 The Chaget Affair of Switzerland, Mr. Stefan Kvertzli, Chair of the John Curtin Medical Research Foundation Board, Dr. Cam Weber, Foundation Board members, ladies and gentlemen, welcome to the award ceremony for the Curtin Medal for Excellence in Medical Research for 2013. But first we must acknowledge and celebrate the first Australians on whose traditional lands we meet and pay our respects to the elders of the Ngunnawal people past and present. The Curtin Medal is awarded annually to a person who has made an outstanding contribution to medical science and is an Australian citizen or an Australian resident, or a person whose work has significant Australian relevance. The recipient I am about to announce with the medal certainly satisfies many of these criteria. The award may be made for either a major discovery or for a lifetime's achievement in medical research. It gives me great pleasure to announce Professor Rolf Zinkernagel as the recipient of the 2013 Curtin Medal for a lifetime achievement in medical research in the field of immunology. Rolf received his MD degree from University of Basel in 1970 and his PhD degree from Australian National University in 1975 and was during his PhD studies that he actually carried out the work in collaboration with Peter Doherty which eventually won the Nobel Prize for Physiology or Medicine in 1996. So that's something for PhD students in the audience to realise that you don't have to be a scientist being in the field for 30, 40 years, you can get it really right at the start of your career. Rolf continued to make major contributions to immunology throughout his career and he was awarded other prizes, the Albert Alaska Medal for Research Award in 1995 and the Cancer Research Institute William B. Coley Award in 1987. So as I said, Rolf just didn't rest on his laurels after carrying out fantastic work here at the John Curtin Scholar Medical Research in the mid-70s. He continued to make major contributions to immunology in the ensuing 40 years and he's continuing to express a great interest in this subject and today he's going to give a very controversial lecture. He always does, he's very entertaining and the title is Why Do We Not Have a Vaccine Against HIV or TB? But before he gives his lecture, I must present him with the medal. So Rolf, please come forward. In Switzerland you do that only to cows. Well dear Chris, ladies and gentlemen, first of all let me thank you very much indeed and particularly the foundation for this medal. It's a very special moment to get a medal from your own group of people and your own university because usually if you are in a university competition and likes and dislikes are not so obviously leading to such an end result. So it's very special and I thank you very much indeed. And of course it's always a pleasure to be back in Australia and I'm very honoured to be a sort of an honoured Australian. Australia has played a major role and you have heard why I could have been given this medal. Well I'm not an Australian, that's for sure, but our youngest son is an Australian. He was actually born here in the Road and Valley Hospital when I did my post-doc here. And he again came for part of his clinical training as an ophthalmologist to Perth and had another son in Perth. So there is a sort of, you know, on the beach type of mentality in our family. So things are guaranteed at least for the next few years, you know. Well Australia has played a major role in my immunological education. And Australia has really a long standing history and culture in studying immunity against infections. I just mentioned, you know, Burnett, who was sort of at the beginning of that development, played a major role. And some of the offsprings of Burnett, of course, like George McCanist, like Gordon Aida, like Bob Blanton, like Fenner, who worked for many years with Burnett, they all played a major role. And I have profited very much from them. Now what I'd like to do today is talk about that. Why do we have excellent vaccines against polio, or smallpox, or measles, or diphtheria, or tetanus? But we don't have a vaccine against HIV or TB. Now a few years back I used a similar title. But at that time I always put in brackets, yet, question mark. Because that was, at the time, politically more correct. But the older I get, the less politically correct I get. And there's a good reason why we don't have a vaccine against HIV and TB. And that is all basically due to co-evolution of certain infectious agents with higher vertebrate species. And that's basically, that includes us. And the final conclusion of my lecture will be that, in very general terms, we cannot do better than what evolution has achieved if we use the same tools as evolution has chosen for regulating certain things like infectious diseases. So, all the childhood infections, the classical ones like measles, polio, smallpox, tetanus, and so on, they, for evolutionary terms, had to meet a very efficient immune response in any host they chose or were selected for infection. And the reason is very simple. If you get killed by infection before reproduction, the species obviously has a problem. And for viruses, that even goes further. Because since viruses only can multiply or replicate within living cells, if a virus kills all hosts, it kills itself very directly. So, there is overall a very balanced evolutionary history in all of us and in these infections. TB doesn't kill you unless you are immunodepressed or suppressed. And this usually happens in old age, after, let's say, 50 or 60, or in HIV-infected patients, or in immunosuppressed patients that are treated with anti-cancer drugs that usually also have an impact on the immune system and so on. Then TB can become a problem, but overall TB is not really a huge health problem. And the same can be said for leprosy. You know, almost 100% of people who have been infected with leprosy, but only a small portion, 0.1%, also, actually showed the disease consequences of leprosy. So, in evolutionary terms, what you read in the Canberra Times, you know, doesn't reflect necessarily the true worldwide evolutionary