August 03, 2010

Meningitis

May 21st, 2010


Have just been tidying up “My Documents”, and found this that I wrote a few weeks ago but had forgotten about. Have fun (btw, I won't be offended if you can't be bothered to read all of this) :-P


If any of you have seen any of my recent Facebook updates, you should have some idea about how much I hate revision. I’ve got eight productive days of revision left before the exams start, so you must be wondering why on earth I’m wasting my time writing a Facebook note. Well, you see all day I have been trying to entice my brain to take in the most boring facts possible, but I think it has shut up shop for the night. “Get lost, no room at the inn!” The cause of this mental barrier? Are you ready?

...brace yourselves...

... it’s the Vaccination and Gene Therapy module.

I do a fair bit of complaining about this module, as some of you will know, and again, as all you poor buggers who’ve also got to take the exam on this evil subject will understand, my complaining is not entirely unjustified. It consists of 12 lectures just listing the different classifications and statistics of literally tens of vaccines. No biology involved – just statistic after statistic after statistic.

Indeed before the year had even started I went to speak to the head of department to beg him to let me drop the module – he refused. So anyway, I find myself trying all sorts of tactics to try and learn some of this shit, and after having tried:

• Writing out facts over and over and over again
• Writing in pretty colours
• Reading out-loud
• Highlighting
• Mind-mapping on rolls of wall paper

I’ve had enough. I can’t take it anymore. So I Googled, “how to learn something really boring”, and clicked on a link at random. One of the suggestions was “to write an article or blog”. AHA! I rather enjoy writing those, and I hadn’t thought of that before. Maybe I can make a very boring subject into something more interesting by telling other people. So yes, the purpose of this blog is as a last-ditch attempt at a revision aid – and to tell you something about vaccination. The topic is rather large, so I’m just going to talk about vaccinations for meningitis, because it’s quite a nice, round topic.


Meningitis is nasty. Really nasty. It causes the deaths of literally thousands of people each year, and leaves many of its victims brain damaged or severely disabled. Not surprising really that there have been various attempts to control it via vaccination attempts.

There are two types of meningitis; viral and bacterial. Viral meningitis is the most common type, and tends to be less severe than bacterial (although we’re talking about meningitis here – none of it is particularly desirable) and usually patients make a full recovery.

There are three main types of Bacterial meningitis caused by three different bacteria:

• Streptococcus pneumoniae (known in the trade as pneumococcus)
• Haemophilus influenzae
• Neisseria Meningitidis (meningococcus)

I’ll talk about each one in turn.

Pneumococcus is the most common cause of meningitis, causing 25% of meningitis deaths in the UK. It’s a nasty little beast that’s responsible for quite a few infections, including Otitis media (earache), influenza, septicaemia, sinusitis, peritonitis and arthritis. Usually, however, it lives perfectly harmoniously in your nasopharynx; part of the nasal cavity behind the nose. For all you singers out there, your “head voice” is generated by resonance of air in this cavity.
By the time you reach your first birthday, everyone, yes EVERYONE carries Pneumococcus in their nasopharynx, but usually it lives there causing no trouble. Invasive disease is caused only occasionally, and the reasons why it might suddenly become activated are complicated, and in many cases aren’t completely clear.
Like a lot of diseases, the risk of Pneumoccoccal meningitis massively increases if your immune system isn’t working properly. The main cause of immunosuppression that springs to mind is HIV infection. HIV destroys a major group of cells in the immune system, laying your body open to lots of diseases that usually would not cause a problem, including Pneumococcus. There are an estimated 27 million people worldwide who are living with HIV, and HIV infection increases your chances of catching Pneumococcus forty-fold. Pretty sobering fact, eh?

If you catch an infection from Pneumococcus, you’ll know about it. About 30% of Pneumococcal infections require hospitalisation, and about 25% of those patients who develop meningitis will die - a rate which can increase to 75% in very young children. That’s a hell of a lot – by comparison, tetanus has a 10% fatality rate, and MRSA has a fatality rate of 11.2%. Of those that don’t die, mental retardation, deafness, epilepsy, blindness and behavioural problems are common.

