Bacille Calmette-Guérin Vaccine

Participants in the workshop on immunological responses to Bacille Calmette-Guérin, held in Toronto, Canada, on July 11–13, 1994, gathered on those dates to discuss some of the issues raised by the papers that were presented. The following is a partial transcription of that discussion. The participants were as follows: Andreas Böhle, Saroj Bakshi, Peter Bretscher, Timothy Brewer, Dennis Clements, Anne Fanning, Herbert Flad, Luis F. Garcia, Marina Gheorghiu, Earl Hershfield, Dan Hoft, Michael Jewett, Dennis Kunimoto, Donald Lamm, Don Marks, Richard Menzies, Tim Mosmann, Stanley Plotkin, Stephen Prescott, Timothy Ratliff, Denis Schamhart, Donald Smith, Peter Tilley, Brian Ward, and Robert C. Wittes. Dr. Plotkin: If exogenous reinfection means an airway infection occurring in an individual who has already been infected, then it appears that prior infection confers no immune protection in that instance. Is there any evidence in the guinea pig model that this is in fact the case? Dr. Smith: BCG [vaccine] does not protect against exogenous reinfection. The infectious implant in the apical area of the lung comes as a result of repeated exposure to tuberculosis. The animal model tells us that, after an animal has been sensitized to BCG, the bacillemic pathway is eliminated. Dr. Hershfield: How do we determine if the implant in the lung is caused by exogenous reinfection, not endogenous? Dr. Smith: There is nothing to indicate if the infection is exogenous or endogenous. If this is the first infection and there has been no prior immunization by earlier infection, then it could have occurred through the endogenous pathway. The exogenous pathway is more common in developing countries. Dr. Hershfield: How do you explain the predilection of the upper lobe for this kind of infectious implant? Dr. Smith: The presence of a vulnerable region in the lung seems to implicate the strength of macrophage activation against tubercle bacilli in that region, versus somewhere else in the lung. It could be that macrophage response is not uniform throughout the lung. Dr. Ratliff: An alternative hypothesis could be linked to fibronectin binding that's associated with the bacterium. We know that transitional epithelial cells in the bladder phagocytose the bacterium. It is entirely possible that this region of the airway has either higher deposits of fibronectin or [that] the epithelial cells in that region are capable of phagocytosis. The pathogenicity in tuberculosis could be associated with ingestion in that region. Dr. Kunimoto: Dr. Brewer has told us that BCG is protective against pulmonary disease. Dr. Smith, would you like to comment on that, in terms of your hypothesis that BCG would not be protective against exogenous infection. Dr. Smith: The pathogenesis of tuberculosis in Canada and the United States is primarily due to endogenous reactivation. Tubercle bacilli enter the lungs and are carried to the vulnerable regions via the bloodstream. BCG vaccine virtually shuts down that carriage through the bloodstream. This protection does not help in areas where tuberculosis is caused by exogenous reinfection. That is the hypothesis that we are proposing. Dr. Wittes: So if we are to develop a better BCG vaccine, it has to prevent against exogenous infection. Dr. Bakshi: It is important to show a correlation between immunogenicity and protection, especially in the pediatric studies. Dr. Brewer: My sense is that there is no good correlation right now, and since the issue is immunogenicity, not efficacy, how do we go about choosing the markers that we want to study? Dr. Clements: We already have a few good studies on cytokine excretion, spot urine collections, and 24-h urine collections. We also have standardization on certain assays. Dr. Hoft: Regardless of efficacy, it is important to measure immunological responses. Even with randomization, there are problems in our placebo groups. We have seen increased baseline reactivity with mycobacteria and lysates. But we still need to know the correlates of protective efficacy. To do that, we need to measure immunologic response. Dr. Wittes: I think that [it] is essential that we look at these correlates in animal models where we can directly test the efficacy and look at the immunologic correlates. So, for example, if you show a high level of interferon γ being produced by peripheral blood monocytes at week 8 after BCG [vaccination], and if we show that BCG is protective of those mice who produce high levels of interferon γ, that's good, partial proof. Dr. Fanning: I am wondering if we have any information about the cytokine profile of normal individuals. Dr. Hoft: In our human studies of cellular and humoral immunity to intradermal BCG, we have studied cytokine responses in the placebo group. We found borderline immune responses in T-cell proliferation and in cytokine-production levels. Dr. Kunimoto: Is there any evidence that BCG can survive in the gut following oral vaccination? BCG has been shown to be effective in inducing respiratory immunity as well as cellular immunity. But this protection is short lived unless there is a niche in which the antigen or vector can survive in the system. Dr. Hoft: Dr. Gheorghiu's studies with oral and intradermal BCG have shown that small numbers of viable BCG can persist in the lymph nodes for at least 16 weeks. Dr. Mosmann: Is it possible to induce [both] an immune antibody response to prevent initial infection and a cell-mediated response that would fight an