balance states. And I'll try to explain that a little bit. So, let's get into, and, you know, those, most of the slides I show and most of the points I try to make are slightly exaggerated, but that makes it more easy to attack them and say this is all rubbish. Probably about half is rubbish, you know, but the other half is probably okay. So, you know, what do we need? We need to survive for 20 to 25 years. Well, there's needed to have the next babies and bring them up to, let's say, independence five to eight years after birth. That's all there's needed. All the rest is luxury. Most of you won't like that, you know, definition of life expectancy and life quality, but that's, that's biology. Of course, we all have recognized that too many, that we have too many humans on this earth. I mean, this is a big world problem, too many humans. That's the biggest problem. There's all the consequences of, you know, energy usage of the CO2 balance and so on. It's all simply too many humans. So, you know, I hope you're going to solve that problem. That's another issue. Maybe you need more dictatorships like in China, you know, can solve the issue. Then there's another huge problem that our behavior is, of course, not always optimal. You know, mine of course is, but I mean, even if we learn about things and at school or in families and so on, we don't usually translate it into consequences. That's just part of human nature. And then, of course, what today is also politically absolutely incorrect. Not all humans are equal because otherwise we wouldn't have variability and in evolutionary terms, the possibility to select, you know, that nice example of HIV infection where a certain variant of a certain, you know, receptor on white blood cells actually renders you very resistant against HIV infections. So, there are these mutations around that for certain diseases make you more or less resistant and then, you know, dependent on the overall importance of these infections, you get a shift of the genetics of the genes selected within co-evolution that are favored or not favored. And then, of course, all this is confronted with, you know, responsibility versus freedom. As I said, dictatorships would be an excellent form of solving many of these problems. Unfortunately, most dictators, you know, within a few years overdo things. And, you know, many discussions about are vaccines good for you or bad? Of course, they are good. But if you believe they are bad, then if somebody in a Lancet paper publishes some, you know, believed in correlation with autism between autism and measles vaccines, I think then, of course, we have a problem as society. If the society doesn't know about the shortcomings of such a seemingly scientific study, which it isn't, it has been retracted in the meantime. And if we, as scientists, cannot teach the general public about these issues, another problem, of course, is that in some countries, you know, scientists are not amongst the highly regarded. And that, of course, is at least partially our own mistake or problem. So what I first want to do is give you a sort of a poor man's quick introduction into immunology or immunity. And then from there go into two aspects which are mentioned here. I was promised a pointer. It even, well, it misses, still misses something. Well, I can probably, you know, you can read. So specificity is a nice definition of what we mean when we say, if you are immune or vaccinated against polio number one, you are not immune against polio number two. Very simple. Now, specificity usually in immunology is measured with a ELISA assay. That is, you stick your antigen on plastic and then you put serum on it and you show how much of the antibodies in that serum, in that blood, stick to what you have stuck on plastic. Very simple. However, there's a problem because what you stick on plastic doesn't stick on plastic unless it's usually denated. So it's not, you know, the original stuff that sticks onto plastic. It's something like a destroyed car compared to a functional new car that is on the plastic. So you measure things that stick to plastic and antibodies that stick to that denated stuff on the plastic, but this does not necessarily correlate with the real stuff you would like to measure. And this is a very general problem. You know, methods are there to measure many, many things, but very, very often in science, while we measure accurately and you can repeat the measurements, we most of the time don't measure the right stuff. And that has some consequences and I mentioned some. Part of the problem in infectious disease is that we measure how many antibodies stick to the stuff stuck on plastic. But the only thing we are really interested is whether the serum of the blood of the patient can actually eliminate or neutralize a certain bacterium or a toxin or a virus. And this is a more complicated assay, of course, and people don't like to do experiments with infectious agents. And that's why they use the ELISA. So 98% of immunology is done with these ELISA assays. So if you do and measure something with ELISA, you are proven right because 98% of the immunologists use the same assay, so you're okay. But in biological terms, you may be miles far away from the real target. And this is almost a philosophical or societal issue, which is very important. So specificity is one. Now the only thing, immunity, which means the protection by an immune response, we call immunity. And immunity only looks at so-called serotypes because the difference between polio one and polio two is what the protective antibodies recognize, whereas the ELISA antibodies, you know, are 99% shared between polio one and polio two because it simply sticks to the stuff stuck on plastic. Now I don't talk about tolerance, a very difficult idea and very difficult experiment, but I will talk about memory. And memory in immunology says, you know, if you get immunized with an antigen or a vaccine, maybe once or twice or even three times, then you have memory. And that memory is responsible for protection lifelong against that particular infection. And I will try to show you