Oxford's role in new meningitis vaccine
A vaccine to protect children against meningitis B – the strain that now causes the vast majority of bacterial meningitis cases in this country – could soon be introduced in the UK.
On Friday the European Medicines Agency (EMA) recommended Novartis' Bexsero (MenB) vaccine for approval for babies 2 months and up. The step paves the way for a Europe-wide licence for the vaccine, and for national governments to decide whether to include it in childhood immunisation programmes.
'As paediatricians we have seen the devastating effect that MenB disease can have on young children and adolescents, so welcome the recommendation for approval for this vaccine as an important step towards the prevention of childhood meningitis,' says Dr Matthew Snape of the Oxford Vaccine Group, who is hopeful that the vaccine can be introduced into the routine immunisation schedule in the near future.
Oxford researchers, including Matthew Snape, Professor Andrew Pollard, Professor Moxon and others, played a significant role in the almost 20 years of work behind the development of the Novartis vaccine, from the early stages to clinical trials, as our earlier news story reported.
Matthew takes up the story: 'Developing a vaccine against MenB infections has been very difficult primarily because, unlike the MenC organism [a strain for which a successful vaccine was introduced in 1999], the outer coating of MenB is not recognised by the immune system.
'Over several decades many different proteins had been studied as vaccine targets without success. To overcome this, Professor Richard Moxon and others developed a novel approach whereby the MenB bacterium's DNA blueprint was used as a tool to find new protein targets,' says Matthew. 'This vaccine is a direct result of this work. It represents an entirely new approach to vaccine development, and one that has important implications for developing vaccines against other diseases.'
Professor Moxon of the Department of Paediatrics at Oxford University explains: 'The story of the underpinning science goes back to 1995. This is when the first complete genome sequence of the bacterium Haemophilus influenzae was completed and published.'
This advance opened up the possibility of using the sequenced genomes of other disease-causing bacteria as a new approach to making vaccines, as Richard later outlined in the Lancet. After all, a complete genome sequence would provide an inventory of all the genes encoding every factor responsible for the virulence of the disease, or that would prompt an immune response in the body. Vaccines that target one or more of these genes could then be developed.
'There already was a H. influenzae (type b) vaccine, so an obvious candidate for using a genomic approach was Neisseria meningitidis (meningococcus),' says Richard, 'and specifically the B strain, since for technical reasons a vaccine for this strain needed a completely new approach from that used for the ultimately successful MenC vaccine.'
Oxford had been one of the main collaborators on the project to sequence the entire DNA of H. influenzae, Richard explains, and he was then in position to persuade Craig Venter – the US scientist pioneering novel DNA sequencing methods at his private research institution, The Institute for Genomic Research – to consider sequencing meningococcus B.
Richard's laboratory in the Department of Paediatrics sent DNA from a B strain of meningococcus to Venter's group at TIGR in 1995. The strain was one isolated from an outbreak of meningitis in Stroud in 1981. Richard explains that some preliminary sequencing work began to demonstrate how powerful the genomic approach could be. At this stage, Rino Rappuoli, lead scientist at Chiron Vaccines in Italy, came in with serious project funding and, crucially, all the resources of a commercial vaccine development company. The result was a collaboration, initiated in 1996, between Chiron (later acquired by Novartis), Oxford University and TIGR in Maryland USA.
'Between 1996 and 2000, the sequencing and analysis of the B strain was carried out and culminated in two back-to-back papers in Science,' says Richard. 'The second of these papers identified a number of candidate vaccine antigens which, after much further research led by Mariagrazia Pizza at Novartis, culminated in formulations that went into clinical trials.
'The Oxford Vaccine Group was a huge player in the clinical trials that resulted in the decision by EMA,' says Richard.
The Oxford Vaccine Group, also in the Department of Paediatrics, has been involved in 7 different clinical trials of the MenB vaccine, enrolling a total of over 1000 participants (over 800 children and more than 250 students). These included the first studies in children which were performed in 2006.
Professor Andrew Pollard, head of the Oxford Vaccine Group and Matthew have been closely involved in the design, planning and analysis of results for these studies.
Matthew says: 'The initial paediatric studies conducted in 2006 enrolled 2 month old and 6 month old children to receive one of two formulations of this vaccine. One of these formulations induced a broad immune response against multiple strains of the MenB bacterium, and was therefore taken forward for further assessment in a larger study conducted across five European countries.'
The results from this larger study, in which the Oxford Vaccine Group was again involved, enrolling 400 of the 1800 infant participants, provided data critical to determining how the MenB vaccine might be incorporated into existing child immunisation schedules.
So what can we expect from the new MenB vaccine now it's on its way to being licensed? After all the meningitis C vaccine has been enormously successful. There have been only 2 deaths in children and young people under 20 in the last 5 years, compared to 78 deaths in the single year before the vaccine was introduced.
Matthew says: 'Each year between 460 and 860 children and adolescents suffer either meningitis or septicaemia (blood poisoning) due to MenB in England and Wales, with the highest rates being in children below 2 years of age.
'Calculating what proportion of these cases are likely to be prevented by immunisation with the MenB vaccine has been a considerable challenge, as the proteins targeted by the MenB vaccine vary between different MenB bacteria. But early estimates are in the region of 75%, which would be an enormous step forward in the goal of preventing childhood meningitis.'
He adds: 'As with all new vaccines, ongoing surveillance is going to be the key to understanding how the vaccine can be employed most effectively. One key question is whether using the vaccine in a large proportion of the population will reduce circulation of the organism in the community, thus providing "herd immunity" to people who have not received the vaccine.'