BRITISH BROADCASTING CORPORATION
RADIO SCIENCE UNIT
CASE NOTES 8. - Vaccination
RADIO 4
TUESDAY 25/05/04 2100-2130
PRESENTER: MARK PORTER
REPORTER: TRISHA MACNAIR
CONTRIBUTORS: DAVID ELLIMAN
JONATHAN WEBER
MARK LARCHE
CAMPBELL BUNCE
AMANDA SANDFORD
PRODUCER: HELEN SHARP
NOT CHECKED AS BROADCAST
PORTER
It is now over 200 years since Edward Jenner put vaccination on the map by showing that it could provide protection against smallpox - the scourge of the 18th and 19th Centuries. In some cities smallpox was responsible for one in five of all deaths - and nearly all its victims were children.
By the beginning of the 19th Century smallpox vaccination was widespread and being undertaken across Europe. So effective was mass vaccination that, 24 years ago, the World Health Organisation declared the disease had been eradicated. Smallpox was extinct.
Today vaccinations are part of our everyday life - a series of jabs and drops now provide us with protection against a minimum of 11 different diseases, from diphtheria, tetanus and polio to TB and meningitis.
In today's programme I'll be finding out why we are still waiting for a vaccine against HIV/AIDS - the 20th Century equivalent of Jenner's smallpox.
CLIP
I think HIV has become the biggest communicable disease worldwide. My volunteering really was my kind of commitment to the cause really and so this was just something that I wanted to do in order to help find a cure.
PORTER
I'll also be discovering how vaccines could help people who are allergic to cats and other pets.
CLIP
When I'm around cats I get streaming eyes, sneezing, occasionally I get rashes as well and obviously a tight chest and find it hard to breathe.
PORTER
And I'll be finding out how vaccines could one day be used to help smokers quit or, more controversially, stop them starting in the first place.
My guest today is Dr David Elliman, a consultant in community child health at Islington and Great Ormond Street.
David, how does a vaccine work?
ELLIMAN
Well for many years, long, long before Jenner produced the first vaccine, people realised that there were some infectious diseases - although they didn't realise they were infectious diseases - that you didn't get more than once in your life, you had it and that was it. And so what Jenner did was make use of this but giving the person a mild form of the disease. And that's basically what underlies the vaccines we use now.
PORTER
And there a number of different types aren't there - there are the live ones or dead ones - can you explain that?
ELLIMAN
Yes, ideally what you want to do is stimulate the person's immune system so that there's memory there and you can do that in a number of ways. One is to give a live but toned down version of the virus - for example MMR - another would be to give the whole germ but it's been killed - and that would be the whooping cough vaccine that we use. Or yet another would be to take a part of the germ and perhaps tag something on to it, so that that stimulates the immune system - and that's the HIB and the meningitis C. And then you can take the poison from some germs - diphtheria, tetanus - and detoxify them, make them safe, and use those.
PORTER
So in those situations the person actually becomes immune to the toxin rather than the bug that produces the toxin.
ELLIMAN
Well that's right, in theory they could get the infection but they wouldn't have the bad effects of the infection.
PORTER
What are the required ingredients for a successful vaccination programme?
ELLIMAN
Well obviously you need a disease that's relatively common and also causes a problem. If it's a very mild disease or it's very rare then it really isn't worth it. And you need a vaccine that is safe, obviously if it causes more harm than the disease it's pointless, but also needs to be very effective.
PORTER
Well thank you for now David.
The first case of AIDS was described in 1981 and the discovery, three years later, of the virus responsible was a major breakthrough and one that prompted an overly optimistic prediction from the then US Health Secretary, Margaret Heckler.
HECKLER
The probable cause of AIDS has been found. A variant of a known human cancer virus called HTLV 3. Second, not only has the agent been identified but a new process has been developed to mass produce this virus, we now have a blood test for AIDS which we hope can be widely available within about six months. Finally, we also believe that the new process will enable us to develop a vaccine to prevent AIDS in the future. We hope to have such a vaccine ready for testing in approximately two years.
