What are pneumococcal infections, who do they affect and what causes them?
The pathogen that we are talking about is called streptococcus pneumoniae. That is a fairly common bacteria and if you did a nasal swab you would find that quite a lot of people have this bacterium living in their nasal passages.
However, in certain situations what happens is that that the bug, which is otherwise safe, invades and it causes what is known as invasive pneumococcal disease (IPD).
It is a big healthcare issue. If you looked at the epidemiology you find around 4 million deaths a year from it. About half of those are in the under 5’s and quite a lot of the others are in the aged population.
So it tends to be in the very old and the very young. The group in the middle can be affected but usually when they have some underlying co morbidity or condition.
What happens is the bug moves from the nasal passage to the alveoli – the air sacs in the lungs. This is the lower, as opposed to upper respiratory tract where infection is often more serious.
The alveoli respond to the infection by filling with fluid and this reduces your capacity to bring in oxygen. So in effect you drown.
If you are otherwise healthy, you are generally ok and will recover from infection, but if you are young, you’re elderly, you’ve got other conditions as well, your ability to fight off and manage the infection is reduced.
You can use antibiotics to intervene, but they tend to be quite slow acting even if you deliver them intravenously. As they take a bit of time to kick in, you can become overwhelmed before the therapy can act. Respirators are also used, though this adds further costs as well.
Overall the message is that pneumococcal infections are big killers in particular groups – the young and the old and prevention is much more preferable than reliance on therapy.
ImmBio is based at the Babraham Research Campus Cambridge. Home to the Babraham Institute, the campus is centred around Babraham Hall shown above.
What conditions can pneumococcal infections lead to?
There are actually three distinct disease types that the pathogen can typically induce. One is what we classically label pneumonia.
Just to bear in mind the medical world confuses itself because it often describes where the infection is, separate from what is causing it. Physicians primarily identify the site of infection, without the additional work of identifying what the pathogen is – and if it is susceptible for example, to use of a broad spectrum anti-biotic, that is sufficient.
Therefore, what is called “pneumonia” can be caused by a variety of pathogens infecting that area of the body. In the same way, bronchitis or meningitis can be due to lots of different pathogens.
The most common form of invasive pneumococcal invasive disease is pneumonia.
The second condition that pneumococcal infections can lead to is meningitis. The meninges surround the brain. An infection of the meninges is called meningitis. S. pneumoniae is one of the pathogens that can lead to meningitis.
Meningitis is particularly prevalent in babies. The initial symptoms are often flu-like which means mothers often don’t spot it fast enough- and infection progresses very fast. It is very hard to distinguish it from flu fast enough for therapeutic intervention to be sufficient
Because the problem is around the brain, you get disability and deafness occurring quite fast.
The third condition is septicaemia. This is when the bacteria infect the blood supply and it becomes systemic.
The Babraham Research Campus Cambridge is a major Life Sciences site with state of the art laboratories and multiple organisations.
Please can you give a brief introduction to prevention versus therapeutics for pneumococcal infections?
Therapeutic intervention and respiratory support etc. are typically what you do if you are hospitalised but there are significant inadequacies.
Quite often infection is picked up as a community acquired pneumonia (CAP). So it is not necessarily in a hospital setting. You can become infected and then be hospitalised already with significant infection.
By that stage you are going to be infectious to other people and be in an environment where you are likely to infect other people. The consequences are severe therefore this is one of those classic conditions where prevention is much better than therapeutics.
In health economics you need to look at when you use a vaccine versus when you use therapeutics. But in this case, if you have a good vaccine, you would use it because prevention provides better health outcome than waiting for therapeutic intervention and its consequences.
Are there different strains of streptococcus pneumoniae?
There’s been a constant battle between pathogens and humans in terms of infection and the host’s response. The immune system has evolved to try and cope with the pathogen but at the same time the pathogen mutates forming variant strains, which as a consequence means they can escape the immune system.
What you find is that there are lots of differences – strains - in Streptococcus pneumoniae bacteria. Those can be categorised in a number of ways but the most common way is serotyping. This looks at specific difference on the outside of the bacteria. If you looked at the clinical isolates identified, you’ll find there are over 90 different sero-subtypes in circulation.
In fact what you see are new ones emerging quite often. There is a new one emerging in Vietnam at the moment. You would expect it to continue to evolve. And so even if you were successful at stamping out one serotype, others would continue to colonise and propagate.
In other words you’ve got to address the diversity of the pathogen to ultimately provide protection. Only where there is no reservoir of infection such as in animals, can complete eradication be feasible, as is the case for smallpox or polio.
What pneumococcal vaccines are currently available?
There are several products that are available and these use two different technologies. There is what’s called a pneumococcal polysaccharide vaccine (PPV) and this actually is composed to essentially tackle 23 of the 90-odd different serotypes. It tends to work better in elderly subjects and it isn’t indicated for use in infants. It is used from age 5 upwards but particularly in the elder group.
