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Vaccine against AIDS?
, Number 8896 EDIT
ORIAL
Vaccine AIDS is
against AIDS?
To comprehend this stark fact it is enough to realise that even when efficient drugs and vaccines become available the insurmountable problems will be those of accessibility and affordability. As it happens, a satisfactory drug is not yet in the offing, and vaccination faces manifold difficulties despite an unparalleled research effort towards a better understanding of the disease and of its causal agent, the human immunodeficiency virus (HIV). The main stumbling blocks in the successful development of vaccines are the enormous antigenic variation of retroviruses on the one hand, and the transmission of HIV directly from cell to cell by fusion on the other. Consequently, antibodies present in the body fluids have no opportunity to inactivate the virus. Nevertheless, these difficulties are not sufficient reasons to give up on the idea of vaccines. Several candidates (fifteen at the last count) have been developed with awareness of these limitations. They are based mostly on HIV-related a
calamity.
peptides prepared by genetic engineering or by chemical synthesis, these approaches being far more appealing than the use of live attenuated or killed whole retroviruses. Another approach is to use a different, relatively harmless, live virus such as canarypox to carry HIV proteins into cells. As science progresses, we are constantly faced with new approaches that may require several years of additional work before reaching the stage of field trials. If we postpone the first trials until we have the perfect vaccine against AIDS-one that gives total protection to all the population-we may have to
February 26, 1994
wait for twenty years, even forever. This does not mean that we should start to use vaccines that are unsafe or inefficient, but we should be alert for the propitious moment at which a cocktail of vaccines might improve matters and decrease the total viral load of humanity. Such a vaccine, not being foolproof for one individual, will not permit him to change his lifestyle, and of this he will have to be made aware. One of the great worries is the tremendous variability in the aminoacid sequence of the viral protein. This variability is also characteristic of the principal neutralising determinant, denoted V3, of the gp 120 envelope protein. Nevertheless, there is a more or less constant frame within this area; one possibility is that a mixture of several such frames might give immunity against most HIV viruses.2 Another great worry is whether immunity can be successful against a virus that arrives within a human body already wrapped within a cell. However, we now know that macaques immunised with SIV, as well as chimpanzees immunised with HIV, are protected against the virus administered within a cell. The limited enthusiasm generated by early vaccine trials has been considerably diminished by the finding that antibodies prepared in volunteers against a vaccine related to one specific HIV virus, the original virus, did not inactivate viruses isolated from several AIDS patients.3 This is a sobering observation but we should certainly not give up on our
although efficiently neutralising
493
efficient solution. Meanwhile, as evidence is accumulating that neutralising antibodies are not adequate protection against HIV infection, recent studies suggest that protection is possible and may be mediated by cellmediated immunity rather than by antibodies. For example, a small population of prostitutes in Nairobi seem to be protected, and remain seronegative and disease-free despite repeated exposure to HIV.4 In addition, a significant number of seronegative individuals have been identified in every known at-risk group who remain HIV seronegative and disease-free but exhibit strong cellmediated immunity to HIV.5 Many of these individuals continue to be exposed, but do not seroconvert. When macaques were exposed to extremely low doses of live SIV and then challenged with an infectious dose of SIV, those that had not been pre-exposed made antibodies, did not show cell-mediated immunity, were polymerase chain reaction (PCR) positive, and developed an AIDSlike condition. By contrast, the animals that were pre-exposed to a very low dose of SIV acquired cellmediated immunity, did not produce antibodies, were PCR negative, and did not develop AIDS.6 Moreover, low-dose immunisation of human beings with the rgpl60 AIDS vaccine can induce cellmediated immunity without antibody formation.’7 These results open the possibility that for vaccination one should use much smaller doses than have previously been considered. In vaccines for which production is a limiting factor, low-dose immunisation might permit increasing 100-fold the number of vaccinees. On the other hand, little is known about the persistence of cell-mediated immunity, and we have to worry also about the best route of immunisation, which probably should not be by injection. There is a growing awareness among AIDS scientists that cell-mediated immunity could be the crucial defence against HIV, and that perhaps something can be done to improve it. What has not been considered until now is the possibility that we may not even have the option of maximising both arms of the immune system simultaneously, owing to cytokine cross-regulation. In these circumstances the cell-mediated arm of immunity is likely to be more protective than the humoral and it might indeed be the only protective component.8 The issue here may be that type 1 (leading to "TH1 ") and type 2 (leading to "TH2") cross-regulatory cytokines will govern the relative strength of these two components of immunity. The vaccines we have discussed until now are all of a prophylactic nature. In the case of a disease like AIDS, there is also urgent need for vaccines of a