PORTER
Twenty years on and there is no still sign of an effective vaccine against the virus, now known as HIV. Jonathan Weber, Professor of Communicable Disease at Imperial College, London has been working on the virus since those early days and I asked him why a vaccine against HIV has proved so elusive.
WEBER
I think there are three problems that we've uncovered now as to why it hasn't worked. The first is that there's no natural immunity in HIV infection, so people are either infected by HIV, in which case they will ultimately develop AIDS unless they have treatment, or they're not. No one gets infected and then spontaneously recovers from it, as with influenza or something. So there's no immune response to model a vaccine on. Secondly, the virus is immensely variable, the outer part of the virus particularly differs from strain to strain by a very great degree and even within individuals you develop variance over time. And it's been very difficult to understand how we will encapsulate those variants in a vaccine or even a series of vaccines. And I think finally, I'd say that it's highlighted that our knowledge of what makes a vaccine and of immunology is still at really quite an early level, we can't make a vaccine from first principles, we can only try and see if they work.
PORTER
And researchers' first attempts, based on using bits of the outer coating of HIV to stimulate the immune system to produce antibodies, didn't work. Despite getting as far as being tested in thousands of volunteers across the world, the vaccine failed to live up to expectations. It produced antibodies in the volunteers but not enough to offer protection. So researchers have had to go back to the lab and look for another option.
WEBER
Current work on vaccines is at a much earlier stage going into human volunteers for the very first time and rather than going into thousands of people we're doing this in small groups of between 20, 30 and a hundred people at a time. And it's looking at trying to illicit immunity from the other arm of the immune system, not the antibody side, but what we call the cellular immune system and in particular to try and generate T cells that can kill virally infected cells.
PORTER
So basically what you're saying is we've almost gone back to the drawing board and starting a completely different approach.
WEBER
That's exactly right, the antibody approach, at the moment, hasn't worked and so we're now looking at the cellular approach. I think most scientists in the field believe that both arms of the immune system are going to be important at protection against HIV, both antibodies and the cellular immune system. We don't know how to make better antibodies, so at the moment we're concentrating on the cellular side.
PORTER
Jo Robinson is one of the volunteers in Professor Webers new approach.
ROBINSON
Well I thought it was a really good thing to do, given the stigma surrounding HIV and I knew that it was a safe vaccine, so I just wanted to volunteer my time. I had to attend the clinic over a period of about 18 months and I had to receive a couple of vaccinations and then just get regular blood tests to monitor my blood.
WEBER
What we're doing is we're priming the human volunteers with a high dose of DNA derived from HIV - a non-infectious DNA - and then a few weeks later boosting that immune response with a live viral vector based on Vaccinia, which is the vaccine for smallpox, carrying HIV antigens within it, an engineered form of Vaccinia.
PORTER
But there's no way that the vaccine itself - one of the big concerns you often read about in the media that people tend to get - well they get scare stories about how people given vaccines could develop the problem themselves, the human guinea pigs, if you like, at this stage, but that can't happen.
WEBER
Absolutely not. Only a very tiny part of the HIV virus - a single gene from the virus - is incorporated into the DNA and into the boost with Vaccinia and this is just a tiny part and in no way can produce an infectious virus. So people can't, in any way, acquire HIV from this. It's been a slightly depressing time for HIV vaccines because although the science has progressed and these sorts of vaccines I'm talking about now have promise for the future they're still at a very early stage and it could take anything up to 6 to 10 years before these could give us some results from a phase 3 study.
PORTER
Professor Jonathan Weber talking about ongoing efforts to develop an effective vaccine against HIV.
You are listening to Case Notes, I'm Dr Mark Porter and my guest is David Elliman a consultant in community child health.