established infection? I am thinking particularly of viruses, and, possibly, BCG, where antibody might be able to prevent that first infection but may not be useful thereafter. Dr. Bretscher: Empirically, what we have found is that if we carefully titrate the antigen, we will get a situation where there is no antibody production. If we wait, we will lock the response into a cell-mediated immunity and there is no antibody production. Dr. Mosmann: What I am suggesting is an immunization protocol where you would be able to induce a good cell-mediated immune response in the presence of a certain amount of antibody. Dr. Bretscher: By our criteria, we can't observe delayed-type hypersensitivity [DTH] at 2 months. Dr. Plotkin: If I understand your hypothesis correctly, antibody is not an indicator of immunity, nor is the DTH that is induced initially. What you are looking for is memory DTH. How would you test for memory DTH in a human trial? Dr. Bretscher: You would perform a 2-step test for DTH using tuberculin-purified protein derivative [PPD]. Your desired outcome would be negative on the first [test] and positive on the second. The desired outcome on a third PPD test, about 2 months later, would be negative. Dr. Flad: Then you have established memory. Theoretically, the negative can then be upgraded towards a positive reaction. Dr. Kunimoto: I am not sure that you can. We do have evidence that DTH is important in mycobacteria, as opposed to cell-mediated immunity, which I see as being 2 different things, although they often go hand in hand. We think that's because they are regulated somewhat by the same subset of T cells. But they are not necessarily the same phenomenon. Dr. Bretscher: I agree. We only know that we are locking something to DTH that correlates with protection. And yes, we do know that CD8 cells are important in Mycobacterium tuberculosis infection. Dr. Brewer: What happens in a chronic low antigenic-stimulation environment where individuals are given a low dose of an antigen? DTH is created, and then it disappears? We are giving BCG in developing countries where the population is chronically exposed to atypical mycobacteria. What happens if the DTH response disappears? Does this population have memory DTH? Dr. Bretscher: I agree with you. It's very complicated. I think it depends on the frequency of the impingement and the nature of that impingement. For example, in our model with Leishmania, we give an initial low dose. One month later, if we administer a high dose, we get accelerated disease. If we wait for two-and-a-half months to administer the high dose, the ratio of interferon γ to IL-4 is phenomenal. Dr. Plotkin: The clinical trial to test low-dose BCG in humans will tell us if we can push the immune response toward the Th1 direction. Do you plan to challenge the groups with high-dose or standard [-dose] BCG at the end of the protocol? Dr. Tilley: I believe that BCG is safe when given in multiple repetitions. That would be a possibility, but we had not planned on a giving a challenge. If we did such a challenge, we would hope not to see an exacerbation of the reactions. Dr. Gheorghiu: It may be that the second BCG injection, the standard dose of BCG, will result in a rapid local ulceration. But I am not sure we can vaccinate again without prior PPD testing. Dr. Plotkin: I think the study could be done in a way that, assuming that, after a year, a number of individuals in the trial have reverted to skin-test negative, then you could these individuals. You would then be able to observe these individuals in terms of cellular and humoral responses. You could the initial high-dose as your group. for you were to give the standard dose you could the responses of the low-dose to the challenge with the that the first standard dose. Dr. Fanning: I think it is very important to those individuals in very those individuals not in In the very first of it would be very to show the protective efficacy of BCG and to tell that we know what test will be and that they will this as a measure in the in the that is not at high for the of they will also the of the test for Dr. Brewer: There is a of at least in that you can Dr. Mosmann: we know what the clinical of protective I think we will any trial of efficacy when we with the standard dose. Dr. Tilley: This would not be an efficacy What we want to look for in this study is we can the in that we see in the The is that this of immune response is to be But we are not looking at BCG efficacy at the Dr. Wittes: If I understand Dr. correctly, if the a good DTH response with antibody then this would the We could then the protocol to an efficacy An alternative would be to the in the human with efficacy in an animal If you are able to show the correlation of that of response to efficacy against they human could then be to a I think there may be for Dr. I if there is any about the of exposure in this of My second is the fact that we are looking at for the are given to or we be able to these into a on Dr. Tilley: I think we can this study directly to the We would have to the responses that we and a number of Dr. Fanning: In terms of the hypothesis in a would be are the only population that we know that has no prior the only that BCG are the We that we to trial on first to determine if we were able to get the kind of responses we are looking But this trial would be Dr. Mosmann: Is it possible to the in this trial and One trial could test the hypothesis that low-dose immunization will protective immunity. hypothesis