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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.'

This video [see below] was put together as part of a set of webpages that provide a great showcase of Oxford's research on the world's most pressing health problems in the parts of the globe where it matters most. It's life-changing research that perhaps we don’t celebrate enough.

After all, Oxford's global health programme got special mention as the university retained its crown as best in the world for medicine in the Times Higher Education's World University Rankings recently.

And the university's Tropical Medicine research pages note that currently recommended treatments for malaria, dengue shock syndrome, typhoid, melioidosis, TB meningitis, diphtheria, leptospirosis are all based on work conducted by Oxford scientists.

The video and the mini-website on Oxford’s partnerships in global health give a taster of some of the projects going on in over 30 different countries around the world (check the pins in the map).

It's clear even from a quick browse through these pages that the success of this research – from tackling infectious diseases like malaria, HIV/AIDS and flu to the burden of cancer, diabetes and depression is built on long-standing partnerships with local hospitals and universities.

This is not a new model. The Wellcome Trust has funded overseas units in Kenya, Thailand  and Vietnam for decades, in which Oxford faculty members based overseas work with local doctors and researchers on an equal footing. Developing training and infrastructure has also been important, helping to inspire the next generation of health leaders in the developing world.

Nor is this research happening in a bubble or an ivory tower. It is research committed to providing practical solutions that will save lives.

One example comes from last week, with an assessment of a programme in Africa to increase access to the most effective malaria drugs.

The recommended first-line treatment for malaria are artemesinin-based combination therapies, or ACTs (the effectiveness of which Oxford researchers based overseas demonstrated). But access to these drugs in many areas is incomplete, and the use of less effective, poor quality or fake drugs can make the development of drug resistance more likely – and indeed resistance has been detected in parts of South-East Asia (thanks to partnerships involving Oxford researchers based there).

Recently, the Affordable Medicines Facility for Malaria (AMFm) has sought to increase the availability and affordability of ACTs massively in a number of countries in Africa – particularly among private-sector outlets where many buy treatments when they have a fever that might be malaria.

This hasn't been without controversy (see pieces online at BBC News and The Guardian), but an independent review in The Lancet  last week suggests the data so far show the programme has transformed access to ACTs. And a smaller piece in Science, again last week, uses maps of malaria prevalence across Africa (put together by partnerships led by Oxford researchers) to argue the case for the facility to continue.

A decision will be made this month on whether to continue the AMFm in a modified form or not. As that decision comes up, a comment piece on the Lancet research, written by a group that started discussions that led later to AMFm being set up (including Oxford’s Nick White and Richard Peto), notes that where the programme was implemented to a substantial degree, AMFm met or exceeded benchmarks for availability, price, and market share of ACTs. They conclude: ‘We must acknowledge that an efficient approach to subsidising antimalarial drugs has worked, making them available in the private sector where people go to buy them.'

You get the picture. Yes, the political, economic and social aspects of delivering effective healthcare in resource-poor countries is complex. But Oxford’s overseas partnerships are delivering the evidence and change that can help save lives. 

‘When Suzanne Ludgate of the Medicines and Healthcare products Regulatory Agency (MHRA), the government regulator of medical devices in the UK, says she was "appalled at how many devices are brought to market with a lack of appropriate clinical data," you know there must be a problem.’

So Dr Carl Heneghan, director of the Centre for Evidence-Based Medicine at the University of Oxford, begins a blog post on The Guardian site.

The term 'medical device' covers a huge range of products that have a medical use and are not medicines. The MHRA notes that this includes anything from walking sticks and hip replacements to glucose monitors, blood pressure machines and pregnancy testing kits. Every day in the UK, millions of people safely use medical devices.

But it is the regulation of these devices that Carl and colleagues at Oxford are concerned with. They have just completed an analysis of product recalls in the UK as part of a joint investigation by the BMJ medical journal and Channel 4’s documentary series Dispatches into medical device regulation. Carl’s post explains the main findings:

‘For the past 6 months, my group at the Centre for Evidence-Based Medicine at the University of Oxford has been looking at how many devices are recalled in the UK each year and what evidence supports their clinical use ... Device recalls are rising dramatically, from 62 in 2006 to 757 in 2010: a 1,220% increase. And yet, when we asked manufacturers for clinical data related to the recalls, we were stonewalled. Of 192 manufactures we contacted, only 53% (101/192) replied, and only four (2%) provided any clinical data.’

In Europe, he writes, high-risk devices only have to establish safety and performance and do not have to prove they make a difference to patients. Carl contrasts this situation with that in the US, where approvals are undertaken by the FDA, and information held is readily available.

Carl calls for the current system of medical device regulation to be tightened so that it requires evidence of improvements in clinical outcomes for patients.

Carl is not alone in this opinion. The BMJ has published a series of commentaries from leading academics as part of its assessment of the issue, from Nick Freemantle, Stefan James, Alan Fraser, John Skinner, and C Di Mario.