David, let's get back to the present and the routine vaccination programme offered to everyone. A lot of those jabs are given as multiple combined vaccines and there has been some concern from some quarters, hasn't there, that these are too much for the immune system, there's a popular conception that that's the case. Before you answer here's Nicky Lewin, she's a listener from Scotland, voicing her concerns about triple vaccination - and that's diphtheria, tetanus and pertussis or whooping cough.
LEWIN
I've got two girls, one's five and one's almost two, and we live on a redundant farm. We're totally homeopathic and haven't given any immunisation to either of them. But we thought we ought to consider tetanus seeing as we do live on a farm and they're outside all the time. But when we went to the doctor's to find out about having the tetanus on its own we were told it wasn't available anymore and they'd have to have a triple which is tetanus, diphtheria and whooping cough. We were very reluctant to take the triple jab anyway just because I think putting three things into your system at the same time it must compromise the system. But also this is the only thing available since January as a triple, so how they can possibly say that it's not causing any harm I don't see how they can have the evidence for that because it's just not been on the market long enough to even be able to give you that information. So we certainly didn't want our children being one of the first in a trial and then 10 years down the line realise that it actually had caused them problems.
PORTER
David, first of all, a number of issues there, first of all, why only a combination vaccine, why can't you get tetanus on its own anymore?
ELLIMAN
Well the necessity to have it by itself has totally gone, there is no indication to do so and that's not just in this country, that's around the world. So any time when you would need tetanus you'd also need a booster of diphtheria. And for infants, for young children, that would also include whooping cough.
PORTER
So what you're saying is that if you have your normal routine immunisation schedule, you have your normal jabs as you grow up, you don't need tetanus ever again?
ELLIMAN
That's right, if you've had five doses - the last one leaving school - no more.
PORTER
So there's no market for the single one, so it's gone so …
ELLIMAN
That's right.
PORTER
Okay. If it's only just been introduced, she was saying there that it's been introduced in January, my understanding the triple jab's actually been around for a lot longer than that but she's obviously concerned that how do you know it's safe - your answer would be?
ELLIMAN
Well it's been around for 40 years and we know both from experience and trials beforehand that it is safe.
PORTER
Right, so it's only that it's replaced tetanus recently that's a problem. Because in adults you can't get tetanus on its own for adults either can you?
ELLIMAN
No it's DT - diphtheria, tetanus.
PORTER
And what about this belief that multiple vaccines can overwhelm the immune system? This is a criticism that was levelled at the MMR as well wasn't it.
ELLIMAN
It is and people have looked at this specifically, they've looked to see if after the immunisation, either MMR or the DTP, more children are admitted to hospital with infections because that's what you might expect if you overwhelm the immune system. In fact if anything there are fewer children admitted to hospital after the immunisation. Now one obvious explanation is they don't get the disease that you immunise against, the other is that probably people are very, very cautious when they immunise, so they only give the injection to a child who's perfectly well - no temperature, not brewing anything - so you wouldn't expect much difference. So there's good sound evidence now from this country and the States that overwhelming the immune system doesn't happen.
PORTER
Because the immune system's far more capable than most of us give it credit for isn't it.
ELLIMAN
Well I think some people have in their mind that you can only cope with perhaps a few hundred different insults, when in fact you can cope with hundreds of thousands. And what we're being bombarded by all the time is complicated germs, foods, other sorts of insults and we cope with those perfectly well.
PORTER
Thank you for now David.
Now for something completely different - allergies. At least one in five of us have a significant allergy of some form with common triggers including grass pollen, cats and the house dust mite. Applying vaccine know how to allergies could be used to protect allergy sufferers, including pet owners, as Trisha MacNair discovered.
CAT MEOWING
MILLER
When I'm around cats I get hay fever like symptoms - streaming eyes, sneezing, occasionally I get rashes as well and obviously a tight chest and find it hard to breathe. Usually I then take my inhaler and will take some antihistamine tablets to help with the sneezing and my eyes and then if it does get worse I'll go on my nebuliser.
