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Why Don't We Have a Schistosomiasis Vaccine?
The Search for a Schistosomiasis Vaccine
Why Don’t We Have a Schistosomiasis Vaccine? R.A. Wilson and P.S. Coulson Over the past 30 years there has been a concerted effort to understand host immune responses to schistosomes, with the ultimate aim of producing a vaccine for human use. In this issue, Bergquist and Colley, in summarizing recent meetings in Cairo, provide a detailed appraisal of progress towards that goal. It seems an appropriate time to ask why, with reference to Schistosoma mansoni, the development of a vaccine has proved so difficult. This question is explored here by Alan Wilson and Pat Coulson. Mature schistosomes inhabit the bloodstream, potentially the most hostile immunological environment, yet they are long-lived parasites. They have evolved highly effective mechanisms1 for evading the consequences of the cellular and humoral immune responses which they provoke. Indeed, they apparently exploit those responses to assist the process of egg excretion from intestinal tissues2. Everything points to the evasion mechanisms being deployed by larval schistosomes in the first 24 h after skin penetration which, on the face of it, provides little opportunity for immune attack. In these circumstances, the development of a vaccine was always going to present a challenge. Do we have the right paradigms? Research on immunity to schistosomes has thrown up ideas which, at their inception, appeared to provide promising routes to an effective vaccine. In the event they have not proved fruitful and, with the benefit of hindsight, we can offer plausible explanations as to why. The phenomenon of concomitant immunity, first demonstrated in rhesus monkeys3 and later in mice4, dominated schistosome vaccine research from the 1960s to the 1980s. It described the situation where a primary worm burden persisted while the host was resistant to a secondary challenge. It seemed a simple matter to discover how the mature worms induced protection and reproduce this in a vaccine. Concomitant immunity could well hold true in the rhesus monkey, and merits reinvestigation, but in the infected mouse5, and more recently in the black rat6, it has proved to be an artifact of egg-induced pathology. The host appears immune due to an altered portal vasculature which prevents establishment of worms, an effect so dominant that it masks any potential contribution from immunologically specific mechanisms. Antibody-dependent cellular cytotoxicity (ADCC) was another major concept which followed on from, and complemented concomitant immunity. Stated succinctly, newly transformed schistosomula are susceptible to killing in vitro by various combinations of antibody isotypes and leukocytes (primarily from humans R. Alan Wilson and Patricia S. Coulson are at the Department of Biology, PO Box 373, The University of York, York, UK YO1 5YW. Tel: +44 1904 432830, Fax: +44 1904 432884, e-mail: [email protected] Parasitology Today, vol. 14, no. 3, 1998
and rats)7; this vulnerability is lost from 24 h posttransformation. Clearly, a vaccine which replicates this process would be highly effective. Unfortunately, evidence for the efficacy of ADCC in vivo is sparse, and it is plausible that schistosomes have evolved a strategy to reduce their susceptibility. Newly penetrated parasites remain in peripheral epidermal locations for 48 h (Ref. 8), by which time their immune evasion mechanisms have developed; does this place them beyond the reach of lethal dermal inflammatory responses? Another contributory factor to the failure of ADCC in vivo may be the dominance of antibody isotypes which block rather than mediate the process9. In light of the above, there is presently little to suggest that a vaccine based on ADCC mechanisms is going to be feasible. Leaving aside the question of antifecundity effects10, there are two contrasting strategies to develop a vaccine that minimizes worm burden11. One is to demonstrate protection in a host which has been exposed to a schistosome infection and then seek to replicate its mechanisms by vaccination; analysis of acquired immunity in humans falls into this category. The second strategy is to invoke by vaccination a novel response not normally encountered by the parasite and against which it has no defence; the radiation-attenuated vaccine may be such an example. In human schistosomiasis, the decreased prevalence and intensity of infection with age (particularly noticeable around/after puberty12), provide the strongest evidence for acquired immunity. Genetic analysis of human populations has also highlighted the presence of a co-dominant major gene controlling the intensity of schistosome infection, which has been localized to a region of chromosome 5 encoding immunological molecules13. If we accept that immunity occurs in humans, then the nature of protection remains problematic, with an IgE-mediated mechanism as one of the strongest candidates14. This in itself poses dangers since a vaccination regime to promote IgE production may well elicit undesirable side-effects such as exacerbation of allergy. More pertinent is the lack of evidence for immunity in children before puberty12. As these are the individuals most in need of protection, it is presently difficult to envisage how a vaccine strategy based on human responses after natural exposure to schistosomes could work for them. There is one paradigm that has stood the test of time; the radiation-attenuated schistosome vaccine, which protects both rodents and primates15. In mice, cell-mediated mechanisms operating against lung-stage parasites appear highly effective and immunity can be augmented to very high levels by co-administration of radiation-attenuated cercariae with interleukin 12 (IL-12) as an adjuvant16. Clearly this model is a cause for optimism that a schistosome vaccine is a realistic goal. However, a live attenuated schistosome vaccine is not a practical proposition for use in humans; it can only serve as a precursor for a defined recombinant vaccine.
