Rolf Zinkernagel (2007) - Why do we not have a vaccine against TB or HIV (yet)?

HANS JÖRNVALL. …the scientific talks in the series. And the speaker is Professor Rolf Zinkernagel. He is from the Institute of Experimental Immunology at the University of Zurich in Switzerland. And he received the Nobel Prize in physiology or medicine in 1996. And the quotation was 'for the discoveries concerning the specificity of the cell mediated immune defence'. And we now continue that subject in the title of his talk, why we do not have a vaccine against HIV or tuberculosis yet. Please, Dr. Zinkernagel. ROLF ZINKERNAGEL. Thanks very much for the invitation to come and talk to you today. And it’s a pleasure to be here to talk about a, I think very important problem. Why do we have excellent vaccines against most acute childhood infections such as tetanus, diphtheria, smallpox, measles, polio and so on. And why haven’t we succeeded in developing a vaccine that protects against tuberculosis, HIV, hepatitis C, malaria, schistosomiasis, leishmaniosis and you name it. The reason why we don’t have these vaccines is, first and above all, that co-evolution, that is the balance between infectious agents and us as vertebrate hosts haven’t in a way foreseen a solution that could be easily corrected or let’s say improved by a vaccine. In contrast against acute cytopathic types, acute killer types of infections, evolution had to find a very efficient solution. And I’ve tried to summarise some of these very general aspects in this slide. If we talk about immunity and not immunology - and there is a big difference, you know - immunity is about protection via specific immune reactivity by vertebrate hosts against basically infectious agents. Now, most of immunology actually deals with so called small chemical groups called haptens or sheep red blood cells or similar things. And of course the difference between infectious agents and these model types of antigens is simply that infectious agents kill and model antigens don’t. And therefore you can measure many things, you know, with these surrogate model systems, but you very often cannot measure what really matters in life, namely to avoid disease and certainly to avoid death before the age of 25. Because if you die after 25, you know, it doesn’t really matter, because by that time you have done your biological function, which is to create the next generation. And all the rest doesn’t really matter. Now you see immediately the solution to the question I raised. If you get killed between, let’s say before you are 15 or 18, then you are out of evolution. If you get killed after 25, doesn’t matter. So it’s interesting to recognise that, besides specific immune responses, there is a whole gamut and background of resistance mechanisms which are very important and in fact cover let’s say 95 or more percent of our resistance mechanisms. And they include for example interferon alpha. There have been models created in mice where the interferon alpha receptor is lacking. These mice die of viral infections if they see a virus at 10 metres distance. So without interferon there is no way to survive, and so on, there are many incidences. I will not talk about these innate or natural resistance mechanisms. There are however highly specific adaptive types of immune mechanism, including antibodies and cell mediated immunity. And there it is interesting to note that antibodies are actually at high concentrations and in enormous amounts, for example in chicken eggs, actually also in reptile eggs, in fish eggs. Why is that, why should the mother hen hand over grams of immunoglobulin, of antibodies to the offspring. And this question I think is very interesting. Then we also can recognise that all the vaccines that are successful protect via antibodies. There is not a single vaccine that protects us from the consequences of infection via cell mediated immunity. Which of course would be necessary if we were to develop a vaccine against tuberculosis, HIV, malaria, schisostomiasis and so on. But so far we haven’t succeeded, although many people promised, you know, within the past 10 years we should have developed HIV or TB vaccines. Then there’s another very general observation that autoimmunity, that is the deviation of the immune system to start attacking our own antigens or organs, resulting in let’s say diabetes, multiple sclerosis, hashimoto’s thyroiditis, rheumatoid arthritis and so on. Actually these diseases, in very general terms, come up let’s say after 25. And this fits again with what I’ve, oversimplified stated before, that after 25 it doesn’t really matter what happens. The other point is that female people are much more susceptible to so called autoimmune disease, particularly if the autoimmune disease is dependent on autoantibodies. Rheumatoid arthritis, lupus erythematosus and so on. Then of course tumours also come up after 25 or 30, and this again would correlate with the fact that it doesn’t matter. Of course individually it matters but in terms of overall population balance it doesn’t. And the question there arises of course in parallel with tuberculosis and HIV, why are we so inefficient in using immune responses against tumours to actually change the tumour prognoses and outcome. And above all is the question, you know, does that failure to come up with solutions to this HIV, TB vaccine problem, have something to do with the way we measure things. We can measure many things, in fact we can measure more things than ever before. And molecular measurements just make measurements more easy and more accurate. But it doesn’t solve the problem