MACNAIR
As many as one in eight people are, like Francesca Miller, allergic to cats. Normally the immune system tolerates or ignores the millions of different foreign proteins that we ingest or inhale every day. But when someone is allergic the immune system launches an exaggerated response to one or more of these proteins. In cat allergy there's a reaction to cat hairs or more specifically to a protein in cats' saliva which the cats wash over their fur as they groom themselves.
Mark Larche, reader in respiratory immunology at the National Heart and Lung Institute in London, explains that allergy to foreign proteins can lead to a variety of symptoms.
LARCHE
Many things can happen and actually one of the most interesting aspects of allergic disease is the heterogeneity that we see, so a child, for example, who's allergic to peanut proteins may ingest a very small amount of protein and have absolutely catastrophic reactions to it - a loss of blood pressure, asthma, swelling of the throat and the tongue - whereas in other people, people who have hay fever for example in the summer, they will generally get relatively mild symptoms - sneezing, itching of the eyes and throat - and occasionally this can be more severe and be asthma.
MACNAIR
With nearly eight million cats in this country it's not easy for people like Francesca to keep control of their allergies.
MILLER
It's quite hard because quite a lot of my friends have cats, so you go round and you stay there and I know what's going to happen, so I can kind of now prepare beforehand - like take antihistamine tablets before I get there and make sure that I've taken my inhaler before I go as well, so that it's not going to be as bad.
MACNAIR
Many allergy sufferers rely on regular medication to help control their symptoms or keep the allergy at bay. This can mean years of taking a cocktail of drugs and inhalers. Dr Larche has been working on a vaccine for allergy which would re-educate the immune system to see cat proteins as harmless, so preventing a reaction. But a vaccine for allergy is not a new idea, desensitising shots have been in use for about 90 years.
LARCHE
This involves injecting the protein to which the subject is actually allergic and therefore you can induce potentially life threatening side effects. With the more refined vaccine approaches that we are attempting to develop, along with many others, we challenge the patients with those parts of the molecule that are important leaving behind those which often induce these allergic side effects. And so we hope to increase the safety in doing this and thereby improve the efficacy - we can give larger doses for example more safely.
MACNAIR
The target of Dr Larche's vaccine is a vital cell in the immune system called the T lymphocite.
LARCHE
The T cell is really a cell that controls the immune response to a large extent, it can be thought of as the sort of general that marshals the forces of the immune system and in autoimmune diseases and allergic diseases and indeed the response to tumours it's often T cells that are really driving the response from grass roots level. And so if one can modify the response of the T cell the downstream effects of that are multiple and we feel that this is probably the most valid approach.
It's relatively easy to target the T cells, one merely needs to know what protein they recognise and within that protein what particular fragments they recognise. We synthesise those fragments and they form the components of the vaccine.
MACNAIR
It sounds simple but the idea of an allergy vaccine is complicated by the fact that many people who are allergic develop symptoms when exposed to a variety of foreign proteins, not just one. As well as cats Francesca has to steer clear of horses.
MILLER
That was quite hard because when I was younger I did really enjoy riding but horses were almost as bad as cats. When I'm round horses I come out in big white lumps all over my skin. I couldn't really face going riding because I knew exactly what was going to happen and I couldn't really enjoy it.
LARCHE
Many people in fact are multiply allergic and this does create a problem in the sense that the vaccines we're developing are disease or even protein specific and so if a patient presented with allergies to cats dander, to house dust mite and to tree pollens, for example, we would have to treat that patient for optimal effect with all three vaccines. Although having said that it's fair to say that in the majority of patients there is one major trigger and if one could take an allergic asthmatic and turn back the clock and make them an allergic individual who only had symptoms in the nose and eyes then that would be of benefit. So there are relative benefits and it may not be a strictly on or off scenario.
