12th Greek Australian Legal and Medical Conference
Samos, Greece 2009

“BUGS OR US – WHO WILL WIN THE WAR?”

Professor Ian Frazer

Thank you for your kind introduction, and it is certainly a great pleasure to be here and to talk. I am not quite sure why I chose the title I did, except that I think I had to come up with something extremely quickly when I was asked to. What I would like to do is talk a little bit with you about the competition between the pathogens that potentially assault us and our own defences against them. I am going to lead you to the conclusion that at the end of the day it is up to us whether we win the war or not, but the terms of winning might not be as clear cut as you think.

Microorganisms are us!

To put this topic in perspective, we carry around with us 10 times as many micro organisms as there are cells in our body, so right at the start we are actually “sleeping with the enemy”. However, these micro organisms are necessary for us – they are if you like saprophytes that exist with us, but actually help to keep us healthy. They support the process of digestion, they keep our skin free of other much worse pathogens and we kind of need these organisms. So, we can’t actually win the battle completely. It really comes down to a matter of who is the fittest, and if we start looking at it from the bug’s point of view (the lawyers amongst you will recognize “eminent domain”) they were here first, they have been around a lot longer than we have and they have had plenty of opportunity to adapt to us. I am not going to spend much time talking about how bugs actually cause disease because, I won’t have time to cover that but, to summarise in its simplest terms, bacteria by and large cause disease either because of toxins that they produce, which are bad for our metabolism although they perhaps help the bug, or alternatively because our own defences against the bacteria make us sick. In contrast, viruses by and large, kill cells, although as I will tell you later at least one that I am interested in actually not so much kills the cells but it turns them into cancer. The next slides shows cartoon pictures of bacteria on the top and a virus on the bottom. Viruses don’t just infect humans. The picture is actually of a virus that infects bacteria. Bacteria have their own infection problems to deal with – it is not just us who gets into trouble viral infections. The picture is of a rather elegant virus. You can see it is constructed to do a particular job, deliver its genetic information to the organism it will infect, and it is a design that an engineer would approve of, I think.

What the bugs have in their favour

  1. Bugs have a very short generation time – they really like to breed, and it is what they are very good at doing. Some bacteria will double in numbers every 20 minutes and viruses also can produce thousands of copies of themselves in a single cell in the course of 4 hours, so they have plenty of opportunity to adapt to the environment they find themselves in.
  2. They learn from each other – bacteria trade information on how to be resistant to antibiotics, for example, and they have a very well defined process for doing that. They actually indulge in sexual intercourse. You don’t think of them getting up to that but they have pili which are the equivalent of penises and they can use them to pass genetic information between themselves.
  3. Bugs also learn from us – viruses do this particularly. They hijack bits of our own genetic machinery. When a virus gets inside your cells, if there is a bit of useful genetic information there that will enable it to do better in the next cell, it may pick that up and take it with it when it goes. If you look at very complex viruses like the smallpox virus, they have hijacked a whole range of human genes which they use to defend themselves against our immune system. Basically, there are control mechanisms in our immune system which are hijacked by the viruses, and indeed we have learned much about these control mechanisms simply by seeing what viruses do to avoid the immune system defences that we can produce.
  4. Bugs can do without us, by and large. There are not many of them that actually need humans to survive – they may need other animals but they rarely need humans.
  5. As I have said to you already, we really cannot do without the totality of the bacterial kingdom because we need them to help ourselves stay healthy.
  6. Many microorganisms have the advantage that they can remain dormant until times are more favourable – we can carry bacteria that causes tuberculosis around inside us for the whole of our lifetime, which causes no problems. When our immune system gets weaker as we get older, they recognize that their time has come and get out and start producing again, and can be passed on to other humans at that time. So there is plenty going for the bugs.