Copyright © 1998, Elsevier Science Ltd All rights reserved 0169–4758/98/$19.00 PII: S0169-4758(97)01198-8
97
The Search for a Schistosomiasis Vaccine Do we have the right antigens? It is axiomatic that a schistosome vaccine will comprise one or more recombinant antigens in an appropriate formulation or live vector. The selection of six candidate vaccine antigens by WHO for independent evaluation (see Bergquist and Colley, this issue) was something of a mixed blessing. On the one hand it raised expectations that a vaccine was within reach. On the other, the existence of the WHO programme, together with reported successes by the antigen donors, inhibited the search for new vaccine candidates. For a variety of reasons, none of the six candidates performed to the required standard in trials with mice. The human studies now under way may reveal whether the intensity of responses to these candidates, resulting from preceding exposure to schistosomes, correlates with resistant status. What is surprising about the vaccine candidates is that five of them are intracellular, and only one a membrane protein. The five intracellular antigens are abundant constituents of adult worms and turn up frequently when cDNA libraries are screened with antischistosome serum. Intuitively, they are not the kind of molecules one would expect a parasite to release into its environment unless it was first damaged by some non-immune process, and so they would not be available to the immune system under normal circumstances. Exceptions are the holocrine secretion of cercarial acetabular gland contents during skin penetration, and the shedding of the cercarial tegument plasmamembrane during transformation, where natural release might occur; these early events would implicate the newly penetrated parasite as a target for protective mechanisms. In this context, Gobert (this issue) attempts to rationalize, in terms of schistosome biology, the choice of S. japonicum paramyosin as a vaccine candidate. Latest estimates suggest that the schistosome genome contains 1.5 to 2.03104 genes, so that pinpointing the antigens mediating protection is obviously going to be difficult. Sher17 credits Waksman with the postulate that ‘we should focus on molecules against which little or no response was (normally) directed’. Furthermore, ‘it would be a mistake to expect antibodies (or T cells) from infected laboratory or human hosts to identify these potentially effective immunogens’. For schistosomes, with the exception of ADCC, proposed immune effector mechanisms require the release (ie. secretion) of antigens from the intact parasite into its environment to invoke a response. However, an examination of DNA databases (excluding expressed sequence tags), has revealed that out of 300 schistosome cDNAs so far sequenced, only nine code at the 5' end for a signal peptide characteristic of membrane/ secreted proteins (B. Shah, pers. commun.). Clearly, there is enormous scope for identification of new vaccine candidates. In this issue, Doenhoff addresses the point by reviewing other antigens which may have such merits; in addition, Mountford and Harrop focus attention on the lung-stage schistosomulum as a source of antigens capable of stimulating protective Th1-mediated responses. These approaches do not exhaust the possibilities for antigen identification. To take just one example, secretions of the head gland, which the schistosomulum uses to penetrate the blood vessel wall during migration out of the skin8, are completely uncharacterized but represent a potential target for immune attack. 98
Do we need a schistosomiasis vaccine? In view of the manifold obstacles, it is worth asking ‘Why develop a vaccine?’, particularly when the efficacy of chemotherapy apparently makes one unnecessary. There appear to us two potent arguments. The first is that the clinical course of disease is insidious18; in the minority of individuals with a high worm burden transition to severe and irreversible pathology is usually diagnosed at too late a stage for chemotherapy to affect the outcome. In those individuals who acquire low to moderate worm burdens, the rationale for vaccination or chemotherapy appears to be similar, provided that the two therapies are equally effective. Arguably, in that situation a vaccine would be preferred because of its capacity to limit worm accumulation whereas chemotherapy removes worms after they have accumulated. The second reason is that with continuing chemotherapy it seems almost inevitable that drug resistance will appear. Indeed, seven laboratory passages of the life cycle with subcurative chemotherapy were sufficient to select for resistance to praziquantel19. Furthermore, there are already reports of low efficacy of the drug in Egypt20 and Senegal21. The multiple drug resistance acquired by helminth parasites of livestock, which has compromised control measures22, provides a salutary warning in this respect. In summary, we suggest that a schistosome vaccine is both desirable and feasible. However, not only are new protective antigens needed, but they must be developed in the context of defined effector responses. Only then can we address the complex question of antigen formulation to manipulate immune priming in a specific direction which will maximize parasite elimination. References 1 Pearce, E.J. and Sher, A. (1987) Mechanisms of immune evasion in schistosomiasis. Contrib. Microbiol. Immunol. 