaccine is working.


In the case of meningococcal meningitis, the disease comes in three main types - A, B and C. Since the late 1960s, vaccines based on purified sugar molecules known as polysaccharides from capsules on the outer coat of the bacteria have been used against groups A and C.


But these vaccines do not work against meningococcal B. There is an added danger that the polysaccharide-based vaccine has a chemical which resembles substances in brain tissue. In theory, this could trick the immune system into attacking the brain as well as the disease.


So researchers in the 1970s decided to change tack. They reasoned that since most people who came down with meningococcal B disease seemed to be immune to second episodes, the meningococcal B bacterium itself must contain the tools for immunity.


Studies showed that the blood of patients recovering from meningococcal B contained antibodies which had formed against the outer membrane protein (OMP) and a lipopolysaccharide (LPS), a lipid-sugar molecule.


There have since been encouraging but mixed results with this method in three countries closely studied by New Zealand researchers - Cuba, the Netherlands and Norway.


In the 1980s, Cuban researchers reported an 80 per cent success rate among 106,000 students with an OMP-based vaccine. But when the same vaccine was given to 2.4 million Brazilian children aged 3 months to 6 years old, it proved only 47 per cent effective for 2-to-4-year-olds and did not seem to work at all for children under 2.


New Zealand eventually rejected the Cuban vaccine. However, Professor Lennon says, the poor result in Brazil may have been caused by a badly conducted trial, rather than the vaccine itself, which later showed promise in Chile.


In 1996, New Zealand came close to an agreement with Dutch public health officials, who had been working on a similar vaccine.


But neither country pursued the idea hard enough - Professor Lennon says the epidemic here had waned and some officials thought it might be over - so momentum was lost.


Meanwhile, Norwegian researchers had put together a vaccine which initially did not seem as promising. It was only 58 per cent effective when tested on 171,800 children aged 12 to 16 and protection levels later fell away. Not surprisingly, Norwegian public health specialists did not recommend that all children should be given the vaccine.


Professor Lennon says the results turned out to be better than they looked. As in the Brazilian trial, the children had been given only two doses instead of three. The vaccine had protected 87 per cent after 10 months, suggesting that a third dose could lock in the immunity.


The other potential problem was that experience showed every strain of meningococcal B was different, so the proteins collected from one strain had limited effectiveness against another.


The answer was to take a protein from the New Zealand strain and use the Norwegian technique to make a new "designer" vaccine.


That was the approach taken by American vaccine maker Chiron - whose meningococcal C vaccine has been widely used in Britain and Canada - in collaboration with Norway's National Institute of Public Health.


Their proposal secured the contract with the Ministry of Health, announced by the Government last month.


Ministry public health specialist Dr Jane O'Hallahan says the Norwegian-Chiron bid was not just the best product. One of the main difficulties in getting a vaccine had been finding a company able to supply more than three million doses for the New Zealand market.


Chiron met several important criteria, including manufacturing capacity and company expertise to back up its product.


Dr O'Hallahan says she is 90 per cent confident that the vaccine will work, based on positive comments by a panel of international experts which the Health Research Council has commissioned to check on the ministry's work.


For Professor Lennon, the immediate hurdle is gaining ethical approval to begin trials in May. It looks likely, but as the trials continue, obstacles are bound to become tougher.


For instance, she says, half the children in the second-phase trials will be given the new meningococcal B vaccine. The other half - the control group - will receive a jab for meningococcal C, which gives limited protection, rather than a placebo such as water.


This is for ethical and practical rather than scientific reasons, she explains.


It is hard enough to persuade parents to volunteer their children for tests of an unproven vaccine, without the prospect that the children will not benefit at all.

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