whether what we measure is really what we should measure. And I think in terms of medical disease it’s very simple what we should measure. Either this disease is ameliorated, is improved, is less severe or death is avoided, or not. All the rest is in a way, from a medical point of view, rather not so important. So let me now get into matters directly, give you my biased view of the functioning of the immune system, then get into some peculiarities of the virus host relationships and then go into ideas and concepts about vaccines which include of course the idea of immunological memory. Now, memory, you know, is something very interesting, because that’s what you lose when you age. But immunological memory seems to persist for the rest of our lives. So once having had a disease will cover you and protect you for the rest of your life. How is that guaranteed and how does that function? Of course, there are two very extreme interpretations. Either you can remember like with your neuronal networks, or it’s not true and in fact neuronal memory isn’t really understood. So there are some postulates that in fact, to keep up your memory, you need to see or reencounter the same thing, you know repeatedly, be it during your dreaming time or your wake time. And it’s only this repetitiveness of encountering certain inputs that keeps your memory up, that’s certainly true for myself. But immunology of course, the idea of memory says ‘once seen, always remembered’. Measles virus, once contracted as a child, you’re resistant against measles virus infections disease, for the rest of the life. And the question is, is that some sort of mystical type of interaction or mechanism, network or is it simply that measles virus persists in fragments in our body to keep the immune system sort of reminded by boosting it all over the years. And that of course isn’t really what we understand academically or theoretically from memory, it would be simply an antigen driven process. And of course if that were the explanation, then you would have to rethink about the way we make vaccines, because if vaccines cannot imitate that situation, that is persist at a very low level, that is innocuous, but keeps driving the immune response at a sufficiently high level, then we have a problem. And my conclusion will be that for TB, HIV, malaria, schisto and so on, we actually would need a vaccine of that type. Ok, so the problem is summarised here, infections basically destroy host cells very efficiently, like in this case, pox virus, smallpox or polio or rabies would do that within a few hours after infecting a cell. And of course, in this case the only thing that can lead to the survival of the host is immediate rejection of that infection within a few days. Because if that continues for more than 7 to 10 days, then the chances of these types of agents hitting neurons is so high that you die. And of course this situation, where a virus infects a cell but leaves the physiology of that cell rather and largely intact, doesn’t need immunology because the virus actually doesn’t cause primarily any harm. And many more viruses actually belong to that category than to this. Because it is not in the prime interest of an infectious agent to kill all hosts. Because if all hosts are killed, then the virus by definition is gone as well, because the virus needs living cells to replicate. So it’s relatively easy. So that’s why here immunology plays a major role. In fact here immunology doesn’t play a role and most of these viruses jump from one infected subject to the next before or at birth. And why is that? Because before birth the offspring doesn’t have a functioning immune system, actually at birth the immune system doesn’t function, isn’t mature. So this is our optimal time for these agents to jump. And there are examples of that, HIV, for example, jumps, usually at birth, with that small blood transfusion from the mother to the offspring. And the mother of course is a carrier because her immune response against that virus infection is inadequate. Well, for HIV, I will come back to that, the problem hasn’t been solved yet, as you know, because it is a new or emerging virus. So the co-adaptation of host and virus hasn’t happened. But eventually it will end up like HIV 2, you know, the West African form of HIV infection, where it is very clear that the balance between host and virus has already reached a very balanced situation, in fact HIV 2 doesn’t make people sick or doesn’t kill them. So it’s just a matter of time. But in this case what is interesting is if now an immune response comes along, like a T cell, a solo immune response, then you see immediately it’s not the virus that causes the tissue and organ failure, it’s actually the immune response because this immune response now kills infected host cells that otherwise wouldn’t be killed by the infection. And this we call immunopathology, that is an immune response with pathological consequences where in fact there wouldn't need to be such a confrontation. And that’s why these agents jump at a time when there is no immune response. Now, I try to illustrate the same aspect with this cartoon. Just try to follow. If you take a virus that jumps through the placenta or at birth, then this virus will be all over the host and this antigen or this virus will behave like a self antigen. Because it was there before birth, it was there at birth, and therefore these viral antigens are considered from the functioning immune system as self. Because if that were not so, then the immune response would be against all these host infected cells and this would result