What we have in our favour

  1. We are good at sex – now that is very important because it leads to genetic diversity and the genetic diversity gives us better defences. One of us may die as a result of infection but if we are all genetically different there is a reasonable chance that the whole human race will survive.
  2. Most importantly, we have an immune system. This is a specialist part of our body which is designed to protect us against micro organisms, and it comes in two flavours, if you like. There is an innate immune system, which we share with everything from earth worms upwards. We are not really that advanced as a species – something like 70% of our genes are shared with earthworms and 95% with most mammals. These innate immune defences recognize patterns. They don’t know one bug from another, but they know that what is there is a bug rather than us. We have a whole selection of these detectors called pattern receptors which will distinguish the different features which are unique to micro organisms e.g. genetic information as RNA rather than DNA. We don’t have genetic information as RNA, we have it as DNA.
  3. There are also proteins on the surface of bugs which are unique to bugs. And then we have an adaptive immune response. The major feature of adaptive immunity is memory – it learns from what it has seen before. If we see an infection for the second time, we will do much better at getting rid of it than when we see it for the first time. Those defences come in the form of cells, and soluble proteins called antibody. Again I am not going to spend a lot of time detailing those I’ll just say that they exist, and that all mammals have them. By and large they are pretty necessary, because if we don’t have them - if we are born without them - then we are very vulnerable to infection. If you don’t have antibody, you can survive into adult life, albeit with problems. If you don’t have cellular immunity then you don’t survive childhood without some drastic intervention like a bone marrow transplant. So adaptive immunity is an important part of our defences against infection.
  4. We are smarter than the bugs are, and we have learned how to deal with micro organisms at a practical level if you like. We have been engineers of our own survival. We have produced antibiotics, largely learned from what funghi do to protect themselves against bacteria. The funghi produced the first antibiotic that we recognized (penicillin) and they have given us patterns for other ones subsequent to that. We have produced anti virals like “Tamiflu” synthetically, designed to match up precisely to the flu virus. We also produce vaccines, which is what I am interested in.

What are the challenges for the future?

Our challenges are two fold – one in relation to the immune system and one in relation to the use of antibiotics and vaccines. When it comes to the immune response that we produce, bugs reproduce very rapidly, and they can adapt to evade immunity. They can work faster than the immune response – the flu virus, about which we will hear more later in this session, is one to which you really don’t get time to make a decent immune response before the virus gets the upper hand, and it does take time for the body to learn to fight of a virus infection. For an adaptive immune response, it is about 7-14 days before your response is maximum. Alternatively, bugs can choose to destroy the defences. HIV, the AIDS virus, specifically attacks the immune system and destroys the very cells that are necessary to protect you against it. Eventually, when it has done that, it wins. Bugs learn to mimic our own regulatory mechanisms for our immune systems. I have already referred to how smallpox can do this – the smallpox virus picks up genes which allow it to switch off our defences and therefore it survives. Or, bugs can simply choose a place, where the immune system does not bother to go. The papilloma virus, which is the virus that I am particularly interested in, chooses to infect the superficial layers of the skin where there is really no need for defences except against for that particular virus. And finally, by providing antibiotics, anti virals and vaccines we can change the natural selection process that gives us the diversity that enables us to protect ourselves against infection. While that has not been a problem yet, just remember that we have really only had antibiotics for 3 generations of humans although in that time we have had thousands of generations of bacteria. Over twenty generations, we will be enabling the survival of people whose immune fitness is perhaps not what it should be. Bugs themselves adapt rapidly to evade antibiotics, and drug resistance to most common antibiotics is now extremely common for very many of the common pathogens that causes us problems.

Bacteria which were once thought to be pretty much immune to this evasion mechanism have now acquired resistance. The bacteria that causes gonorrhea for example, which used to be exquisitely sensitive to penicillin, now in many parts of the world is totally resistant not only to penicillin, but to the other antibiotics that are used as second line antibiotics against this bug. Of course, the more we use the antibiotics, the more resistance you are going to see, particularly if we misuse them. If you use antibiotics to treat viral infections which don’t respond to antibiotics then, by doing so, it is not a zero sum game. We actually lose because we acquire the risk that the bugs will pick up resistance, and pass that on to other bugs. Resistance is transferrable: once the new bug learns the trick, it can pass it on not only to its prodigy but to other bugs in the neighbourhood. And we are not always very smart at using our smart technologies.