that this is simply not true. The experiments that are usually done are correctly done. And you can measure and show, yes, this memory that is quicker and the higher response, you easily can repeat and show that this is true. But quicker and better responses are not equal to protection. So it's worthwhile, you know, even with these classical terms to simply go through the textbooks and look at them very critically. And you do that particularly if you have to teach, you know, I had to teach immunology for 30 years. So I bought all the textbooks and, you know, made my own fruit salad of immunology with all these textbooks. And doing so, you find many discrepancies that simply don't make sense. And I'll try to develop that to actually just remember what I want to do is to show you why there is that two class of agents against some we can do excellent vaccines that are protective and against others we simply can't do it. Now, you know, I like to do high-alp mountaineering. And there, that's a bit like measuring things. It depends on which side, you know, of this ridge you walk. On one side, it's very easy and you survive. On the other side, you probably, you know, go down the drain and that's a bit of a problem, of course. So now let's get into immunology proper. Now, on this little figure there, it's just a scheme of how an infection usually happens. You know, here, a virus called one hits you in the skin, like smallpox, for example, or the mucosa. And then from there, after a day, two, three, the virus actually reaches the draining lymph node. This is that ball in the groin of this figure. And there it replicates again. But at the same time, infecting cells, these infected cells stimulate the immune cells in that lymph node. And that's why the lymph node swells. One feels that, you know, as a pain. After another two, three days, the virus spreads through the blood system. And of course, there's a huge danger that the virus then reaches the brain because the blood goes to the brain. And that must be avoided because we all have only one brain. So if that is gone, that's it. So the early immune response that is generated in that draining lymph node actually is responsible for a very early antibody response, you know, which is called an IgM response, which is extremely efficient, very, very early day to, already, you can measure this particular type of antibody response. And this really efficiently prevents the virus from spreading too widely. Now, in the bottom part, you see a histological cut through a lymph node or a spleen. This happens to be a spleen, but it's, I'll say. What I want to make the point is summarized in this upper left corner. You know, the immune system consists of single mobile cells, and there are thousands of them. And these cells, about one in 100,000 or one in a million, recognize one particular virus or bacterial antigen that may cause your death. So it's a very rare specificity, very rare T cell or B cell within that system. So the chances of such rare cells to actually meet and collaborate, and this is often necessary for an immune response, is almost nothing. You know, it's 10 to the minus 12. It doesn't happen. So a lymph node or the spleen with these brown structures there, which we call follicles, you know, they actually are responsible with a very sophisticated type of anatomy to actually make the cells traffic through these structured environments so that cells that should meet each other have a much higher likelihood to meet. And the center of this meeting of these cells is, for example, a macrophage, that thing in the middle, or a so-called antigen presenting cell. Because they're the antigen and the T and the B cells that are specific for that antigen are sort of attracted or get stuck to that cell within that circuit of cells. So lymph nodes and spleen are called secondary lymphatic organs, set them apart against the primary, which is basically bone marrow where the stem cells come from, and the thymus, that is sort of like a college for cell-mediated immunity for T cells. That's why they're called T cells, and you remember well another Australian, Jacques Miller at the Walter and Eliza Hall Institute actually found that thymus is key to develop these T cells. So these lymph nodes and these follicular structures are extremely important, otherwise these various lymphocytes do not meet and then immune response is not met. And this is particularly interesting in some infections, like HIV, but also in the infection Peter Daughty and I studied here, which is called lymphocytic corium meningitis virus, forget the name, it's LCMV, it's a mouse infection that is very similar to HIV infections in humans. What happens there is that if you infect mice with that virus and you look at it eight or ten days after initiation of the infection, the whole anatomy of that spleen or lymph nodes is completely shot to bits. If, however, you treat the animal with an antibody that eliminates all the so-called killer T cells, the CDA T cells, then your follicular structures remain intact. And that is an indication that it's not the virus that destroys some of the host cells in the immune system. It's actually the immune response against virus infected cells that destroys the virus infected cells, which otherwise wouldn't have been destroyed. It's like looking at immune responses from an upside-down type of perspective. And several diseases exist that actually where the immune response causes disease and not the virus. I will get back to that. Now, the second is exactly trying to explain that point. You see, a virus, but you could make the argument for classical parasitic infections or bacterial infections, infects a cell without a living cell the virus cannot replicate. So two things may happen. There are viruses that simply use or misuse the cellular machinery to such an extent that the cell dies. We call these cytopathic viruses. Those are viruses that basically cause the pathology or the disease directly. They simply go into cells, the cells get destroyed. And this then leads to an enormous multiplication or amplification of the virus. Now, there