The BMJ’s press release says its investigation [see articles here and here] with Dispatches raises ‘serious concerns about the regulation of medical devices and ask how well these high-risk devices are tested before they come onto the market.’ It continues:

‘[BMJ and Dispatches] explore a European approval process negotiated by private companies behind closed doors and reveal a worrying lack of public information about the number of devices being used and their potential risks. They also discuss links between surgeons paid to design devices and the companies promoting them. The investigations findings are clear. The current system is not fit for purpose and we urgently need better regulation to protect patients.’

The Channel 4 Dispatches programme was broadcast last night at 8pm.

The BMJ/Dispatches investigation also saw coverage in the Daily Mail, Independent and online in the Daily Telegraph.

Separately, in an article in the European Heart Journal, heart specialists have called for an overhaul of the system for regulating medical devices such as heart valves and diagnostic imaging equipment, Andrew Jack notes in the Financial Times.

Jack’s article in the FT also offers a comparison of the current approaches to medical device regulation in the US and in Europe:

‘[The British Medical Journal has] published a series of articles highlighting weaknesses in the EU regulatory system for medical devices at a time of growing debate on reforms on both sides of the Atlantic ... European medical device trade bodies have also called for reforms to clarify existing regulatory standards and embraced with counterparts in North America, Australia and Japan through a Global Harmonization Task Force. However, they have also cautioned that excessive regulation risked damaging the medical device sector and could delay access to patients. They pointed to the US, where medical devices are introduced more slowly than in the EU as a result of tighter regulation, while, they claimed, not improving safety.’

Jack points to examples where UK regulators were the first to identify problems, and conversely where devices were rejected in the US but accepted then subsequently withdrawn or discontinued in the EU.

An MHRA spokesperson responded to the BMJ/Dispatches investigation, saying:

‘Medical devices bring widespread health benefits for patients and the public but no product is risk-free. We ensure that the benefits always outweigh the risks. Our priority is to ensure that patients have acceptably safe medical devices. We monitor all adverse incident reports and take prompt action to address any safety or performance concerns.'

The regulators note that manufacturers of all devices are required to have clinical data to support their performance claims for the device. In most cases, and in particular for higher risk devices, this information will come from a specific clinical trial on the device itself. However clinical data may also come from a literature review of the clinical information on equivalent devices. Where a manufacturer plans to carry out a clinical trial in the UK, agreement must be obtained from the MHRA. 

The spokesperson adds: ‘What must be borne in mind is the balancing act of generating clinical data pre-market and the benefit to patients of innovative products reaching the market place.’ 

Where this balance should lie is the question that concerns all of these parties. 

A trek to Everest base camp is helping Oxford University researchers investigate the links between heart failure and the low oxygen levels suffered by patients with a range of serious diseases.

Dr Cameron Holloway, Dr Nick Knight and Dr Andrew Murray from Oxford University's Department of Physiology, Anatomy and Genetics and the Oxford Centre for Clinical Magnetic Resonance Research were among several hundred volunteer hikers walking to the foot of Mount Everest to study the body’s response to the thin air.

The team wanted to simulate the condition of hypoxia – when the body or part of the body is deprived of sufficient oxygen. Patients with pneumonia, smoking-related diseases and some forms of heart failure suffer hypoxia.

It was Dr Holloway’s first experience of such a severe climate and he was startled by some of the findings. Among the most significant were changes to blood oxygen levels and energy synthesis.

‘I was amazed at how low the arterial oxygen levels fell in our blood,’ Dr Holloway said. ‘Saturation was in the 70 and 80 per cents during simple exercise at altitude when normally you would get worried if it dropped from normal at 98 per cent to 93 per cent.'

‘Usually that level isn’t compatible with life. If someone came in with levels that low we would rush them into intensive care.’

Another ‘huge shock’ was the 25 per cent drop in the cardiac phosocreatine/adenosine-triphosphate (PCr/ATP) ratio – a measure of the amount of energy available to the heart.

‘People with heart disease often have this ratio impaired. We experienced similar impairment, even reaching the levels of heart failure. We don’t know if it was due to adaptation to low oxygen or showed that our hearts were not coping.’

Dr Holloway’s study of 14 of the volunteers ran alongside a larger research project by Caudwell Xtreme Everest, part of the UCL Centre for Altitude, Space and Extreme environment medicine (CASE). The findings were published recently in The FASEB Journal.

Before leaving for Nepal, participants underwent wide-ranging tests, including assessments of heart, vascular, brain and exercise performance. Blood and other tests were carried out at several points during the 11-day ascent from Lukla’s Tenzing-Hilary Airport at 2,850m to 5,360m base camp.

The initial tests, which took place in Oxford, were repeated within 48 hours of the group’s return from Everest and carried out again six months after the trek ended. By then all changes to the heart and energy levels had returned to the pre-trek baseline.

Dr Holloway suspects that the findings witnessed during the Everest trip may have parallels with the cause of some forms of heart failure:

‘At base camp the symptoms we had, including breathlessness and exercise intolerance, were similar to those experienced by heart failure patients.'

‘Even a small amount of exercise was really difficult. That’s what people have to deal with when they have pneumonia or other diseases.’