MACNAIR
Dr Larche's team are about to start trials of their vaccine in small groups of volunteers to find out how safe and effective it is. However, it's still some years before you'll be able to stroll down to your doctor's surgery for instant protection from your allergies.
LARCHE
It's unlikely that this will be a one off shot, it's more likely to be a series of injections, perhaps four or six injections, at least in the initial phases. Our long term aim is to develop a single shot vaccine but I think in the drug development stages that we're in at the moment we need first of all to establish that the approach is workable and then we can fine tune the dose and the dose intervals whether multiple doses will be required in the later stages of drug development before we reach the clinic.
CAT PURRING
PORTER
Beaton the cat ending that report from Trisha MacNair.
Vaccines have helped transform public health over the years by protecting us against a wide range of infectious diseases but a new development using vaccine technology to help beat addiction could prove at least as beneficial. It's already proved helpful in cocaine addicts and is now being tested in smokers. Amanda Sandford is research manager for ASH - that's Action on Smoking and Health and Dr Campbell Bunce is Project Manager of Vaccines for Addiction at pharmaceutical company Xenova. I started by asking Dr Bunce how it's possible to vaccinate someone against a chemical like nicotine.
BUNCE
Well under circumstances smokers who are exposed to nicotine on a daily basis do not develop an immune response towards nicotine, nicotine's too small for the immune system to see. So in order to present nicotine to the immune system we have to link it using a chemical bond to something that the immune system can see and that tends to be a large protein that's foreign to the immune system. So for a nicotine vaccine what we've done is to link a nicotine like molecule to a very large immunogenic protein called cholera toxin B, now that's the non-toxic part of the cholera toxin molecule. The immune system can see cholera toxin very easily and by association it also recognises nicotine. So it develops antibodies that are very specific to nicotine as well as cholera toxin B.
PORTER
So once somebody is vaccinated with this vaccine presumably then if they then have a cigarette and nicotine enters their bloodstream what happens then?
BUNCE
Well the idea is that when nicotine enters the bloodstream the antibodies that are present bind to the nicotine and create a complex which is far too large to allow the nicotine to get across the blood/brain membrane, this is a membrane between the blood and the brain that only allows very small molecules to get past, nicotine on its own is small enough to get into the brain and create this feeling of pleasure associated with smoking a cigarette.
PORTER
So they'll smoke the cigarette but they won't get any of the reward, if you like, from getting a nicotine hit?
BUNCE
Well the target is to reduce nicotine to a level whereby we do not receive the normal level of hit or pleasure that tends to reinforce the smoking habit.
SANDFORD
I think that the particular potential for this vaccine may be to help smokers who find it very hard to quit and they tend to be people in particularly disadvantaged backgrounds or they're in a workplace or social situation where they're surrounded by the smokers, it's much harder in those circumstances to quit and to stay a quitter. And so if the vaccine can help those particular people then I think it has a huge potential.
PORTER
How long do you envisage that people who are using the finished product might be "immune" to the effects of nicotine for?
BUNCE
Well so far what we've found in our clinical trials is that an antibody response is generated towards nicotine with the nicotine vaccine can least between three to six months and in some cases even longer.
PORTER
Campbell, what happens to those molecules in nicotine then that are wrapped up in the antibody, where do they go?
BUNCE
Well once the nicotine binds to the antibodies ironically enough actually it enhances the half life of nicotine in the bloodstream, so if the nicotine's bound to the antibodies nicotine survives for longer in the bloodstream but it's unable to get anywhere and induce its usual pleasurable effects. But then it's subject to the usual mechanisms of breakdown - the antibodies will be taken out through various mechanisms in the liver etc., and when that happens the metabolism of nicotine will take place.
I mean one thing that the regulators have been concerned about is the safety of the vaccine because we don't know what the safety aspects of having nicotine last for longer in the bloodstream are combined to the antibody and that's what the clinical trials are all about. We're looking to establish what impact these antibodies do have on overall safety of the people that have been vaccinated. So far, so good - there's no indication that antibodies that are bound to nicotine have any toxic effects, in fact on the contrary, we are blocking the effects of nicotine and we are actually disposing of nicotine in a more efficient manner.