it's clear, as I've said, antibodies, these little Y structures, have to come up very early. Otherwise, the virus spreads through blood and gets into brain or liver, let's say, and then destroys these organs and that's the end of it. Now, many more viruses take the left-hand part and are called non-cytopathic because their replication in a living cell has no consequences. The physiology is all intact. Nothing happens. But of course, on the cell surface, there are certain alterations seen that then are perceived by the immune system. And now the immune system cannot distinguish between this type of infection versus the left-hand side. So the immune response comes up, it's generated, and kills these cells. In this case, in the left-hand side, it would not have been necessary because the virus by itself doesn't do any harm. And that causes a problem. Hepatitis viruses often use that pathway. Hepatitis B, hepatitis C. The same is true for HIV, as I've shown you, or LCMV, as I've shown you with the destruction of the lymphatic tissue. And of course, the destruction of lymphatic tissue causes that subsequent immune responses are not any longer possible because the lymphatic organs are destroyed. So that's why HIV, although it is not cytopathic, causes a pathology that then ends up destroying the immune system. But at one time in life, this doesn't happen. Namely, if the immune response is responsible for the cell damage, for the pathology in the host, these viruses use a time slot where there is no immune response. Because that avoids, of course, this damaging immune response. And when is that? Before or at birth. We are all born without a functioning immune system. That has several reasons. For example, we are a foreign graft in a mother. So if we had an immune response as a fetus, we would start to react against the mother, which is of course not very productive because we need the 270 days or so. So before or at birth, there is no immune response. So these viruses of the left hand side, they jump from a mother carrying the virus during that period. And the examples for that are hepatitis B, hepatitis C, HIV, many infections. Many of which we probably haven't even discovered. So there is, you know, in a way, these viruses have reached a very high degree of co-evolution. Because they basically, in a way, know their immune kinetics, the time plan of development of the immune response. And they hit it just right not to make their own life miserable, but also not that of their host. Which of course, as I have said, goes in parallel. So there is a second point I would like to make on this slide. This is, you know, this is a typical virus. And what you see, this is rabies virus. What you see on that graph up there, that negative staining of an electron micrograph, you see that there is a highly repetitive, identical unit on the surface of these viruses. And this is true for all classical acute infections. Bacteria, parasites, viruses. This is basically the standard building plan. And there's a reason for that. Because this highly repetitive demonstration of the identical units on the surface is capable of triggering the B cells that make the antibodies in the complete absence of so-called helper T cells. So that gives you an enormously efficient and quick response already by day two or three. And this goes in parallel with this highly organized repetitive structure. And you can imagine this by simply looking at your fingers. If I put them together like this, then you have about the correct dimensions of such a structure on the surface. And only the fingertips actually are exposed on the surface of an intact virus. So only antibodies directed against these tips of my fingers, that is, glycoproteins, are actually can sort of cream up the virus and prevent it to dock onto the next susceptible cell. It's the construction of this glycoprotein, what I show here, that actually is key to understanding an immune response. And any antibody that would bind not to the tip but somewhere in between can simply not get there because there is, you know, competitive inhibition. Simply there's not room for an antibody to get there. It's too narrow. So there's only one, let's say, Achilles heel that is shown to the B cells. And that explains then very easily why there are serotypes. Basically you only have to exchange a little bit or change the tip of your glycoprotein or finger. And you can keep the rest all constant because that's the only tip that is or the only site that is important for protection. So that's my introduction and now we go into the nitty-gritty. You see when a mouse or a human is infected, then their immune response goes in parallel with the two types I've said. You know, there are cytopathic, cell-destructive viruses and there are non-cytopathic, non-cell-destructive infections. And the top scheme shows rabies-like, cytopathic infection like measles, like polio, like smallpox and so on. And what you see there is on the time axis versus amount you can measure that the virus replicates, there's a T-cell response and then there's an ELISA antibody response and the neutralizing protective antibody response. The ELISA response you measure with that plastic plate and the neutralizing one, you simply plant a few virus particles onto cells and you add antibodies and you then look whether these antibodies actually can prevent the virus from infected your tissue cultures cells. But that correlates very nicely with protective titers you can measure. So what you see is both the ELISA, this artificial measurement and the neutralizing protective antibodies have an extremely quick, early, enormous response. Now for all the non-cytopathic viruses, the ones that usually jump before or at birth from the mother carrying the virus to the offspring, it's the lower panel. What do you see there? Lots of virus, lots of T-cells, I call them CTLs here. Early ELISA antibody responses, but for the neutralizing protective antibody responses it takes something like 100 to 300 days. So it's completely different, particularly concerning the neutralizing antibodies which basically tells you the