efforts
494
to
find
an
therapeutic nature-immunomodulatory vaccines for immunotherapy-and most of the available vaccine candidates should be tested also for possible retardation of disease onset. The three essential issues in the development of a vaccine should now be considered. Is there a need for a vaccine? The answer is clearly yes. What about the safety and toxicity? These obviously have to be established unequivocally. The third issue, which must be recognised, is that all trials should be conducted under the guidance and approval of recognised ethics committees. In the middle of a battle a commander cannot say: "Let us stop for a year until we get better weapons, better ammunition". By analogy, this is no time to slacken our efforts to secure usable vaccines. A cocktail of several vaccine candidates might be the best answer. And we must not forget that the main purpose of a vaccine is to prevent disease and transmission, and not necessarily to prevent infection itself. The Lancet 1 2
3 4
Cadoz M, Strady A, Meignier B, et al. Immunisation with canarypox virus expressing rabies glycoprotein. Lancet 1992; 329: 1429-32. Holley LH, Goudsmit J, Karplus M. Prediction of optimal peptide mixtures to induce broadly neutralising antibodies to human immunodeficiency virus type 1. Proc Natl Acad Sci USA 1991; 88: 6800-04. Cohen J. Jitters jeopardise AIDS vaccine trials. Science 1993; 262: 980-81. Plummer FA, Fowke K, Nagelkerke NJD, et al. Evidence of resistance to HIV among continuously exposed prostitutes in Nairobi, Kenya. IX International Conference on AIDS, Berlin, 1993:23
(abstr WS-A07-3). Clerici M,
5
Berzofsky JA, Shearer GM, Tacket CO. Exposure to human immunodeficiency virus (HIV) type 1 indicated by HIV specific T helper cell responses before detection of infection by polymerase chain reaction and serum antibodies. J Infect Dis 1991; 164: 178-82.
6
Benveniste R, Kuller L, Hu S-L, et al. Prior exposure to subinfectious doses of SIV protects macaques from subsequent virus challenge. Bethesda: Gallo Laboratory Meeting, 1993 (abstr). Salk J, Bretscher PA, Salk PL, Clerici M, Shearer GM. A strategy for prophylactic vaccination against HIV. Science 1993; 260: 1270-72. Clerici M, Shearer GM. The aetiology of AIDS: a TH1→TH2 switch? Immunol Today 1993; 14: 107-11.
7 8
COMMENTARY
Rethinking cancer oncologist colleague lately returned from an autopsy conference at my hospital and proudly announced that his patient, who had had widespread cancer, had died "cancer-free". The patient had succumbed instead to chemotherapy-induced lung disease. It is precisely this sort of thinking and practice, where our zeal to eliminate the cancer sometimes eliminates the patient as well, that Schipper and colleagues take issue with in a comprehensive critique of the cytotoxic model for cancer treatment.’.2 An
ORIAL
Vaccine AIDS is
against AIDS?
To comprehend this stark fact it is enough to realise that even when efficient drugs and vaccines become available the insurmountable problems will be those of accessibility and affordability. As it happens, a satisfactory drug is not yet in the offing, and vaccination faces manifold difficulties despite an unparalleled research effort towards a better understanding of the disease and of its causal agent, the human immunodeficiency virus (HIV). The main stumbling blocks in the successful development of vaccines are the enormous antigenic variation of retroviruses on the one hand, and the transmission of HIV directly from cell to cell by fusion on the other. Consequently, antibodies present in the body fluids have no opportunity to inactivate the virus. Nevertheless, these difficulties are not sufficient reasons to give up on the idea of vaccines. Several candidates (fifteen at the last count) have been developed with awareness of these limitations. They are based mostly on HIV-related a
calamity.
peptides prepared by genetic engineering or by chemical synthesis, these approaches being far more appealing than the use of live attenuated or killed whole retroviruses. Another approach is to use a different, relatively harmless, live virus such as canarypox to carry HIV proteins into cells. As science progresses, we are constantly faced with new approaches that may require several years of additional work before reaching the stage of field trials. If we postpone the first trials until we have the perfect vaccine against AIDS-one that gives total protection to all the population-we may have to
February 26, 1994
wait for twenty years, even forever. This does not mean that we should start to use vaccines that are unsafe or inefficient, but we should be alert for the propitious moment at which a cocktail of vaccines might improve matters and decrease the total viral load of humanity. Such a vaccine, not being foolproof for one individual, will not permit him to change his lifestyle, and of this he will have to be made aware. One of the great worries is the tremendous variability in the aminoacid sequence of the viral protein. This variability is also characteristic of the principal neutralising determinant, denoted V3, of the gp 120 envelope protein. Nevertheless, there is a more or less constant frame within this area; one possibility is that a mixture of several such frames might give immunity against most HIV viruses.2 Another great worry is whether immunity can be successful against a virus that arrives within a human body already wrapped within a cell. However, we now know that macaques immunised with SIV, as well as chimpanzees immunised with HIV, are protected against the virus administered within a cell. The limited enthusiasm generated by early vaccine trials has been considerably diminished by the finding that antibodies prepared in volunteers against a vaccine related to one specific HIV virus, the original virus, did not inactivate viruses isolated from several AIDS patients.3 This is a sobering observation but we should certainly not give up on our