is to see if protective immunity is as DTH. This of memory does not show Is there a good population where the second hypothesis could be in with the that, if you do get the result you are looking you will know it is an there individuals with to test how they Dr. I if it might be possible to studies in where individuals have already been and tuberculosis infection has been We could cytokine to determine who are infected, who are and cytokine at the of If we could this trial in a we might be able to some Dr. Fanning: population could be the small of individuals who are BCG in small But this trial also the issue about the that you the phenomenon. We would like to know cytokine profile and after PPD testing. We are to get some in the but we know who they are We need some PPD or and cytokine we administer the different Dr. Tilley: We are that, by an alternative that the we will be able to information the baseline blood and with with PPD giving the Dr. Kunimoto: So, if you the of your placebo you could test the at the and through to see if PPD has an on cytokine cellular response. Dr. Bretscher: we of individuals to be PPD Dr. That is the that what you see in terms of immune response is an of response. This in some In antigen you do not see a DTH response but you do have in Dr. Mosmann: The individuals that we want to get at are those who are to be We would like to know cytokine profile at the of infection, they are infected, that profile We are looking at a study in to those individuals who will to infection. Dr. Ratliff: What were the who the there a of Dr. in either the in or the or has had months. we will need to look at But this is the that we have at Dr. Ratliff: This might to be a very the that a by a second on the is about This has been very the Dr. Wittes: Dr. is a study on the and of BCG in the the study are it may be that BCG in the bladder to 2 following the Dr. study on the of BCG by the of a who had an of BCG and had a a One following the pulmonary BCG Dr. There have been of following BCG for bladder have been associated with high or that would the that the may be at for Dr. The and to be a very Is there a better the Dr. One is the that for by an at months for Dr. How important is the of in the immune response to Dr. Gheorghiu: In the and were in the of tuberculosis. Dr. There is no that BCG is good for bladder BCG are We need to the good response and Dr. It could be that, for some are and [that] are In the of good clinical in this we need a that can tell us how are to We do have who very in terms of these are the who the some are with first in at number we be the But this is a Dr. There is some clinical that show that a in BCG dose by the response and the but did not the I also think it is very to on an response Dr. has that are a of BCG efficacy. I if to the will efficacy. Dr. I think there is a But I also think that with this high-dose and we may be in the I think and efficacy are but only to a certain Dr. Ratliff: The number of in dose has an on the In some the to This response. It could be that a of the seen with the when the to may more a better of these will be more effective in Dr. Wittes: an And I think it be studied more in animal BCG is a that is more the clinical does not show it to be It could be that the BCG is but [that] the better may be in a This would with a that is because of Dr. Ratliff: If you BCG to there is a And we can We these and in our If you and versus that you have to for you see a in the response with the Dr. Gheorghiu: It would be to BCG with If you BCG to what would be the Dr. Ratliff: I have an Dr. Gheorghiu: We at the of when there is or BCG we see with Dr. Wittes: We have the between versus It would be important to study the same and the same dose and the 2 We would have to a clinical trial to about the Dr. Ratliff: I think that vaccine is and if you your then you would have to do Dr. I would about the intradermal to the of because when you it in the bladder in with the bladder that is for the in that may be effective the Dr. Ratliff: cells do not fibronectin into So, by or by we will not see fibronectin on the The cells produce and positive in regions the or in Dr. Gheorghiu: Dr. Prescott, you have Th1 and local but you did not the responses. Dr. We have not responses in the clinical it has been our that if you of the with BCG, you will in the often in the and the areas which are not in with the vaccine, and it seems very those clinical that something local that is the immune response to be effective at with a short and the same of And that's is being on the local immune response and not on the immune response. Dr. Gheorghiu: In terms of using BCG to prevent of bladder would it be possible to the fibronectin by better which would be better through the we an animal model to see if we could implant bladder Dr. Ratliff: That has been done with Dr. There are a number of in and studies using animal studies have also at the of a following the of either or by But the have been Dr. Ratliff: There are studies of and that So, if you an model and the bladder and then a it will implant and But if you that with you the of that does Dr. Flad: I by this fibronectin and if this a and, if it would be to BCG with for And the is since it is a you for immunogenicity against with Dr. Ratliff: I think you may be It is a that we Dr. Flad: I think this has for looking at BCG Dr. Ratliff: as the immune response is we have because we have not had to to it we are to do Dr. We know that cells are capable of BCG they are for