I mean by this that we deploy vaccines in a piece meal fashion – they are really designed to protect communities. Therefore, communities have to be protected – in other words everybody has to be immunized to get the benefit. If you introduce these piece meal, and at random, then you just suppress the problem you don’t get rid of it. We have to make sure that vaccines are equitably available by distributing them worldwide. There is no use protecting everybody against polio virus in Australia, if there is still polio virus circulating in India, as we found out quite recently when a patient came to Melbourne infected with the polio virus. A lot of people who were not too worried about vaccines suddenly realized that maybe they were not protected. You have to understand that vaccines offer a community protection and not individual protection. We have to use our knowledge wisely, and make sure that we continue to immunize. We have also got to take threats seriously. If we sit by and wait and decide that the current epidemic of let’s say SARS is gone, that may be true. However, we have learnt something from that, and it could come back again, so we have to work to make sure that we are ready for it the next time round, otherwise we are not using our research well. This picture shows the recurrence of measles after a period of time after the immunizations were introduced. The previous ones showed that measles had gone away with immunization. What happens after a while is that firstly a lack of compliance with vaccine policy occurs and secondly we learnt that the measles vaccine does not last for life - it gives you protection until you are you in your teens or a bit later. The two things together enabled epidemics of measles to occur amongst populations that thought they were immunized. In other words we have got to be smart in making the use of technology available to prevent infection.

So the conclusion from the first bit of this talk is that, if I had to take a bet, there is more going for the bugs than us and they may win and we may lose. As the populations of humans increase and people get closer and closer together and there is more chance for pathogens to spread, and as we override natural selection by the use of antibiotics, and anti virals and vaccination, the odds in the bugs favour will increase and therefore we need to work smarter as well as harder to overcome this. A win in this war is not going to be a victory for us, and the bugs disappear – rather it will be a Mexican stand off at best. We will live with them, and they will live with us, and it won’t necessarily be an entirely pleasant outcome. At least it will be better than the epidemics of viral and bacterial infection that used to shorten our life span. Remember we live on average 25 years longer now than we did 100 years ago. That extra 25 years of life is pretty much entirely due to antibiotics and vaccines.

The war on papillomaviruses

I am going to spend the other half of the talk talking about my own personal interest in papillomavirus – not to tell you what I told you when I was here last time, because that would be a bit unkind, but rather just to make an issue of what is necessary to get these vaccines used across the world. Papillomavirus causes cancers - it is a skin virus which, if you are unlucky, and you are one of the 2% that get persistent infection, it gives you a risk of developing cancer. It is one of many pathogens that can cause cancers, as I discussed when I was here last time. From our point of view there are a great diversity of these papillomaviruses: over 200 types known. Four broad groups: Two of them pretty harmless – they cause cutaneous warts, skin warts and genital warts – these two groups are very common and we have a very high chance of getting them, but they don’t cause major health problems.

Two groups that cause cancer in ephitheal surfaces; one group in the cervix (so called genital cancer high risk group) and one group which cause cancer in the skin. Now, the skin cancer connection is not entirely clear. I will come back to that in a moment, but let’s say for the moment that it is accepted that at least some skin cancers are caused by these viruses. So, who wins the war for this virus – the virus or us? These infections are trivial from our point of view, and silent for the most part – we don’t really worry about them too much so we ignore them, even though we now know that 2% of them can cause cancer. So, we are not thinking too smart, if we ignore them. Our immune system chooses to ignore them, because they are on the surface of the body and they don’t kill anything – these are viruses which don’t kill cells and our immune system is particularly designed to turn on when there is cell death occurring, so if the viruses don’t kill the cells the immune system says “I am not worried about that” and nothing happens.