host survives without a neutralizing antibody response. In the first case you have to have a neutralizing antibody because otherwise you would be dead in 7 to 10 days. Now this is not an artifact in MACE, I just, schematically, down hepatitis B virus or HIV virus, it's exactly the same. You see virus, you see the T-cell response, you see the ELISA response, the punctured line and the neutralizing antibodies slowly come up after 80 to 300 days. And the reason why we don't have a vaccine against HIV is actually due to that. There is no neutralizing antibody response made and by the time it starts to be made there have already been accumulating so many virus mutants that have mutated their, you know, their fingertips, so to say. That this antibody cannot catch everybody any longer, so a new mutant will win. And there will be the start of a new immune response, but this takes another 100 to 300 days and by that time, you know, there's a new variant, a new mutant. So in a way viruses know in quotation marks very well how the immune system works because over many, you know, thousands, if not hundreds of thousands of years the cohabitation of infections and an immune response have resulted in a balance that leaves sufficient numbers of the hosts surviving and sufficient numbers of the infectious agents surviving that basically both get away with it. So you always have a little bit of damage, but, you know, damage in evolutionary terms means you kill 99%, if you kill 90% no problem. I mean of course for the individuals it's a problem, but in biology 90% not to worry about. Okay, now let's look at some actual finding because we looked at exactly that problem in LCMV in the mice infected with this non-cytopathic virus similar to HIV and what you see is in this particular case we infected mice on day zero with a certain dose of virus and then simply followed the blood titer in these mice and what you see the virus goes up and then it's eliminated, you can't measure it. Now, you know, not measuring is not that it isn't there. Absence of evidence is not evidence of absence. And this is a classical example, you just technically cannot detect it any longer but then you find, you know, another 30, 40 days suddenly the virus comes up again. So the virus was somewhere. So you let these mice all go and then you let's say on day 150 you take blood from all the individual mice and you find virus in some of the bloods, but in some of the individual mice you don't find any virus on the bottom part because that means, you know, you can't measure. And then you look at the antibodies in the blood of every individual mouse. So let's take the open square mouse. You have taken blood, you have isolated virus from that blood and you have taken the antibodies from the open square and now you take the open square antibodies and test them against open square virus for protection or neutralization, nothing happens. Otherwise the virus wouldn't be in the blood, of course. But then you can take the virus from all the other mice, you know, black triangle upwards, black triangle downwards and so on. And you can criss-crosswise test all the serum, the blood, against all the isolated viruses. And what you find is that the open square serum, the blood of the open square mouse, although it cannot neutralize the open square virus, it does in fact neutralize all other viruses. And this is true for any of these isolates, after let's say 150 to 200 days. But now interesting, let's take the open triangles, either up or down. Bleed them, you don't find virus, but if you take that serum and look for antibody activity against all the other isolates, you find that in fact these serra, this blood of the open triangle mice can neutralize all the isolated viruses. Which basically means that the virus mutates all the time, gets away with it. And the mouse makes eventually a neutralizing protective immune response against all these mutations and accumulates, you know, lots of antibodies against many mutations. And if everything goes optimally, then the virus is controlled below the detection level. But in some cases, the virus just finds a slight delay or a slight weakness in the response, delay in the response, and that virus escapes and will persist in the end. And this is exactly the problem of HIV. But it's also the problem, for example, of malaria, Plasmodia. The same, exactly the same happening. So it's overall like, you know, like a play between the repertoire, the coming up of these antibody responses over a long time, and the timing of the, and the title, of course, of all this. So sometimes the immune system wins, sometimes the virus wins, but in effect it doesn't matter because the virus by itself doesn't cause any harm. Remember, this is a non-cytopathic virus. But the teachers are enormous amount about the virus and about the functioning of the immune system. But at the end of the day, one neutralizing or protective antibody that usually is, you know, produced after vaccination with a defined vaccine is obviously not good enough because basically there are probably 100,000, maybe 500,000, maybe a million different viruses that all are called the same, HIV or LCMV or hepatitis C or Plasmodium falciparum. But behind that, there's a huge variety and that's why it's difficult to make a vaccine. It's impossible so far because of that variability because you would need the good antibody. So now, in the past few years, and this is, you know, an ongoing discussion for almost 100 years, and Burnett, for example, was very much involved in the early times with influenza. You know, each year you go back and get a vaccine with two, three, four strains of influenza. Hopefully that vaccine covers whatever is coming during the next season. And people said, you know, this is stupid. Let's be clever and make one vaccine that protects against all the influenza. And now comes what I've tried to tell you before. You see, also in influenza, on the virus surface, it's like fingertips. You know, the fingertips are accessible to antibodies or B cells. And there are many determinants, you know, that can be recognized by ELISA