There is a second technology called pneumococcal conjugate vaccine (PCV) which was originally produced by Pfizer against 7 of the 90 or so. They have recently changed that to target 13 strains. That has been widely taken up by many countries. The UK started using it in 2006 in what is called the Universal Schedule – so anybody reaching a certain age is automatically offered a vaccine on the NHS as part of their standard immunization schedule.
Not all serotypes are found in equal numbers so inevitably the 13 or the 23 that they’ve picked tend to be the more common ones in circulation at the moment in Developed Countries. But the issue is you are always going to get new serotypes appearing that your vaccine doesn’t protect against. That’s true right now and it will certainly continue to be the case in the future.
So one big unmet need that the vaccines have problems with is providing “breadth” - they only protect against specific sero-subtypes. They are designed that way.
The other aspect that is important is that if you produce a 13 valent subtype vaccine, in effect you are adding 13 vaccines together, so the cost and complexity of manufacturing is considerable.
If you are in the UK and you are prepared to pay a decent price for the vaccine then that cost of goods can be absorbed within the price that the NHS will pay. However, a lot of the deaths are in developing countries where the health care system is less able to cope with infection in terms of hospitalisation, therapeutics and everything else.
Therefore, developing countries would particularly benefit from a prevention strategy rather than a treatment strategy, but those countries will find it harder to pay the price for a very complicated product.
The bottom line is that there is a health economic cost issue that factors in to this as well. You want a vaccine that:
Is cost effective
ImmBio has laboratories in two main campus buildings including Meditrina pictured above where vaccine production is undertaken.
ImmBio have recently been awarded approximately £0.2 million ($0.3 million) by the UK government-backed Biomedical Catalyst to support pre-clinical development of their pneumococcal vaccine. Please can you give an introduction to this vaccine and how it will differ from currently available pneumococcal vaccines?
The way that the current vaccines are produced essentially looks at one component of the pathogen which generates an immune response (“antigenic”) and presents that into the immune system leading to what is called described as memory – the ability to respond fast if it sees that bug again. The vaccine can’t stop you coming into contact with the pathogen again but what it does is to prime the system so that if it does come into contact, it will be able to clear it before it takes hold.
The current vaccines are going to do that against a subset of serotypes you may encounter. That is inherent in their technology. Our technology does something somewhat differently. Essentially our starting point is asking how does the immune system normally respond? What you see a lot of other vaccines doing- which we accept can work - is using tricks. They trick the immune system into responding.
What we fundamentally do is to understand how the immune system normally operates and use that to the maximum. What you would normally see when you are infected is the whole of the bug with all of its bits, therefore we use the entire bug. It turns out that when you talk about different serotypes, most of the bug does not change, it is only a very small percentage. Most of the bug is common across serotypes. So by taking the whole of the pathogen we do not have that strain sero-subtype restriction.
The immune system normally has two components – the innate response and the adaptive response. The innate response is ‘I don’t know what the bug is but I am going to attack it’. The body then finds out more about the pathogen so it can mount a more targeted response called an adaptive response.
The first thing that happens when you get infected most typically is that when the innate response attacks the foreign object, it creates heat, inflammation, stresses it and does something to it. In essence, that is what we do – we mimic that innate response.
The objective of a vaccine is to be safe and also effective. Giving an individual the bug may create memory but you’d get the disease along the way which you may or may not recover from. The whole point about vaccines is to try and generate a primed response safely.
So in essence what we do is we start off with the bug, we grow it up, we mimic the innate response against it, we kill it, and we then put that in the vaccine. Essentially we are mimicking the first stage of infection but we are doing it in a factory, not in that person.
So we are making something that is safe, which has lots of bits of the pathogen in the vaccine, it’s killed but it will still is taken up by the immune system. This is as opposed to what some earlier approaches took to vaccine production, which was to blast the vaccine with heat, which destroys it, changing is protein composition along the way – this does not create an immunogenic vaccine.
It is the insight into understanding how the immune system operates and doing that in a factory to generate the vaccine is essentially what we do.
We do not therefore have that restriction in terms of serotype and our manufacturing is cost-effective. This addresses the unmet market need of something that works, irrespective of the diversity of the bug, cost-effectively. It also addresses human diversity as well as pathogen diversity.
Please can you tell us more about ImmBio and how you plan to use the Biomedical Catalyst funding?
We have already done some work on our S. pneumoniae vaccine (“PnuBioVax”) with University College London (UCL) and some work at University of Bristol but actually this isn’t our lead vaccine. Our lead vaccine started off in TB. We had the benefit of UK Government money alongside our investors, followed by Gates funding to look at TB.
After that we added a new program which is against the major causative pathogen causing invasive meningococcal disease. This pathogen infects the meninges and is one of the main sources of meningitis. It is a bug called Neisseria meningitidis. There are vaccines used universally in the UK protective for the serogroups in circulation apart from one, serogroup B. So again there are vaccines against some but not all forms of the pathogen
As a company we first worked on TB, we then moved to meningitis and then we started the program on pneumococcal. So we have the benefit of data from TB and meningitis and have confidence that the approach works.