Meningococcus is just as nasty as pneumococcus, causing really really severe meningitis. It’s carried in the nasopharynx by around 20% of the population, but can increase to as much as 70% during outbreaks. Imagine that! 70% carrying such a dangerous pathogen with them everywhere they go. Meningococcal Infections are characterised by a very sudden onset of all the typical symptoms of meningitis, (headache, photophobia, stiff neck, etc – all the symptoms on the posters stuck up all over the halls of residence), and if infections are left untreated, they cause 100% mortality within days. That’s more deadly than Ebola, leprosy, malaria and cholera.

There are 13 types (serogroups) of meningococcus, and six have the potential to cause infection in humans. They have different global distributions, with Serogroup A being found primarily in Africa, and Serogroup B distributed globally. Serogroup B causes around 80% of the Meningococcus cases in Europe. However, outside of Europe, Serogroup A is responsible for virtually all human cases.
Partly due to the severity of these diseases, their widespread nature, and the massive HIV pandemic, the development of pneumococcal and meningococcal vaccines was seen to be somewhat of an emergency. There are currently two types of vaccine available each against Pneumococcus and meningococcus. For Pneumococcus; a 23-valent polysaccharide vaccine, and a 7-valent conjugate vaccine. For Meningococcus, similarly a polysaccharide vaccine and a conjugate vaccine.

Valent? Conjugate? What on earth am I talking about?!! Polyvalent just means that the vaccine contains multiple strains of Pneumococcus. Let me explain. Viruses and bacteria evolve very quickly – much faster than plants and animals, and if you were to round up all of the Pneumococccus bacteria from all over the world and look at their DNA, you would find that there were some differences where they have mutated and become slightly different from each other. Some of them would have become sufficiently different so that the immune system would actually recognise them as two different viruses – these would be said to be two different strains.
One of the pneumococcal vaccines contains 23 different strains, and the other contains seven different strains. There are around 90 different strains of Pneumococcus, but to include ALL of them in a vaccine would be impossible. Instead, the strains that are the most common culprits for disease were picked. Make sense? As for conjugate, I’ll explain that later.

Polysaccharides are long strings of sugar molecules all bonded together. Starch is a polysaccharide, for example, which is made from a long string of glucose molecules. Many bacteria have a coat of polysaccharides on their surfaces which carry out lots of different functions for the bacterium. Unfortunately for them, the immune system is able to detect these polysaccharides and recognise them as pathogens that shouldn’t be there, so mounts a great big offensive response against them.

The 23-valent, polysaccharide Pneumococcal vaccine is pretty good at inducing immunity. About 70% of adults will develop immunity after vaccination. HOWEVER, it does have some pretty major disadvantages.
As I said earlier, the majority of infections and deaths occur in children under two years of age, and sadly, the vaccine is not very effective in this age group. There are two reasons for this. A baby’s immune system is still immature at the time of birth, and simply cannot respond to the injected vaccine in the same way as an adult could. However, a baby is not completely unprotected. Before birth, some of the antibodies in the mother’s blood are able to cross the placenta into the baby’s blood to give the child some protection until its own immune system is ready. Antibodies are also found in breast milk, so by breast-feeding a child, a mother is using her own immune system to protect her baby. But, unfortunately for vaccine scientists, these maternal antibodies interfere with the vaccine. They inactivate the vaccine before the child can respond to it, so giving a vaccine to a baby is, in a lot of cases, completely pointless.

Also, rather crucially for a vaccine, the current 23-valent vaccine does NOT provide any immunological memory. What that means is that the vaccine will initially produce an effective response, but this quickly wanes (after around 5-10 years) and a booster vaccine dose is needed. This is fine if you’re trying to vaccinate only a small group of people, but trying to administer repeated doses to an entire country is just expensive, time consuming and impractical.