type antibodies, but there are, let's say, underneath this uniform surface. So people say, you know, because I measure, not me, but them, measure all the antibodies in ELISA. And I've told you, you know, ELISA is basically stuff stuck onto plastic that is denated. So it's basically the virus decays and is put and, you know, many, many determinants show on plastic that never are exposed like the fingertips on an intact virus. Now they come and say, well, you know, this is all stupid. We make a vaccine against the constant lower part of the glycoprotein. In terms of my fingertip, you know, not against this part, but against something below here, because that is common to all influenza viruses. But, you know, as I've said, and actually Kevin Lafferty, who worked also in this school, did very early experiments on this issue. Antibodies other than these neutralizing simply cannot reach in between and reach these common determinants. And therefore, while this is a nice thought experiment, you know, and not unintelligent, it's simply wrong because it doesn't happen on an intact virus. So now people postulate, let's do a common determinant vaccine that is broadly neutralizing and broadly protected. This will not work. And it will not work in humans. You know, they can heal mice, but I have healed thousands of mice. But that's irrelevant because influenza is not a mouse problem. Influenza is a human problem and a pig problem and a bird problem, but not a mouse problem. So in mice you can measure things, as I've said initially, you don't want to measure because it's irrelevant. But you can publish these things in native size because it's wishful thinking, you know. I can prove that you can make a broadly protective vaccine, but it's not true. Now repetitive units, you know, is a very common pattern in biology. This is my flower garden at home in the best of all times. Of course, early June when all the delphiniums come up and all these flowers are highly repetitive. And it's, of course, as beautiful as looking at viruses or bacteria or plasmidia. Because, I mean, these biological constructions are just aesthetically extremely beautiful. Also a virus. I mean, you know, these regular tetrahedral or whatever. Constructions, I mean, they're fantastic. And so I think is our plants. Plants are a bit easier to deal with because if you can control the slugs, then the plants usually work and grow very nicely, which is not always the case in the laboratory. Now let's get to the second problem I've mentioned that is immunological memory. Now the definition of immunological memory is given on the left hand side. Memory means you immunize with an antigen and then after some time you come back with the same antigen. And you see the, in this case, I just depicted neutralizing or protective antibodies. You have a certain kinetics, a certain titer reached over time. If you hit the system a second time, it's quicker, the curve is deeper, and you reach high levels. So quicker and higher or quicker and better, that's the definition of so-called memory. Now memory is a very sedusive name, of course, because we all think we know what memory is. But the only thing we know is that with age memory goes down, you know. But we don't really know how neurological memory works. There are basically two schools. One says there's a new hard wiring for each thing we recognize or learn. And the other school says, no, no, no, no, this is not hard wiring, but it's using similar circles or identical circles each time you get re-exposed to the same event. And of course, in the second, let's say, school of thought, you include dreams. Because dreams are part of that fixation of certain, you know, circuits that fix what you have seen, sometimes in very strange combinations of things you have thought about or seen. But it's a similar discussion in immunology, because that basically says, you know, once you have been immunized, or second time or third time, you know, the system is different. It's like changing the hard wiring. But the alternative, of course, is say, this is not true. You simply need re-exposure, you know, periodically. If the stuff comes back, then you get another kick in the system, and that's why you keep the response up and then you get another kick, and that, of course, would be far away from so-called memory. Because it would say, you need the antigen, the re-infection, the re-exposure, or the re-vaccination to actually keep your protective levels up. And I think that's true and correlates. You see, immunity or protection is very easy with vaccines against the ones with the green markers, but we don't have it for the others. So why is that? One general issue, namely the variability we have dealt with. Now let's deal with the memory issue. How long does a response last? Now, again, what I've said, you know, it all depends on how you measure things. If you use an ELISA assay, that is, the stuff stuck on plastic, you see that after an immunization, your antibody response lasts forever. A mouse survives about one to one and a half years. So basically, you know, long antibody response. But the quality you measure with an ELISA assay is as to binding strength, as to the strength of the antibody binding allows equality. It's 10 to the minus 5 to 10 to the minus 6. Whereas from the neutralizing antibodies, you need 10 to the minus 10. So it's about 100, 10,000-fold tighter binding. And when you measure with neutralizing antibodies, you know, your antibody response decays very rapidly, actually. After 30 days, 40 days, you are below what usually is considered as being protective. That doesn't smell like memory, doesn't it? So now, you know, what's going on? Now, there's one interesting thing. If you take simply normal serum from a mouse, you have raised under sterile conditions or specific pathogen-free conditions, which is equal to a very modern type of animal house like Chris Goodenhouse. And you take that blood serum and you check the activity of that serum against a number of viruses. You find we always have a natural titer that is before immunization of 1 in 20 to 1 in 30. This is highly