although efficiently neutralising
493
efficient solution. Meanwhile, as evidence is accumulating that neutralising antibodies are not adequate protection against HIV infection, recent studies suggest that protection is possible and may be mediated by cellmediated immunity rather than by antibodies. For example, a small population of prostitutes in Nairobi seem to be protected, and remain seronegative and disease-free despite repeated exposure to HIV.4 In addition, a significant number of seronegative individuals have been identified in every known at-risk group who remain HIV seronegative and disease-free but exhibit strong cellmediated immunity to HIV.5 Many of these individuals continue to be exposed, but do not seroconvert. When macaques were exposed to extremely low doses of live SIV and then challenged with an infectious dose of SIV, those that had not been pre-exposed made antibodies, did not show cell-mediated immunity, were polymerase chain reaction (PCR) positive, and developed an AIDSlike condition. By contrast, the animals that were pre-exposed to a very low dose of SIV acquired cellmediated immunity, did not produce antibodies, were PCR negative, and did not develop AIDS.6 Moreover, low-dose immunisation of human beings with the rgpl60 AIDS vaccine can induce cellmediated immunity without antibody formation.’7 These results open the possibility that for vaccination one should use much smaller doses than have previously been considered. In vaccines for which production is a limiting factor, low-dose immunisation might permit increasing 100-fold the number of vaccinees. On the other hand, little is known about the persistence of cell-mediated immunity, and we have to worry also about the best route of immunisation, which probably should not be by injection. There is a growing awareness among AIDS scientists that cell-mediated immunity could be the crucial defence against HIV, and that perhaps something can be done to improve it. What has not been considered until now is the possibility that we may not even have the option of maximising both arms of the immune system simultaneously, owing to cytokine cross-regulation. In these circumstances the cell-mediated arm of immunity is likely to be more protective than the humoral and it might indeed be the only protective component.8 The issue here may be that type 1 (leading to "TH1 ") and type 2 (leading to "TH2") cross-regulatory cytokines will govern the relative strength of these two components of immunity. The vaccines we have discussed until now are all of a prophylactic nature. In the case of a disease like AIDS, there is also urgent need for vaccines of a
efforts
494
to
find
an
therapeutic nature-immunomodulatory vaccines for immunotherapy-and most of the available vaccine candidates should be tested also for possible retardation of disease onset. The three essential issues in the development of a vaccine should now be considered. Is there a need for a vaccine? The answer is clearly yes. What about the safety and toxicity? These obviously have to be established unequivocally. The third issue, which must be recognised, is that all trials should be conducted under the guidance and approval of recognised ethics committees. In the middle of a battle a commander cannot say: "Let us stop for a year until we get better weapons, better ammunition". By analogy, this is no time to slacken our efforts to secure usable vaccines. A cocktail of several vaccine candidates might be the best answer. And we must not forget that the main purpose of a vaccine is to prevent disease and transmission, and not necessarily to prevent infection itself. The Lancet 1 2
3 4
Cadoz M, Strady A, Meignier B, et al. Immunisation with canarypox virus expressing rabies glycoprotein. Lancet 1992; 329: 1429-32. Holley LH, Goudsmit J, Karplus M. Prediction of optimal peptide mixtures to induce broadly neutralising antibodies to human immunodeficiency virus type 1. Proc Natl Acad Sci USA 1991; 88: 6800-04. Cohen J. Jitters jeopardise AIDS vaccine trials. Science 1993; 262: 980-81. Plummer FA, Fowke K, Nagelkerke NJD, et al. Evidence of resistance to HIV among continuously exposed prostitutes in Nairobi, Kenya. IX International Conference on AIDS, Berlin, 1993:23
(abstr WS-A07-3). Clerici M,
5
Berzofsky JA, Shearer GM, Tacket CO. Exposure to human immunodeficiency virus (HIV) type 1 indicated by HIV specific T helper cell responses before detection of infection by polymerase chain reaction and serum antibodies. J Infect Dis 1991; 164: 178-82.
6
Benveniste R, Kuller L, Hu S-L, et al. Prior exposure to subinfectious doses of SIV protects macaques from subsequent virus challenge. Bethesda: Gallo Laboratory Meeting, 1993 (abstr). Salk J, Bretscher PA, Salk PL, Clerici M, Shearer GM. A strategy for prophylactic vaccination against HIV. Science 1993; 260: 1270-72. Clerici M, Shearer GM. The aetiology of AIDS: a TH1→TH2 switch? Immunol Today 1993; 14: 107-11.
7 8
COMMENTARY
Rethinking cancer oncologist colleague lately returned from an autopsy conference at my hospital and proudly announced that his patient, who had had widespread cancer, had died "cancer-free". The patient had succumbed instead to chemotherapy-induced lung disease. It is precisely this sort of thinking and practice, where our zeal to eliminate the cancer sometimes eliminates the patient as well, that Schipper and colleagues take issue with in a comprehensive critique of the cytotoxic model for cancer treatment.’.2 An