The 23-valent vaccine also won’t give you any protection against any bacterial strains that are not contained within the vaccine, not only is this terribly annoying, this is more than the trivial problem that it might seem. There is no such thing as a bacterial vacuum – if you remove one type of bacterium from an environment then another one will very quickly take its place. But what if the bacterium that moves into its place is WAY more dangerous than the first one? What if it is untreatable with antibiotics? This strain will spread like wildfire throughout the vaccinated population because you’ve removed all of its competition. In cases such as these, vaccination may cause more harm than good...

Despite these quite severe shortcomings, any safe, moderately effective vaccine is better than nothing, so the 23-valent, polysaccharide-conjugated vaccine has been recommended for healthy elderly people in institutions, and high-risk adults (such as those with underlying health conditions, such as diabetes).

A more modern vaccine, the 7-valent conjugated vaccine was developed to try and overcome some of the shortcomings of the original polysaccharide vaccine. We already know what 7-valent means, but what about conjugate? A conjugate is, biologically speaking, a “hybrid” molecule.
Some of the surface antigens (the bits of the Pneumococcus which elicit the immune response) are not particularly effective if they’re given on their own, so they’re chemically attached to a much more potent molecule – in the case of Pneumococcus, the protein that’s used as the conjugate is actually a toxin from a totally different bacterium – the Diphtheria toxin (Dtx), responsible for the eponymous disease. So the conjugate that is injected is a hybrid of Dtx:Antigen, and the immune response will be raised against the pneumococcal antigen with a bit of help from the toxin.

The conjugate vaccine “take” (efficacy at eliciting an immune response) has been shown to be 97% effective in phase three clinical trials, and much more effective at producing protective antibody in infants and the immunosuppressed than the original polysaccharide vaccine, and as such was licensed for use in the USA in 2000, and routinely given to children at 2-3 months in the UK from 2006. Since its US introduction, there has been a 69% decline in invasive disease in young children, and a variable 8-32% decline in adults, depending on age. So effective is this vaccination campaign, that even unvaccinated adults were conferred some level of protection. How on earth can that work??

There’s this pretty cool phenomenon in disease control called Herd Immunity. If enough of a population is vaccinated, then even those individuals who have not been vaccinated will be protected. This is because in order for an infectious agent to persist in a population, it must have a large enough pool of susceptible hosts to keep an infection going, and this cannot happen if herd immunity is present. Let me explain.
If I were to catch measles tomorrow, I would become very ill for a few weeks, and I would infect all of those around me that I could. Say I’m sitting in a lecture theatre, and I infect all of the people in the front row where I’m sitting. Eventually my infection would run its course and I would get better, and the measles virus would no longer be present in my body, but the infection would live on in the other people I’d infected. They might then pass on the disease to the second row, thence to the third, fourth and fifth row. In other words, the infection PERSISTS in a population.
Now let’s change the situation. I’ve been very unlucky, and have visited my friend on the other side of the country who gave me measles. Upon my return, I’m sitting in a lecture theatre but virtually everyone in that theatre has been vaccinated against measles; all apart from a few scattered diffusely throughout the theatre. Now, because everybody on the second row has been vaccinated, my measles cannot be passed on to anybody – they’re all immune. So, try as the virus might, it can’t infect anyone new. So, the infection will run its course and I will get better, but crucially, the infection will die out from the population and will not be able to persist because there simply aren’t enough people for it to be passed on to. As such, those few individuals in the lecture theatre who were not originally vaccinated will still be immune because there is nobody around them to give them the virus! Make sense?
As you can imagine, herd immunity is a pretty useful phenomenon for vaccination scientists, and it is a bit of a bonus if a vaccine is able to bring about herd immunity.

As I said earlier, the two types of vaccine that are available for Meningococcus are also a polysaccharide vaccine and a conjugate vaccine. The same kinds of problems were encountered with the polysaccharide vaccines as were encountered with the Pneumococcal polysaccharide vaccines, and subsequently a conjugate vaccine was developed following the success of the conjugate Pneumococcal vaccine.

