Meningitis is a word that fills parents with dread. Accurate early diagnosis to distinguish Neisseria meningitidis infection from other milder childhood diseases is difficult. Coupled with the rapid progression from a mild fever to a situation requiring urgent hospital treatment can be truly frightening. On top of all this, even when antibiotic treatment is quick enough to save a life, survivors are often left permanently scarred with tissue or brain damage. An effective vaccine would remove the threat.
Medical research into the development of a vaccine against bacterial meningitis began over 100 years ago. However, it was soon obvious that N. meningitidis, the meningococcus, was a complex bacterium and immunisation against one strain would not necessarily protect against other meningococcal isolates. It would be a challenge to identify the key components of the bacteria needed for such a vaccine and to determine the number of different meningococcal strains causing disease. Thus the development of a broadly effective vaccine has proved to be a significant challenge and taken decades to achieve. Eventually a way of identifying disease-causing isolates was developed using antibodies in blood that recognised the sugar capsule on the meningococcal surface (a process called serogrouping). Twelve meningococcal groups were identified in this way denoted by letters of the alphabet of which five (A, B, C, W and Y) cause the majority of disease.
NIBSC has a long history undertaking testing of candidate and licensed vaccines and crucially performing parallel research work that has supported the UK’s leading role in using vaccines to protect the public from this potential killer. Work on the meningococcus began in the Bacteriology Division back in the 1980’s. At that time an experimental vaccine had been developed against meningitis B strains that had been causing outbreaks of disease in Norway and Cuba. These vaccines were produced by purifying part of the outer surface or membrane of the bacteria. These so-called vesicles contained key proteins, which antibodies needed to bind to prevent disease. However, these vaccines only offer protection against similar isolates of meningitis B and whilst this vaccine was used selectively to prevent disease outbreaks in countries including New Zealand, it was not taken up within Europe.
Clearly the failure of a vesicle vaccine to protect against all serotype B isolates indicated that sero-typing alone was unable to distinguish differences between strains. At about that time, the Bacteriology Division recruited two new scientists Martin Maiden and Ian Feavers who applied new molecular methods that would allow finer discrimination between the different meningococci. They developed methods to sequence the gene(s) encoding the key bacterial proteins present in the vaccine and identified the complexity of variation that existed among isolates. As sequencing methods improved allowing more ready analysis of larger pieces of the meningococcal genome, Martin Maiden (now at the University of Oxford) and Ian Feavers, together with their teams and collaborators developed the first MLST (fingerprinting) scheme to help understand how and where new disease strains have arisen, based upon characterising the sequence of relatively stable “housekeeping” genes as well as the variable genes that code for proteins of the surface of the bacterium.
During the 1970s vaccines that protected adults had been developed based on the sugar capsules of the group A and C strains but the difficulty with this approach was that the immature immune system of babies and infants meant that this type of vaccine didn’t work in those that most needed it. The breakthrough came when an old immunologists “trick” was applied. The relatively poorly immunogenic sugar components from the meningococcal capsule were chemically linked to a protein vaccine (e.g. tetanus or diphtheria toxoid), a process called conjugation, making a much more effective vaccine, particularly for young children.
According to the tabloid newspapers, Britain was under “siege” from Meningitis C, in the latter half of the 1990’s. Clusters of infections were appearing across the country not only amongst young children, but also students off at college. What could stop the deaths of these healthy young people? Under this pressure, in 1999 the UK Government implemented a vaccination campaign with new glycoconjugate vaccines against Meningitis C in infants, with catch up doses given to everyone up to 18 years of age in school. The challenge for NIBSC was to ensure the safety and quality testing of the numerous batches of vaccine needed for such a campaign and, in particular, what tests would be needed for checking this new class of glycoconjugate vaccine. Chris Jones and Barbara Bolgiano working in the LMS group at NIBSC were investigating how to apply physico-chemical methods for characterising complex biological medicines. Nuclear magnetic resonance techniques had been applied to characterise, in detail, the complex sugar structure in the capsule of Neisseria and this method was applied to provide evidence that the same sugar structure was present in the vaccine. Likewise, high performance liquid chromatography was demonstrated to be a powerful way of ensuring that these bacterial sugar structures were coupled to the protein “carrier”. It soon became apparent that physico-chemical methods were sufficient to assure that a batch of vaccine would be effective, meaning that assays involving animals were not required to assure the quality for this type of vaccine and so the Institute was able to stop performing the test.
Within months it was clear that the immunisation programme was cutting the incidence of Meningitis C across the UK and this success has been sustained. The expertise built up at NIBSC assuring the quality of Meningitis C vaccine attracted the interest of scientists trying to grapple with a far bigger challenge of Meningitis A epidemics in sub Saharan Africa. In contrast to about 1000 cases of Meningitis C in the UK prior to the introduction of the vaccine in sub Saharan Africa in 1996/97 there were over 250,000 cases of Meningitis A, resulting in more than 25,000 deaths! As part of the Meningitis Vaccine Project run by PATH and the WHO, NIBSC scientists worked with both the vaccine manufacturer and the regulatory authorities to assure the quality of the new MenA conjugate vaccine MenAfriVac® . Mass vaccination campaigns that began in 2010, have had a striking impact in reducing the cases of disease reported from the 18 nations involved in the project.
Effective glycoconjugate vaccines are now available for meningitis strains A, C, W and Y either alone or in combination. This just left the problem of Meningitis B. Unfortunately, the sugar structure on the B capsule is remarkably similar to the sugars found in the human brain and nerve cells. There was a risk that, if it worked, a glycoconjugate vaccine could generate antibodies that would attack and damage nervous system. As a result vaccine scientists have gone back to the original approach of using vesicles derived from the outer membrane of the bacterium. However, by the late 1990s the meningococcal genome sequence had been deciphered and the vesicles were combined with three recombinant proteins, first identified by their genes, to try and broaden the protection offered by vesicle approach. Once again, in September 2015, the UK was the first country to introduce this vaccine, called Bexsero, into routine immunisation programme. The Meningitis Group at NIBSC has once again worked closely with the vaccine manufacturer to ensure appropriate tests are performed to assure the quality of each batch of vaccine made. One of the innovative approaches being introduced by NIBSC on the evaluation of this new vaccine is an in vitro test to measure the presence of pyrogens. These are components or contaminants of vaccines and medicines that can cause high temperature or fever. One of the prescribed tests for measuring this activity involves the use of animals. However, over the past 15 years, Steve Poole and his colleagues in the Bio-therapeutics Group at NIBSC have developed in vitro assays that quantify the key molecules that initiate the fever response in humans. The introduction of this new vaccine provided an opportunity to implement these in vitro methods thereby reducing the use of animals whilst providing more detailed about the characteristics of each batch of vaccine.
Large, often multi-national, companies are needed to undertake the long and often challenging process to develop and manufacture new vaccines. At the same time, the relatively small team at NIBSC have generated the scientific framework to support the introduction of 2 new meningitis vaccines that have prevented about half a million cases of infection and thousands of deaths both here in the UK and in Africa and continue in their work to support the introduction of a third new vaccine in 2015.