specific because you can cross-absorb it. So your natural antibody activity in normal serum without any immunization is 1 in 20 to 1 in 30. And this is about 1 in 800 to 1 in 1,000. There, you are protected. So from 1 in 30 to 1 in 900, you only need a 30-fold increase of your protective antibody, which is actually very little, you know? And if you translate that back into B cell replication circuit, you know, into multiplication of your specific B cell, actually 2, 3 days is all that is needed. That's up nicely. So you either have the repertoire in your antibody naturally, and then you are very efficient within 2, 3 days you have your response, or you don't have it, and against HIV or LCMV or Hepatitis C or Plasimodia, you actually don't find that natural activity. It's below whatever you can measure. Then it takes you 100 days or 300 days to get to that response, which is much too slow to actually kick the infection out. So again, you see that separation in the two. And, of course, you know, if you want to study and propagate memory types of ideas, you, of course, use ELISE assays. If you think memory doesn't really function, then, of course, you use that redact. So to summarize this little loop, you know, you choose the assay and the method to measure things that gives you the results you want. Now, let's do a very simple experiment. And Hans-Peter Rolsten in the lab did the beginning of his PhDs. You know, you vaccinate a mouse with a rabies virus, and then you take the so-called memory T and B cells. That's, you know, memory, memory. You know what memory is. So you then take these memory T and B cells, transfer them to a naive recipient. They're all histocompatible, so you can do these tricks. And then you challenge, and they all die. If you take the serum from the donor mouse, just the blood, and transfuse it, then everybody survives. So the first part of the experiment tells you that memory T and B cells cannot adoptively transfer protection quickly enough. It's a time question. Eventually, you know, the response will come up and will be slightly better. But it takes four to six days, which is too slow to actually protect you. Whereas in the serum, you already have the necessary titer of antibodies, and that protects you immediately. And this, of course, the second part, the serum transfer, that is the experiment we all have experienced before you were born. You see? In humans, you find the fetus and the placenta, and then you see the mother's side, where you have basically a huge amount of blood that contacts directly the fetal side of the placenta. And on the fetal side, there are FC receptors, special receptors, where IgG antibodies can hook on. And then there is a transport mechanism that takes these Ys from the mother blood, these antibodies, and transports them into the blood of the fetus. And when the fetus is born, the fetus has all the antibodies that it received from the mother. Fantastic, isn't it? Because its own system cannot make an antibody response. In calves, this is even more drastically shown, because in calves, you know, they have, in all ruminants including calves, they have a completely double membrane separation between fetus and mother. And there are no transport systems for proteins across two complete membranes. So the calf actually is born without maternal antibodies. And if it's true what I've told you, you know, if the maternal antibodies protect you, then of course all the calves should die. But they don't, why? Because the cholesterol milk, the first milk, which is a concentrate of antibodies, that concentrates antibodies of the mother up to birth. The cholesterol milk, the first milk, is drunk by the calves. And in the gut cells of the calf, there are FC receptors, the same FC receptors, and they pick out from the cholesterol milk from the mother all the IgG antibodies. And within 18 hours, the calf is, you know, nicely filled up with maternal antibodies. So fantastic co-evolutionary pathways that show you how essential the transfer of the immunological experience of a mother is to be handed down to the offspring, because otherwise the offspring would die. So that's in a way the same experiment I've just shown you on the laboratory conditions where the serum transfer protects your recipients, whereas the immune or memory T and B cells don't. Because that takes too long, 46 days until the response comes up. So in a way things are rather simple. You see, the mother is genetically, let's call it AB. Father is CD. That means the offspring is AC. So the offspring will have foreign transplantation antigens. A rejection of the fetus is avoided simply because on the surface of the fetus towards the mother there are no transplantation antigens expressed. It's naked. So that part is easy. Now the offspring shouldn't react against the foreign B of the mother. And that's guaranteed by the immuno-incompetence of the fetus. Has no immune response. So both sides are basically, you know, inert. Nothing happens. Mother has been previously been infected with all sorts of so-called classical childhood infections. I just call this virus X. So she has anti-X antibodies. And these anti-X antibodies have been transferred to the offspring in the last semester of pregnancy, as I've shown. So now the offspring is born and immediately, you know, not in Canberra of 2014, but under wild-type conditions up to very recently, you know, immediately these babies were exposed to all sorts of infections. So X comes along, but X doesn't cause disease because the offspring is protected by the maternal antibodies. And this sort of repeats itself. And eventually, you know, the maternal antibodies go down because antibodies have a half-life within the system of about three weeks. So eventually things will go down. And at that time, there will be infection only slightly attenuated. And this infection then will cause active immunization because by now, this is one to two years after birth, the system works and, you know, and then you get immune. However, if that first exposure is postponed, let's say, for ten years because your mother lives in Canberra 2014 and