There are three types of conjugate vaccine:

• MenC – monovalent, protects against the group C Meningococcus serotype. The usage of MenC has been routine in UK children since 1999
• MenA/C – bivalent, has not yet been licenced for use in the UK, and is still undergoing clinical trials
• MenA/C/Y/W-135 – tetravalent, licenced in the USA and used in various other developed countries.
• MenAfriVac – an affordable form of MenA, which was especially developed for use in developing countries, where Group A Meningococcus are the most prevalent. It is manufactured in India, and, unlike the usual $7 MenA used in the developed world, MenAfriVac costs only 5p a dose.

Now, if any of you were on the ball, you might have noticed that the notorious, worldwide tyrant, Group B meningococcus were missing from any of the above vaccines. The reason for this is that Group B conjugated vaccines don’t work. Why? Well, the type of polysaccharide which is found on group B Meningococcus is called N-acetylneuraminic acid (NANA for short) The problem with using this in a vaccine is that this NANA is also found on the body’s own tissues.
Your body has got some beautiful mechanisms to ensure that its immune system doesn’t respond to its own tissues. The result would be catastrophic. Diabetes, Arthritis, Multiple Sclerosis, Rheumatic heart disease....all of these are the result of the body’s erroneous destruction of its own tissues. Bad news.
So, going back to our vaccine, one of two things could happen if you injected NANA. Either, nothing would happen at all – your body has eliminated all of the potentially dangerous cells in the immune system, so nothing would happen, OR...you’d start attacking and killing all of the cells that have got NANA in them. SERIOUSLY bad news – if that happened, you’d probably die of clinical Shock within hours. So yes, as yet we’ve not come up with a way around this little problem. There have been some ideas for using different antigens from Meningococcus B, but as yet, they’ve not been hugely successful.

Haemophilus influenzae also likes to live in the upper respiratory tract. There are six types, A-F, and type B (Hib) causes 90% of H. Influenzae infections. Haemophilus influenzae is not only an important cause of meningitis, but also of pneumonia, for which it is much more commonly associated.

There are three vaccines for Hib are all conjugated to different proteins. All of these vaccines were introduced to developed countries in 1992, and all show extremely high – 90% efficacy. As such, their use has virtually eliminated invasive Hib disease in the developed world, and furthermore, due to the TYPE of immunity that they induce, has also massively reduced pathogen transmission within the community. What this means is that if an individual is unfortunate enough to catch Hib, they will be much less likely to pass it on to immunised individuals, as their immunity decreases chance of infection.
I bet you’re thinking, well, surely that’s the point of a vaccine, is it not? Well, not exactly...A vaccine is merely an agent to prevent outright DISEASE - not infection. It is possible to have an infection without disease, even in vaccinated individuals. A vaccine usually just prevents the infection from turning into disease. However, the Hib vaccine is what is known as a “sterilising vaccine”, which prevents infection as well as disease. There aren’t very many of those around at present, and it’s a major area of research.

So given that the Hib vaccines are so fantastically effective all round, why are they only used in developed countries, and not in developing countries where the burden of disease is much, much greater? The simple reason: Cost. It all comes down to cost, sadly. The pharmaceutical companies who manufacture the vaccine simply cannot afford to give away vaccines for free, even though the value of human life is supposedly more important.
The Hib vaccine is extremely expensive, costing $7 for a whole vaccine course. By comparison, a full course of vaccinations for measles, polio, diphtheria, pertussis, tetanus and tuberculosis costs $1 COMBINED. It is hardly surprising that still the burden of disease from H. Influenzae in these developing countries is still astronomically high.

Maybe one day they will think of better ways of administering and developing vaccines to third world countries – but they’re still a long way off. Indeed, vaccinology, as a science, is still very young, so potentially in the future injecting little bits of a dangerous pathogen into a susceptible individual may seem as old-fashioned as drinking pus to prevent bubonic plague...


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