Genital HPV infection

We now have vaccines to prevent at least 2 of these viral infections out of 200 – note, 2 out of 200, but these are expensive vaccines. We don’t have anti virals for this class of virus because this is a virus which actually uses a replication mechanism almost the same as our cells use. Therefore anything which kills them would probably kill ourselves as well. So, we don’t have anti virals, and we do have vaccines but they are expensive, Public health enthusiasm for using these is limited because at the moment people don’t realise just how much disease they cause. It is worth pointing out that they kill at least collectively half a million people worldwide every year, so it quite a significant public health problem. Furthermore, infection with these viruses is very common. This is a graph showing just how common one group of these viruses is, the one that causes cervical cancer. What it shows you is that, over the 3 years after becoming sexually active for the first time, over half of the women tested have acquired infection with one of these viruses. This is, if you like, the common cold of sexual activity. Cervical cancer worldwide and particularly in the developing world is the second commonest cause of cancer in women and kills quarter of a million women worldwide. Cervical cancer is just one cancer caused by these viruses and there are other cancers caused by these viruses as well. Note that the burden is mostly in the developing world because, we have screening programs to prevent cervical cancer in our part of the world. Just a short aside – this is more for entertainment and I think we have time to just be a little bit entertaining.

When I was researching the connection between papilloma viruses and cervical cancer I dug up a paper which has been known for a while, by a pathologist from Verona called Rigoni-Stern. He was interested in who got cancer. Remember, 150 years ago cancer was a disease entirely of women, because only women lived long enough to get cancer. The cancers that we are talking about were breast cancer and cervical cancer, and they are the two cancers that occur commonly in people under the age of 50. Rigoni-Stern was looking at cancer and he noticed that cancers were more frequently in nuns than other women to a ratio of about 5:1. He tried to explain this as an epidemiologist, and he noted that the frequency of cancers of the uterus in nuns versus the rest of the world were inversely related to the cancers of the breast, that cancers of the uterus were common to the rest of the world and cancers of the breast were common to nuns. Now that is fact – that is evidence if you like, and nobody disputes that.

What he then went on to do is to try and explain the evidence, and he probably should not have done. This is what he wrote about uterine cancer “It is not increased through the licentious practices of woman, however the risk is greater amongst women who are excessively sensitive morally and nervously irritable”. I guess that is my wife after I have been giving too many talks and going to too many meetings. So, he did not quite get that right because it is in fact increased by if not “licentious practices”, let’s say sexual intercourse. When it came to breast cancer, he did not do very well either. “So why is it that breast cancer is the most frequent cancer amongst nuns? Could it be that their habits are too tight or perhaps long sustained bent positions assumed while saying prayers with forearms resting on knees and compressing the breasts”. Well, there you are - you have to have a hypothesis for everything – I don’t know how you test that one, but at least it sounds interesting.

Papillomaviruses and skin cancer

When it comes to papilloma viruses and skin cancer we are perhaps no better off than Rigoni-Stern. Each of you, if I plucked an eyebrow hair from you, would have at least 5 different human papilloma viruses in the root of that hair. You are healthy but these viruses are there – we all carry them around with us. This is the group beta papilloma viruses which are associated with skin cancer. We know that if you damage somebody’s defences against infection they are more likely to get these skin cancers, and if you are genetically pre-disposed you are more likely to get them. We also know that there is an animal model where these viruses can do what is called “hit and run” carcinogenesis. In other words the virus comes in there, changes the cells, disappears and then in the future you get cancer. I put that in, to explain the fact that we never find these viruses in the skin cancers, unlike cervix cancer where you always find the virus still there in the cancer. So the evidence is lacking – the courts would not accept it but there is a smoking gun pointing, and I think it very likely that these viruses are responsible for skin cancers as Gerald Orth pointed out two years before Harald Zur Hausan pointed out that papilloma viruses cause cervical cancer. Orth should have been up there getting a Nobel prize along with Harald Zur Hausan last year, in my opinion.