SANDFORD
I could see the potential where the vaccine may have the opposite intention, if you like, because if someone who's just successfully quit smoking feels well I can have the vaccine, I can go to the pub and if someone does offer me a cigarette and I smoke then it's not going to have the desired effect. So it does raise the question of how effective that will be in the long run because giving up smoking is not just simply the removal of the nicotine and the pharmacological effect, it's the whole behavioural aspect as well, in a sense smokers need to be reconditioned into becoming again non-smokers and there is more to it than just simply stopping taking the nicotine.
PORTER
You're talking about using the vaccine in people who already smoke, who want help to give up, do you ever foresee a day where we might have a product that might be used to prevent people taking up smoking in the first place?
BUNCE
I think that's - that's a difficult concept at the moment to address. We first of all need to understand whether this has any use at all in helping current smokers quit, at which point if we do find that it's effective in that target population then I think we can consider other populations, possibly adolescents to prevent them picking up the smoking habit. But there's a lot of moral issues associated with that because it's unlikely that the adolescent would make the choice to be vaccinated, it would probably be down to the parents.
PORTER
Dr Campbell Bunce.
David - assuming that vaccine proved to be both safe and effective in adolescents - would a nicotine vaccine fulfil your criteria for inclusion in a routine vaccination programme because if we look at it this way - one in three adolescents may end up smoking, one in three of them may end up being killed by it - it's an important disease to protect against?
ELLIMAN
It's extremely important and put like you put it yes I would agree, though it's slightly perverse - why don't you just ban cigarettes?
PORTER
It would make a lot more sense.
Now talking about law, there were laws forcing people to have smallpox in the 19th Century, you had to be vaccinated, didn't you - how much pressure do you think it's fair to exert on people to have their basic vaccinations, because it's not just them that they're protecting, it's the herd isn't it - the rest of us?
ELLIMAN
Well I think there are two issues, one is does it work anyway because if you look at countries such as Scandinavia, where they don't have compulsion, they have very, very high uptakes of vaccine. In the States, in fact, they have no higher uptake than we do of most vaccines …
PORTER
And they have compulsion there do they?
ELLIMAN
That's right. To go to school you have to be vaccinated, so they have compulsion. So I think there's an issue about whether it would work. The other issue is, is that something we would like anyway, I mean surely it's much better to take people with you because they believe what you're saying rather than force them. I think it would put GPs in a very difficult position.
PORTER
I can imagine. I mean one of the big problems with the - one of the fall outs of the MMR hoo-hah really has been that people are slightly suspicious of doctors and the authorities and it's very important that they do trust us, isn't it, that's one of the reasons why they're bringing their children forward for vaccination.
ELLIMAN
Well I think as a general principle one would always like people to do something because they are convinced it's right, not because there's some penalty over hanging them.
PORTER
Of course the other thing is - and it sounds a bit harsh this - but they actually need to be scared, they need to be worried don't they, there has to be a perceived threat and it's interesting when we had problems with the MMR and we were trying to get people to come in to have that at the same time we were almost fending people off because meningitis C had been introduced and people wanted that and they were - I mean they weren't quite queuing around the block but it wasn't far off.
ELLIMAN
Well I think the problem is that our vaccination programme has been so successful that most of the general public, or even medical students and doctors now, are not seeing these diseases, so there is no immediacy about preventing them and any little story about a scare takes much greater precedence. If you were to go back a generation - I mean my mother's best friend died of diphtheria and she would be amazed at all the scares there are around about vaccines.
PORTER
Dr David Elliman, we must stop there. Thank you very much.
Next week's programme is devoted to autism - its diagnosis and management - and includes new research that could explain why it tends to be more common in boys.
<< Back to main page
|
ÌýPrint this page