in a graph versus host type immunopathology, and in fact the patient wouldn’t survive. The other extreme is this, I’ve just depicted here an infection with papillomavirus, which is a virus that infects the outer most types of cells of the skin. And expresses the viral antigens only in matured keratinocytes. Now, this is a localisation that is so far out of the immune system, namely lymph nodes or spleen or the blood circulation, that the immune system doesn’t even notice that there is an infection going on in the skin. And therefore the immune response doesn’t happen very quickly, in fact it may take months, as you may well remember from your own warts you may have had, you know, where it takes weeks to months, if not years, to get rid of these warts, eventually these warts will disappear. That means if an antigen, even an infectious agents antigen is outside of the reach of lymph nodes or spleen or the so called secondary organised lymphatic tissues, then there is no immune response. And the antigen, the viral antigen even has to reach draining lymph nodes or the spleen to get a response induced. And of course this happens with warts, if your dear doctor scraps off the warts or cauterises them with hot needles to get rid of these warts. And that’s exactly what you do, you create a wound where cells get necrotic, these cells are picked up by macrophages, the necrotic cells, these bring the antigen to the draining lymph node and now an immune response is improved or accelerated. And of course the usual classical situation is depicted here. The virus, let’s say hits you on the big toe or in your mucosal surfaces, and from there the infection spreads to the draining lymph nodes and eventually via viremia to the spleen. And you know the classical rashes after measles or smallpox correspond to this viremicspread. And this staggered spread of the virus to the draining lymph node and then to the spleen actually amplifies the immune response because once in the lymph node the immune response immediately starts within 2 days or 3 days. The T cells and the antibody producing cells get amplified and by the time there is a viremic spread, this amplification already of the immune response will catch up with the systemic spread and will prevent, and this is the key, will prevent the virus spreading to the brain, because that’s the end of it, once the virus is in a neuron, that’s it. And rabies, tollwut, is of course a classical example, where the virus hits a neuron. Once in, you can’t do much about it. So let’s now take two extreme forms of infections. One being the rabies-like infection of a very close relative to rabies, it’s called vesicular stomatitis virus, which in mice causes a form of rabies because it’s strictly neurotrophic. What you see is the virus replicates, you get T cell responses and you get antibody responses. And you get basically two types, neutralising, that is they can protect you and you get ELISA, that is binding types of antibodies. And they are virtually coincident. If you take a non cytopathic virus type, HIV or hepatitis C and so on, you find that the virus replicates, there’s a good T cell response and actually the T cell response initially that controls the virus load down to undetectable levels. Undetectable means by conventional means you can’t detect it, but it also means that in fact it always persists at very low levels. Now, what is important is that the ELISA, that is, you know, sticking antigens on plastic plates, you can always measure antibodies very early, about as early as for these acute killer viruses. But the neutralising, the protective antibodies take between 80 and 300 days to come up. Now, of course you can ask why should this mouse or human make neutralising antibodies That’s the best sign actually that the virus is never gone completely. So the fact is that eventually neutralising or protective antibodies come up, and this is true for hepatitis B, hepatitis C, HIV 1, 2, malaria, all these persisting chronic types of infections have basically this pattern. Remember it’s crucial that the T cell response comes up early because that’s the mechanism that really reduces viral loads initially drastically. And if that doesn’t happen, basically the virus goes all over the infected host. Now, if a virus needs 100 days for protective antibodies to come up, does it always happen? Yes, it happens always. But in the meantime these viruses or agents, malaria, have started to replicate, every replication of course increases chances of mutations and they mutate in particular also their neutralising antibody target antigens, so the neutralising determinant. And this is illustrated here. So we have this non-cytopathic virus, it replicates,it’s controlled largely by these T cell mediated immunity. You cannot measure it for let’s say 30, 40 days, but then very often the virus is controlled for the rest of the mouse’s life or the human life. But in some cases the virus comes up again. Now, this is strange, isn’t it, because before that point in time there was a very good efficient T cell immune response that controlled the virus. What happens? Well, around this time, 80 days or so, the neutralising antibodies, the protective antibody response has come up. And it is this T cell response plus the neutralising antibody response in these individuals that keeps the virus below detection. In these cases, these are all neutralising antibody escape mutants. So let’s take the open square virus, take the serum from that mouse, test it for neutralising protective capacity against the open square virus and you find that this serum cannot neutralise