Developing papillomavirus vaccines

Any rate, we have vaccines for the genital papillomaviruses. Harald Zur Hausan started the process by showing that the papilloma viruses caused the cancer in 1980 and we and others developed the virus life particles which are the technology which has led to the vaccines – it is always a team effort in research. By 2005 we had the vaccines. That 15 year gap between the technology and the vaccines is, by the way, about typical for development of a new vaccine – important to remember when you are thinking about protecting against a new pathogen. It represents about a billion dollars of cash expenditure, 60,000 women taking part in trials and 2,000 doctors and scientists doing the studies – it is not a trivial effort moving from the technology to the vaccine. So, I have to make a disclosure of conflict of interest. I thought I would put up one of the many titles that was given to me during the course of being Australian of the Year. See, it does distract you from the idea that I might make money off the vaccine. I think it was actually the vaccine that they were talking about – at least I hope it was.

Anyway, the questions that you need to ask about a vaccine are whether they work, whether they are they safe, how long will protection last, who should be vaccinated and what do you need to know next. I am not going to answer any of those questions. The bottom line is that these vaccines work – just look at the efficacy figures. If you use them to protect against infection with the virus types in the vaccine they are 100% effective, and this is common across all the trials that have been done. But, more importantly they don’t protect you if you have already got the infection. These viruses as I have told you are very commonly passed around through sexual intercourse shortly after becoming sexually active. Bottom line is: give the vaccines before you acquire the virus. Now, why is that important? It is important for the prevention of skin cancers because it really means you would have to get the vaccine before you got the skin papilloma viruses. We pick those up in childhood, passed around in the playground if you like, and therefore vaccination would have to be done early to prevent a cancer late in life. Difficult to do a trial that lasts 60 years. Not much enthusiasm for that. You would pass it on to your grandchildren - you start the study, and they answer the questions. So, the other side of the story is are there side effects of vaccines, and this is very complex technical data but the bottom line is that vaccines hurt. It is no surprise if you stick a needle in somebody’s arm and they say ouch and the ouch lasts because of the vaccine itself for about a day. The data shows that the ouch is just about as common as if you just get the placebo as if you get the vaccine. That is no surprise, it is just the needle. But more importantly we want to know if anything serious happens down the track. 40 million women have been vaccinated with these vaccines now so we can be reasonably confident that nothing very serious is going wrong. A few people get an allergic reaction to vaccine – less than one in a million and that is the same as for all other vaccines. I will comment on pregnancy safety, because this is a vaccine that is given to people of an age they might become pregnant. You should not get pregnant when taking part in clinical trials, but nevertheless one in every 10 women in the clinical trials did get pregnant during the course of the trials. They were told not to, which just shows how effective the advice that doctors give to their patients actually is. Indeed there was a rumour going around that the vaccine caused pregnancy, but that of course is why you have a placebo group, and the placebo group did equally well and 1 in 10 of them got pregnant too.

This allows you to look at safety in pregnancy and the bottom line is that the pregnancies went wrong equally frequently in the vaccine group and the placebo group – pregnancies do go wrong, but there were no differences between the two groups and serious complications the same.

Vaccine deployment

So, how is this vaccine being used? It is licensed all over the place – the only two countries of significance that have not licensed its use are China and Japan, and you can ask me why that is in questions later. But the critical question is where the vaccines are being used. Of course they are being used in the countries that need them least – the ones where we can prevent cervical cancer through screening. Australia is taking these vaccines to heart, and we have immunized about 80% of our school children population. Europe is doing just about as well and America is beginning to get there. The developing world – that is where the problem lies and in the last 5 minutes I just want to talk about that.

The vaccine companies are making the vaccines available in the developing world. They are doing it through a number of different mechanisms – cheap pricing for the developing world, free handouts – Merck have handed out over 3 million doses free in the developing world already and they are continuing to do so. But we really need to get these vaccines used in the developing world. What I have been trying to do for the last year amongst other things is to get field trials off the ground and actually use the vaccines in the developing world. It is quite a challenge to deliver vaccines. Let me explain what I mean by that.