the clinical responses is Dr. Ratliff: a of more If you look at the on infection or the the you that there [that] there may be associated with it that a there of a of There are a number of different cells that are in the and there be a to immunity. Dr. Wittes: I think if it were not to have BCG in to then BCG be more effective against it So, I think the issue is that [that] that you need of BCG antigen with and I believe that immunity to BCG that is But or not you that I think you have to that you need the in and [that] it is It's not like BCG is a for by of immunologic Dr. Ratliff: I agree Dr. Wittes: Dr. Ratliff, could you some of us about some of Is it produced by Dr. Ratliff: not It's also produced by epithelial cells and produced by bladder cells. In cells and cells produce This fibronectin is not into a associated with the normal will produce fibronectin that is into the This with although they to produce The bladder In a study looking at in the we found that fibronectin in the apical of of the in the We the to The is that fibronectin is into the of the normal which has the that is also capable of different it also And it it in the same region that BCG So I think that there is of fibronectin on the epithelial and that's there is binding in areas of the Dr. Wittes: Is fibronectin throughout the in Dr. Ratliff: There are different of There is fibronectin and the that is associated with fibronectin produced by the fibronectin is produced by or epithelial Dr. Wittes: If you had fibronectin that to a certain would that be way to BCG to that Dr. Ratliff: I think and the I that it may be there are certain uniform that that have been studied but they to the same and the same and So there is some to there are in Dr. Wittes: How do we BCG to that are not by Dr. Ratliff: The in that is the same in and that is that you can a response in a local environment but you can't a response that in a if they are the same and have it the same So there is some protective in the cells. are the responses. Dr. This also the as to is in more if you are using BCG in a as opposed to a Dr. It's It's more and more That might be and the is that you have more cells in the So you have to cells as Dr. Flad: I think we tell about if we know the Dr. Ratliff: But the the more Dr. And the that we are also Dr. Ratliff: So of those a which they would be more Dr. are more Dr. I think is only more to BCG The with bladder is in a of response with is to with the to the So higher response in in The same with same ratio to and in versus We have to immune to explain the Dr. The human studies that have at the or have been on with or without Is there any on and using the same example, on week and week or of any of these levels of being at those to if you are not to Dr. We have given to observe the clinical and these get at weeks. Dr. In our we were giving a at to and of and we did not see a That in sensitized Dr. is with have had BCG in the they an of BCG at week week they a to that the that you the the it may be that it for of the cells in the blood the first and you get an when you give a more Dr. But you have that the correlates with the cytokine and you see that evidence of cytokine at least at after Dr. But the cellular response for the first for about weeks. Dr. Wittes: the an about BCG for The would as to The would be to BCG as There is also a study looking at BCG with with Dr. of the that we have would that BCG be for Dr. Gheorghiu: And I given the of the it would not be Dr. Ratliff: What kind of of the of the for Dr. There is a to that, and that and is oral BCG for bladder can with Dr. Ratliff: But I the to is that in bladder there is a that you need some some local in to get and if you induce that level of in the what kind of can you Dr. thinking the is a that is and you would I to the situation where there multiple or multiple in chronic disease. Dr. Wittes: for the that might be alternative to The of after it is not that is the presence of at the of or it is due to local with rapid And if it is the would think that BCG be effective in in that as it is in bladder as There are issues that need to be but I would like to if it sense to Dr. I think it good and I think it would be to the with We do have an with and that is with at increased for the of and I think it would be to to standard which is repeated versus oral I think would BCG by Dr. Hoft: I would get to Dr. Gheorghiu's about It is an important issue to give it versus giving it you would the mycobacteria to as well as a local where there is binding to a If we administer it via a it may not be very in and a immune which will to the and induce a local response. So I think your is to on where the If it is to the then an is If your is in terms of local a effective against particularly if the cells that are can BCG and it in an then these cells could be it very important to look at BCG as Dr. Wittes: If we could the I think it is very that a few of BCG by of that might well be as with I think the is in what means by an It has to be something that a Th1 and it may be more the way we think of that induce antibody responses. Dr. I think the is [that] we very bladder with any has a to at a of So it has a very high to with bladder that's it This is different lung and the that we see in lung the same is for we see local in the of The with who has a after local has a very I think we are with a different with bladder and we the clinical with this to I we look for that are to bladder

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