What is this funding about? This really is helping to tip the economic case. So when we said that a lot of the unmet needs are in the developing countries, whilst you can raise investment it is quite a hard environment to raise sufficient investment, so it is important to have someone come alongside you, partly for money and partly to endorse what you are doing as these grants are peer-reviewed.
We have already got some later stage data on other products but the purpose of this grant is to progress the pneumococcal vaccine, which we call PnuBioVax, towards the edge of clinical study. There are various things you need to do that. We are going to progress our candidate vaccine through a series of the pre-clinical stages essentially replicating the path we have already trod for TB and meningitis.
Vaccine production and testing are an essential part of ImmBio’s activities. Here SBA assays are shown to test the efficacy of the meningitis vaccine “MenBioVax”.
What impact do you think PnuBioVax™ will have?
Vaccines need to be safe because you are not “a patient”, you have not presented yourself with a problem and so at the individual level you would not want to be taking particular risks for a potential infection that you may or may not get in the future. So safety is particularly important. However, it doesn’t matter how safe a vaccine is, if it doesn’t work then there’s no point having it at all. So vaccine efficacy is equally important.
We would say that although there are some new potential technologies in the vaccine field, there are not a lot and we have almost reached the frontier of what existing technology can do. If you looked at some analysis, you’d probably say that there are about 40 pathogens that vaccines might be cost-effective to protect against and there are about 25 pathogens where vaccines are currently available.
In other words there is a whole series of other pathogens, the obvious ones might be HIV, malaria, or TB, that if you had a vaccine you would use it. We think that current technologies have just about reached their limit.
What we are about as a business is trying to develop transformational technologies – new ways of tackling these pathogens that current technologies are not going to do.
We’d be the first to say that development of any vaccine takes time, it takes money and there are going to be some risks along the way. Why would you do that if you didn’t think there was going to be a significant return? – that may be a financial return, it may be health care return, it may be lives saved etc. That equation has to pan out and I think what we’re saying is what we’re working on is a very different sort of approach for developing vaccines from others and it has the potential of transforming the vaccine industry.
As we see it, it is a technology platform in that the approach could potentially be replicated against a number of different pathogens. There are other ones that we have in the research stage as well as TB and meningitis. We think that is exciting. We don’t see this as just looking at one product; we see this as validating whether we are correct in the way that our technology operates by mimicking this innate immune system and therefore can be applied to a number of other bacterial targets.
So there is impact at one level in terms of is the platform working, so we can demonstrate that there are all sorts of things we can tackle. But clearly in terms of pneumococcal disease we already talked about the breadth benefits - how many different strains we are going to cover and do it cost-effectively. Without knocking the competition, you would find the current products, left to market prices, very expensive. If you looked at the market size, you would see it is already well over $3 billion each year, with quite expensive products, despite their limitations. Our cost to goods is very significantly lower than existing products.
We think that it will have a very significant impact and therefore it is worthy of both investor and public money to come into this because the payoff is significantly high.
What plans do ImmBio have for the future?
TB, which is where we started the business, received government funding and Gates Foundation money which was very helpful. Gates had an interesting model of funding some plant in the United States that we have had access to. This enabled us to do some early work on how to manufacture products, which is a very important aspect. This enabled us to begin to figure out how this technology operates.
After that though what we have done with our TB is partnered it with Chinese State’s vaccine organisation – CNBG. As I’ve already said quite a lot of the vaccine needs beyond the developed countries of UK, US etc. are in the developing countries where infection levels remain high. So whereas in the UK cancer and cardiovascular diseases tend to be the killers, in many countries it is still infection. To us it is natural to look at one of those countries to partner with. We analysed our options carefully and we decided on China.
We then looked within China and decided that instead of the commercial companies we would go with the biggest, most powerful, best-resourced organisation in China. We have a co-development agreement with them.
Our investors have supported taking the meningitis vaccine into clinical stages on our own.
We want to get the pneumococcal vaccine to proof of principle stage with data showing that our claim of breadth and cost-effectiveness is right, before partnering it up.
Where can readers find more information?
About Graham Clarke
Graham Clarke is CEO & Director of ImmBio, based at Babraham Research Campus, Cambridge, UK.
He has a master degree in Biophysics from King’s College London and an MBA.
Working first in “big Pharma” then as a partner in the Pharmaceutical & Biotechnology Practice of PA Consulting, he returned to industry as VP, Strategic Product Management, SmithKline Beecham. On merger with GW, he became Head of Executive Decision Support, GSK R&D.
Most recently he was VP, Strategy & Business Development, GE Healthcare Biosciences. He was then appointed its CEO of ImmBio at the beginning of 2006, as part of its major funding round.