looks after your superhygenic condition, washing up to your ears and, you know, soap all the time, you do not get exposed to X. But the first exposure is at ten years. You know, by that time, the maternal antibodies have disappeared. So now the first hit by that infection is like a wild-type early infection with all the consequences of severe disease and so on. And polio virus in the late 40s, early 50s, was exactly following that pattern. And then, of course, you know, vaccines were developed and sort of reinvented the wheel because vaccines, you know, bring in the X instead of a wild-type infection of course has a non-disease causing antigen stimulation. So you don't fear any longer the disease, but you slowly, you know, three months, six months, 12 months, 24 months, pediatricians have done that by trial and error, as most of medical practice, you know, you try it. With that you spread your exposure over the time where your antibody goes down because too much antibody, of course, also incapacitates the vaccine. So it's all, you know, a question of how much and over time. So that works out. And you need vaccines to replace what I would call a physiological type of vaccination. So, you know, this is my family. I mean, the next generation, three kids and seven grandchildren, they all have profited from that process. And I come to the conclusion, you know, I mean memory is a nice idea. But it's good for publishing papers in Journal of Experimental Medicine or Nature, but Nature itself doesn't care. The only thing is, do you have a high enough protective titer of your neutralizing antibodies? And if your mother is not properly vaccinated, your baby will have not sufficiently high protective levels and therefore will be susceptible to infections such as pertussis or tetanus or diphtheria, that in former times were well controlled because maternal titers were high. But as a consequence of the tremendous success of vaccinology and vaccines and on the negative side, also the success of actually reducing the circulating epidemiologically active infection in the population in the so-called herd and herd immunity. You know, suddenly your mothers don't keep up your protective titers. So what is the conclusion? Memory is antigen driven. Second point or third point, it's either re-encounter. But if that dwindles, you don't have enough re-encounter to keep your response off. Then there's another for many viruses. It's persistence in the host, like all the herpes viruses. You know, you can't get rid of these herpes viruses. Same is true for tuberculosis. You have your granuloma, your infection. You control it, but you don't get rid of it. And it's that infection that keeps your immune response high up all the time. And then there's an immune system specific mechanism that is antigen, antibody complexes that get hooked to specific cells within these follicles I've shown you at the beginning. You know, that's basically where B cells and T cells walk by. And each time they see these complexes, they get another kick. But the half-life of these complexes that are like antigen depots is only about, let's say, two to three years. So eventually these complexes get lost. And then we must have that next infection, otherwise we lose protection. But that, of course, is not the same as talking about memory. And what can we do about it, of course? Well, I think the only thing we can do is we can vaccinate much more aggressively and much more repetitively. You know, now we vaccinate three months, six months, 12 months, 24 months, and then we stop. And what that all indicates is we must continue, do it again at five years, do it again at 10 years, do it again at 15 years, 20 years, particularly and most importantly to girls and young women. Why? Because of the transfer of protective antibodies from the mother to the offspring. And only revaccination will do that because the epidemiology has so successfully been improved. Now slowly things start to change. For example, against certain bacterial and viral infection, actually girls get revaccinated before they become pregnant. Rubella, for example, is an example. That is again linked to Australia in a very, very important way because it was discovered here that Rubella causes these neurological problems if Rubella hits you during pregnancy. So that is a very practical consequence. We must frequently revaccinate, but we also must educate the public to accept revaccinations because if 10 or 20% say, well, this is rubbish, I'm immune, because of memory, you know, this all needs to be changed. And I think it's a very important task we have to fulfill or try at least to fulfill. This is just a picture of such a follicle with these so-called follicle adendritic cells and the black stuff is actually immune complexes, you know, in such a follicle. This is with the virus we like to work with, like this rabies virus. So we actually can show that these depots exist. Now I want to stop here and simply acknowledge that there's a wonderful saying that we all stand as scientists on the shoulders of giants, you know, because the giants have done all the preparatory work and now we just hop on the shoulder of the giant and look slightly further, you know. And these are my giants, you see. I've worked with these, I mean, you know, Fenner is at the far left. He was direct at the school here when I started. And then is Gordon Ada, head of department here. Next is Bob Lanton, with whom I worked on Salmonella and Listeria. Direct dissentent of machinists, as marked. And the first person is Henri-Licke, who was my first post-doc professor in Luzon. That's where I learned about milk-mediated, cholesterol-mediated protection against neonatal infections. So, you know, it's not only the giants, it's also the just chancey encounter of certain scientific problems that marks one's life as a scientist. And then maybe if you're lucky, you know, 40 years down the drain, down the drain. You slowly start to comprehend and understand, you know what, at the beginning, you had absolutely no idea what was going on. So, I'd like to finish here and thank you for your attention.