Dr Holloway hopes the lessons from the study will improve care for critically ill adults and children, and even babies in incubators.

‘Now we are looking at heart failure patients to see if low oxygen is the problem and if changing oxygen pathways could improve the lives of heart failure patients. We also need to work out what is behind individual differences in the changes people experience as a result of low oxygen.’

In films and books black holes capture unwary spaceships and planets, gobble up whole galaxies or offer portals to other parts of the Universe.

So the idea that, with the start of the Large Hadron Collider (LHC), physicists finally had a machine powerful enough to, potentially, create ‘mini’ black holes caused some alarm.

But what do we really know about black holes? And how would a ‘mini’ one be different from their giant cousins lurking out there in space?

‘The simplest black holes are objects with a singularity in the centre and that are surrounded by an ‘event horizon’,’ explains Cigdem Issever of Oxford University’s Department of Physics. ‘Once something comes closer to the black hole than the radius of the event horizon, it is not able to leave: even light can’t escape and so the name ‘black hole’ was given to these objects by John Archibald Wheeler back in 1967.’

A hole in the Sun
Producing black holes turns out to be about mass (energy): squeeze mass into a sphere with a radius equal to what’s known as the ‘Schwarzschild radius’ – a threshold beyond which gravity causes an object of a certain density to collapse in on itself – and a black hole will form.

‘In fact the size of the Schwarzschild radius is directly proportional to the amount of mass that is squeezed in, as well as being directly proportional to the strength of gravity,’ Cigdem tells me.

‘For example, in order to form a black hole out of our Earth, you would need to squeeze its mass into a sphere about the size of a marble (radius 8.9 mm). By comparison the Schwarzschild radius of the sun is about 3 km.’

So what would happen if we swapped our Sun for a black hole?

‘If we replaced our Sun with a black hole of the same mass, surprisingly, not much would change in our solar system. The planets’ orbits would stay the same because the gravitational field that the black hole would produce would be exactly the same as that of the Sun. Although, admittedly, the solar system would be a bit dark and cold!’

But Cigdem’s interest in black holes isn’t theoretical, as a particle physicist she will be searching for signatures of ‘mini’ black holes in the LHC collisions:

‘I became interested in them as a particle physicist back in 2003 because extra dimension models predicted that they may be produced in high-energetic cosmic rays and, if so, even in particle accelerators. If we are really able to produce them, they could give us experimental insights into quantum gravitational effects.’

She hopes that studying them may lead to a formulation of a theory of quantum gravity: marrying Einstein’s theory of general relativity (which describes gravity on large scales) with quantum mechanics (which describes physics at very small distances).

The LHC is colliding protons on protons. These protons are made up of smaller constituents, the so called ‘partons’ which are actually the particles the LHC is colliding. The Schwarzschild radius of two colliding partons – quarks and gluons for example – at the LHC is at least fifteen orders of magnitudes below the Planck length - the smallest distance or size an object can achieve in our conventional universe.

‘This means that, in conventional models of physics, there is no way a black hole could be produced in a collision of two partons. However, there are models on the market suggesting that the strength of gravity could become significantly larger at very small distances, up to 10 to the 38th [10 with 38 zeroes] times stronger,’ she comments.

‘If this is true then the Schwarzschild radius of two colliding partons becomes large enough that, at the LHC centre-of-mass energy, two partons passing each other at their Schwarzschild radius is not so unlikely anymore. So, we may be able to produce microscopic black holes after all.’

Who's afraid of a 'mini' black hole?
So what would these tiny black holes be like? Should we be worried about them?

Cigdem tells me: ‘According to Stephen Hawking, they will not be that black in fact. They will evaporate with time approximately following a black body radiation spectrum. The evaporation rate will be inversely proportional to the black hole mass.’

‘Astronomical black holes are so massive that their evaporation rate is negligible. In contrast, mini black holes are hot: unimaginably hot. The core of our Sun is at around 15,000,000 degrees Kelvin - to get close to the temperature of a mini black hole you would need to add another 42 zeroes.’

‘What this incredible temperature means is that mini black holes of tiny mass ‘evaporate’ into the far, far colder space around them almost infinitely fast. Their expected lifetime is around one octillionth of a nanosecond – so that they pop out of existence again almost as soon as they are created.’

If they do appear they will almost instantaneously burst into many particles which the ATLAS detector should pick up.

‘These particles will have very striking features. The total energy deposited in the detector will be of the order of a few TeVs [Tera electron volts] and the number of final state particles will be large. Black hole signatures can hardly be imitated by any other new physics so, if they are being produced, it will be hard to miss them,’ Cigdem adds.

So the hunt begins: on 30 March the LHC is aiming for collision energies of 7 TeV that may enable us to see some quantum gravity effects for the first time.

At the beginning of this year Dr Cigdem Issever moved to CERN to coordinate the efforts of the ATLAS Exotics physics group.

Read more about this topic in What black holes can teach us by Sabine Hossenfelder and the LHC Safety Assessment Group report.