the open square virus. Of course this is understandable,viraemia in the presence of all sorts of neutralising antibodies, but not against that particular variant or selectant. But take this serum of that mouse, that is inefficient against this open square virus, and test it against the original virus you stuck into the mouse or against all the other variants or these controlled viruses, and you find that this serum actually is efficient in neutralising all these other variants. So you can repeat that experiment that was done by … (inaudible25:20), and you find that in fact each of these individual viruses, and we have only gone about to 20 or 30, is distinct. So the anti open square serum does not work against this one but against most others. And the controllers down here, in fact this serum has neutralising activity against most of the variants, which means that the virus within one individual changes all the time, mutates and the host makes neutralising antibodies, in fact often very sufficient and efficient, as in this case. But in some cases the relative kinetics between virus mutation and growth, and the slowly developing neutralising antibodies is such that the virus finds the loopholes through which it can escape and this will determine the balance. Now, of course you may want to ask, why should then the T cell response, which has been mounted in this early phase, not be efficient against all these upcoming variant viruses? Well, the conclusion and the answer is very simple: Many mice will die in this period of time, similar to HIV-AIDS, because the T cell immune response destroys infected host cells and the large part of the HIV-AIDS type of disease is in fact immune destruction of virus-infected host cells. And this will result in the death of the patient or at least severe disease. And only in some cases will the T cells actually be deleted, disappear, and thereby the immunopathology gets reduced or eliminated and the end effect is that the virus basically wins, stays, but since the T cell response has gone, nobody cares because the virus itself doesn’t really do much harm. Again I say, HIV 1 isn’t quite there yet, but HIV 2 basically seems to have chosen this outcome. And of course the next question is where does the virus hide, since you say it’s below control. Now, where can you control for virus in a host, in a patient? Well, you draw some blood and hope you find the virus in blood cells or in blood. Of course blood is very important, but it’s not where you would hide as a virus. Because, as I’ve said, if the virus is in the lymphohematopoietic system, then it’s particularly prone and susceptible to immune attack. Therefore these viruses all hide in cells outside of the immune system, particularly neurons, just think of herpes viruses, they hide in the ganglion. Or many viruses hide in neurons. And if they are away outside of the immune system, the immune system basically can’t treat them because the serum antibodies can only reach peripheral solid tissue cells if there is a lesion. Now, if the virus keeps dormant and doesn’t cause cell damage, there is no reason why there should be bleeding into the lesion. And exactly such balances are used in very general terms by viruses, and they use peripheral sites, neurons, kidney, tubular cells, testis cells, long epithelial cells. And of course the advantage of these sites is that the viruses can be spread from these peripheral sites very easily. You know, pissing, coughing, virus around is obviously very efficient in distributing. And this just give an example here in the urethra, here in the kidney tubular cells. So I summarise here that the immune system basically makes antibodies of several types, the IgA on mucosal surfaces, the IgM very acutely and very efficiently within the first few days, then the switch to IgD for long lasting antibodies, of about three weeks half life. And I’ll come back to that because this antibody, the IgD antibody has of course a particular characteristic that via its Fc, the constant path of the antibody, it can bind to Fc receptors. And via these Fc receptors, these antibodies can be transferred from mothers to offsprings via the Fc receptors, not only in the placenta but then to the offspring via blood transfusion, but also in the gut. And this is particularly important with calves or ruminants because we all use in biology foetal calf serum, because foetal calves do not get antibodies from their mothers. Because the membranes in the placenta are fully doubled from both sides. So proteins cannot transgress. So calves have to take up maternal antibodies in their first colostral milk they get within the first 24 hours. T cells control eliminate intracell parasites, but I’ve given you an idea about this sort of dangerous situation because of the immunopathology. They of course regulate these immunoglobulin switch, this long lasting, this is basically to avoid too easy generation of alto antibodies. But the T cells also cause this immunopathological complication. Let me just go now to the key question, why do we need so called immunological memory, which is defined as an earlier and a better response if you already have encountered the antigen previously. And the text books say ‘earlier and better is all there is about immunological memory’. However, if the first infection kills you, you certainly don’t need memory. And if the first infection is well survived, you again could argue whether you need immunological memory. Because if you have survived the first infection, you know the system has proven efficient to survive the next infection, at least for the next 