Studies in Vanuatu

We are trying to do a project in Vanuatu which is a near neighbour Island to Australia and in Nepal where there is a big problem with cervical cancer. The problem is that first of all in Vanuatu we know that cervical cancer is extremely common – we surveyed normal healthy women and 1 in 100 women walking in the street had cervical cancer - now think about that. That is a really serious disease problem and no treatment available. 5 in every 100 had pre-cancer, something that was going to turn into cancer in their life time. So we want to get a vaccine out there. However, girls don’t always go to school in Vanuatu, there are no medical records, and everything is very difficult there. They have, wait for it, 73 parliamentarians in Vanuatu – they 5 doctors. If you had the same ratio of parliamentarians to doctors in Australia we would be drowning in parliamentarians in Canberra – I worked out that that there would be something like half a million parliamentarians in Canberra if that was the ratio. So, we have been trying to get trials off the ground in Vanuatu to see what will actually work there, to help protect those women against cervical cancer. We have been using an incentive to get the kids to come back to get their second and third vaccine in the form of little silicon wristbands which they get when they get each of their vaccine shots. This seems to work pretty well so far but the real challenge there, is actually to deliver the vaccines – how can you get them out there? Putting this into perspective, the first thing you need is education. This is us educating in a village on the far side of Efate island in Vanuatu – the parents and the children are all being told about the vaccine under a Banyan tree. This is the same sort of thing being done in Nepal, with leaflets being handed out for the parents.

This is us educating the media in Nepal in one of the schools there, and this is us educating the doctors which is equally important, and finally the politicians. This is Graeme Lade, the Ambassador, talking to a group of politicians in Nepal about the importance of the vaccine program. You do the education, and then you have to get the vaccine out there. This is our cool chain (an Eski). It is 3 hours driving from Port Villa around to where we were doing the vaccinations, and you have to keep the vaccine at 4 degrees, so that is a significant challenge especially when the fridge in Port Villa does not work half the time. Note the expression on the faces of the recently immunized girls here. Then you have got the problems of the roads – this is actually Nepal. We bounced for 2 hours along a road that was in parts much worse than that, trying to get the vaccine out to the school where we were delivering it. Then you find there is all the documentation – it is just the same as everywhere else. Documentation takes over and you have to do large amounts of paperwork to keep the Government happy and also to make sure that you have documented it for the kids that they have been vaccinated.

In Vanuatu we are doing this by giving them photo ID cards which actually show they have been vaccinated – it is just a little credit card with their picture on it and a hole punch for each vaccine shot but organizing that takes time. This is Bernadette, one of the District Nurses in Vanuatu with the girls lined in getting their photograph taken. Then you need resources. This is the classroom in Nepal where we gave out the vaccine. Note the elegant setting and all the necessary features for teaching. This is the classroom in which, one day a week, they were trying to teach computer science to the kids. They bring in the computer and they have power for 4 hours a week and during that time they have to try and teach them computer science. It is an interesting country with goats being taken to work on the roof of a bus, snapped while we were downtown in Kathmandu. It was a bad day for goats, when we were there – one of the major Festivals was the following day and it is the only day they eat goat meat. Part of that process is to sprinkle goat blood over everything in Nepal. If you have a car it will get hosed down with goat blood. Progress to date is summarized here. The one thing that is missing in Nepal is Government support. Everything else – education, cold chain, distributions from schools, documentation is OK and we have only managed to immunize 100 kids because we don’t have the government support. Vanuatu is much easier – we have the Government support and basically we hope to be able to immunize all children in Vanuatu that need it in the course of the next couple of years.

Conclusions

So the conclusion that I will leave you with is basically we can win this war against the pathogens if we choose to, but we have to choose to, we have to be pro-active about it and go out there and do the right things. It is not about victory, so much as a sustained campaign. We do this for ourselves but we mostly do it for our kids because they are the ones that will really benefit from it and we can only succeed on a global basis through education and through research because without those we cannot work out how best to deliver the programs and make sure they get where they are needed.

Thank you very much for your time.