25 years, and that’s all that matters. Of course I’ve already said that all vaccines that protect do so via antibodies. Now, let’s do a very simple experiment and this was done by Ulrich Steinhoff some time ago, a post doc in the lab, you immunise mice with this rabies-like virus, and then after some time, let’s say 3 months, you say, well, now we have immunological memory, we have so called T cell memory and B cell memory, we take these spleen cells, T and B memory cells, adoptively transfer into a naïve recipient that has never seen this virus, and then challenge the mouse with this same virus and we find all mice die. Now, the prediction would have been that transfer of so called memory B and T cells should provide very solid protection, doesn’t seem to be the case. Now, let’s do a second experiment, let’s take the serum of this mouse with these IgD antibodies which we can measure as protective antibodies, we transfuse those to a naïve recipient and we find that all mice are protected. So that means memory T and B cells is nice for immunologists to play in the lab, this is fine. It’s also interesting to understand what happens, but the key to survival against these acute cytopathic viruses is actually to have a pre-existent level of antibodies and then you are protected against the challenge infection of this neurotropic type of virus. Now, this of course is exactly the situation you all have encountered when you were born. Because you are born without a functioning immune system. Now, of course, not nowadays in Lindau or Berlin or Zurich, but let’s just go 200 years back, when you were born you were basically exposed to all epidemiologically important infections immediately, as of time zero. And at that time the only thing that protected you were your maternal antibodies. Your mother’s immunological experience that was transfused to you and transferred from the mother via these Fc receptors of their antibodies. So that’s exactly that experiment and now let’s see how this looks in general terms. You see, if your mother is a virus carrier, then of course she has viraemia and this virus will be transferred to the offspring either before birth through infection through the placenta or at birth where in every single birth process there is a certain amount of maternal blood being transfused to the offspring. And that’s the way, you know, the problem of rhesus incompatibility and all these problems arise from this maternal blood transfusion. But this is of course a fantastically efficient way of a virus to reach the next generation. Of course you can only do that if you are a virus that is non-cytopathic, otherwise you would kill the offspring, but your mother wouldn’t have been able to be pregnant and give birth to you because she would have died before. Now, the transferred virus will persist because the immune system will not start to react because it was immature at the stage when this first encounter came. So everything goes smoothly and in fact you could argue this is the ultimate way for a virus or infectious agent to behave. Cause no harm, cause no immune response that may cause harm, so called immunopathology, everybody is happy. Actually integrated virus, retrovirally integrated types of mechanism would even be more advanced co-evolution. But I don’t have time to go into. Now, let’s take the acute situation, your maternal experience in terms of anti-infectious agents will have accumulated over 15 years in the mother and this antibody will have accumulated then in the offspring at the time of birth, the offspring will have obtained let’s say therapeutic doses and preventive doses of maternal antibodies. And it is this maternal antibody that eventually will decline according to the half life of this immunoglobulin and during the first 6 to 12 months there will be many infections, namely all the infections that play a role epidemiologically. If an infection isn’t there, of course it doesn’t matter. But until 200 years ago all infections were always all there, always there all the time. Now, these infections of course are controlled very efficiently initially, but eventually with the decline of antibodies less and less, and there will be a point where the protection via the maternal antibodies will be sort of half way or only a quarter and this means the infection will take but will be reduced drastically. So it’s an attenuation process that is very interesting. The virus infection happens but the disease process is so reduced that in fact the offspring doesn’t get sick or get killed. Now, you remember other vaccines we use like polio or measles, we use a different process, we actually attenuate the virus by mutation so that it is less virulent. Therefore we can use the dose that induces immunity without actually making the recipient sick. Evolution has chosen a different way to actually attenuate the whole process, the same is true for virile viruses because there the milk antibodies in the maternal milk do basically the same. So the initial confrontation of infectious agents with maternal antibodies is key to the understanding of the overall epidemiology and outcome. So I can conclude, what drives the immune response, because your mother has to have guaranteed high enough levels of infection. And this is all mediated by neutralising antibodies. It can be by increase of the B cell frequency, this largely antigen independent and I don’t have time to go into that. But the maintenance of neutralising antibodies in the serum of the mother is antigen dependent because of the half life of the immunoglobulin and with the maturation of a B cell to become an antibody producing plasma cell is antigen dependent. And this re-exposure can come from within, from these persisting reservoirs of the virus, can come from antibody-antigen complexes in lymphatic tissues and can come from the outside as is the case for example by all the diarrhoeal viruses which you reencounter on your door handle or in the swimming pool or in school etc. So my conclusion is vaccinations are possible and efficient if you use the same mechanism as evolution has used, namely protection by neutralising antibodies. To keep up the antibody level, we need antigen periodically from these various sources. We cannot yet imitate such a low level persistence antigen driven type of protective immunity for all the chronic types of infections. Just take tuberculosis, you have a granuloma lesion in your lung, in my age more than half would have that lesion. I do not get sick of tuberculosis, why? Because my immune response is still good enough to control that lesion. But without that lesion the T cell immune response wouldn't be driven to control the existing lesion, so it’s well balanced. So why can I not get rid of my lesion? It’s a microscopic lesion. Well, because if I would have to boost up my immune response to such high levels to get rid of these micro lesions, I would kill myself by immunopathology. So there’s a delicate balance. In fact TB, wild type TB is in a way the best vaccine against TB, this is politically incorrect you say, but practically that's the way it goes. And to imitate that process we have simply not achieved. And for HIV it’s the same, for malaria it’s the same, for schisto and so on. So you could say: why haven’t we achieved it? Well, because it looks as if co-evolution in a physiological process has been trying this for a million years and now to imitate that in a few weeks or years is not impossible but apparently not successful. But the other point is much more important. Most of these types of chronic infections can be controlled by antibiotics for TB and leprosy or anti-virals like HIV and others or antiparasitics or vector control, you know, again politically incorrect but necessary, DDT has controlled malaria. But the limiting fact in all these cases is our human stupidity. Because we as individuals could avoid HIV very nicely, particularly in the western half of the world by simply avoiding the procedures that lead to HIV infections, drug abuse, unprotected sex and so on. But we are too stupid to really do as we can think about that would be correct. Thanks very much. HANS JÖRNVALL. Thank you very much for a very educative and also very good lecture. I would normally have had several questions to this but the program which we have participated in doing does not allow that because now we have a round table discussion. And I think after all I would anyway take two questions, who wants to say two questions, yes. QUESTION. I was just wondering, given the vertical transmission of HIV into children, as it goes through the CD4 receptor, it can get into cells which are important for development of internal organs like (inaudible 44:42), is there any evidence that infant children don’t go on to have developmental abnormalities in their…(inaudible 44:50 )cells? And therefore any consequential effects on their ability to mount immune response to other infections. ROLF ZINKERNAGEL. So the question is how does HIV infection in very small kids, in newborns, how does that effect both the host and the virus capability. Well, as I tried to mention, HIV 1 is just at the moment a bad example. You know, let’s wait 500 years, because by that time HIV 1 would have to adapt and adopt more reasonable ways. HIV 2 has done that, but you know you don’t get funding for HIV 2, because HIV 2 is not a problem. So I cannot answer your question because we simply don’t know and the epidemiology hasn’t progressed to a stage where things are balanced. But the prediction is it will have to be balanced, otherwise HIV, either humanity or HIV 1 will not survive. HANS JÖRNVALL. You make answers very simple, very good. Do we have the second question, yes? QUESTION. First I would like to thank you for a very nice lecture. My question is about tuberculosis. It’s known that some population of Ashkenazi Jews are extremely resistant to tuberculosis. But in this population there is a high incidence of Tay-Sachs. Are there any links between the Tay-Sachs disease and the resistance to tuberculosis? ROLF ZINKERNAGEL. Thank you for this question. So the question is, is there a link between a macrophage associated storage disease and susceptibility to TB. And you know that in fact the effector mechanism to control so called facultative intracellular bacteria is the capacity of the macrophages or monocytes to deal with the infection. So, yes, there is a link. I don’t know the molecular details but the point I think you make is a very good one. In biology, medicine, there is never an absolute winner. So you may have a disadvantage with storage, but you buy an advantage against certain infections and this is true for many things. You know, the CCR5 receptor for HIV 1, if you have a certain allele or you lack it, you have more resistance against HIV, so far not discovered but you can bet, you know that there will be disadvantages if you lack CCR5. So conclusion, biology is never black and white. It’s always, you know certainadvantages and you have by them with disadvantages. And I think, you know, human behaviour is of the same type, if you want to buy certain whatever, lost behaviour, it costs, that's biology. Keeps us honest. HANS JÖRNVALL. Thank you very much.

Rolf Zinkernagel (2007)

Why do we not have a vaccine against TB or HIV (yet)?

Rolf Zinkernagel (2007)

Why do we not have a vaccine against TB or HIV (yet)?

Abstract

Survival of vertebrate hosts against infections depends on important natural or innate resistance mechanisms combined with adaptive immune responses of T and B cells. Infectious agents probe the limit of immune responses and help to characterize three basic parameters of immunity specificity, tolerance and memory. Specificity: the specificity repertoire of T and B cells is probably in the order of 104 - 105 specificities expressed by protective T cells, or by protective neutralizing antibodies. Tolerance is best defined by rules of reactivity to eliminate infections while avoiding destruction of normal cells; this is achieved by complete elimination of T cells that are specific for antigens persisting within the lymphohemopoietic system. In contrast, T and B cells specific for self- or foreign antigens, limited to extralymphatic tissues are not induced but potentially can be activated to react. Thus antigen staying outside of lymphatic tissues are immunologically ignored. Induction of a T cell response is the result of antigens newly and temporarily entering lymph-nodes or spleen, initially in a local fashion and exhibiting an optimal distribution kinetics within the lymphohemopoietic system. Memory is the fact that a host is resistant against disease caused by re-infection with the same agent. Protection correlates best with an antigen-driven activation of B cells/plasmocytes to maintain protective antibody levels and of T cells, such that they are protective immediately against peripheral reinfections in solid tissues. While antibodies transferred from mother to offspring are a prerequisite for the survival of otherwise unprotected immuno-incompetent offspring, activated memory T cells cannot be transmitted for several reasons incl. rejection. Attenuation of infections in infants by maternal antibodies is the physiological correlate of man-made vaccines, therefore infections against which antibody-dependent protection is key work. T cells play an essential role in maintaining T help-dependent memory antibody titers, but also in controlling the many infections that persist in a host at rather low levels (including tuberculosis, HIV). We cannot yet imitate this subtle equilibrium between infection and host, therefore we do not have these vaccines. This explains why all efficient vaccines protect via antibodies whereas vaccination against variable antigens or to maintain macrophage activation or protective T cell responses have so far been unsuccessful.

Cite


Specify width: px

Share

COPYRIGHT

Cite


Specify width: px

Share

COPYRIGHT


Related Content