8, 219–232 2 Doenhoff, M.J. et al. (1985) Does the immunopathology induced by schistosome eggs potentiate parasite survival? Immunol. Today 6, 203–206 3 Smithers, S.R. and Terry, R. (1969) Immunity in schistosomiasis. Ann. New York Acad. Sci. 160, 826–840 4 Doenhoff, M. et al. (1978) Factors affecting the acquisition of resistance against Schistosoma mansoni in the mouse. J. Helminthol. 52, 173–186 5 Wilson, R.A. (1990) Leaky livers, portal shunting and immunity to schistosomes. Parasitol. Today 6, 354–358 6 Imbert-Establet, D. et al. Schistosome-induced portacaval haemodynamic changes in Rattus rattus are associated with translocation of adult worms to the lungs. Parasitology (in press) 7 Butterworth, A.E. (1984) Cell-mediated damage to helminths. Adv. Parasitol. 23, 143–235 8 Crabtree, J.E. and Wilson, R.A. (1985) Schistosoma mansoni: an ultrastructural examination of skin migration in the hamster cheek pouch. Parasitology 91, 111–120 9 Grzych, J.M. et al. (1984) Blocking activity of rat monoclonal antibodies in experimental schistosomiasis. J. Immunol. 133, 998–1004 10 Capron, A. et al. (1995) Development of a vaccine strategy against human and bovine schistosomiasis. Background and update. Mem. Inst. Oswaldo Cruz 90, 235–240 11 Wilson, R.A. and Sher, A. (1993) Vaccines against schistosomiasis: an alternative view. Trans. R. Soc. Trop. Med. Hyg. 87, 237 12 Fulford, A.J.C. et al. (1998) Puberty and age-related changes in susceptibility to schistosome infection? Parasitol. Today 14, 23–26 13 Marquet, S. et al. (1996) Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33. Nat. Genet. 14, 181–184 14 Dunne, D.W. et al. (1997) The isolation of a 22kDa band after SDS-PAGE of Schistosoma mansoni adult worms and its use to demonstrate that IgE responses against antigen(s) it contains are associated with human resistance to reinfection. Parasite Immunol. 19, 79–89
Parasitology Today, vol. 14, no. 3, 1998
The Search for a Schistosomiasis Vaccine 15 Coulson, P.S. (1997) The radiation-attenuated vaccine against schistosomes in animal models: paradigm for a human vaccine? Adv. Parasitol. 39, 272–323 16 Wynn, T.A. et al. (1996) IL-12 enhances vaccine-induced immunity to schistosomes by augmenting both humoral and cell-mediated immune responses against the parasite. J. Immunol. 157, 4068–4078 17 Sher, A. (1988) in The Biology of Parasitism (Englund, P.T. and Sher, A., eds), pp 169–182, Alan R. Liss 18 von Lichtenberg, F. (1987) in The Biology of Schistosomes (Rollinson, D. and Simpson, A.J.G., eds), pp 185–232, Academic Press
19 Fallon, P.G. and Doenhoff, M.J. (1994) Drug resistant schistosomiasis: resistance to praziquantel and oxaminiquine in Schistosoma mansoni in mice is drug specific. Am. J. Trop. Med. Hyg. 51, 83–88 20 Ismail, M. et al. (1996) Characterization of isolates of Schistosoma mansoni from Egyptian villagers that tolerate high doses of praziquantel. Am. J. Trop. Med. Hyg. 55, 214–218 21 Stelma, F.F. et al. (1995) Efficacy and side effects of praziquantel in an epidemic focus of Schistosoma mansoni. Am. J. Trop. Med. Hyg. 53, 167–170 22 Sangster, N. (1996) Pharmacology of anthelmintic resistance. Parasitology 113, S201–S216
Schistosomiasis Vaccines: Research to Development N.R. Bergquist and D.G. Colley In this article, Robert Bergquist and Dan Colley deal with the consolidated, international efforts to generate a schistosomiasis vaccine; in particular, they summarize the deliberations of a series of meetings, held in Cairo, Egypt, 21–25 May 1997, with the aim of reviewing the current status of affairs in this respect in order to make recommendations for the future course of schistosomiasis vaccine development. More than 600 million people in the tropics are at risk of schistosomiasis and the number of infected individuals worldwide is near 200 million. Contributing to its severity and spread is the inadequate attention paid to this snail-borne infection in the construction of man-made lakes, irrigation projects, etc. Chemotherapy remains the cornerstone of intervention but rapid reinfection demands frequent retreatment and emphasizes the need for a more long-term approach. The existence of at least partially protective immunity in exposed humans would make a vaccine a logical complement to drug therapy. Studies in experimental models have been highly productive and are still much needed but may not adequately represent the human situation. Preliminary results from coordinated in vitro laboratory and field epidemiological research regarding the protective potential of a set of well-researched, defined schistosome antigens (Table 1) support the initiation of clinical trials. After the selection of suitable vaccine candidates the logical next step would be to scale up antigen production according to good manufacturing practice (GMP) and plan for Phase I/II trials, first in adults and then in children. Since the slow maturation of natural resistance does not temper reinfection in time either to stop Robert Bergquist is the Coordinator of Strategic Research at the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, CH-1211 Geneva 27, Switzerland. Dan Colley is the Director of the Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC), Bldg 102, MS F-22, 4770 Buford Highway, NE, Atlanta, GA 30341, USA. Tel: +41 22 791 3864, Fax: +41 22 791 4854, e-mail: [email protected] Parasitology Today, vol. 14, no. 3, 1998
serious morbidity from developing or to hinder transmission, younger age groups are the prime target for vaccination. The efforts to develop a schistosomiasis vaccine1,2 described here deal exclusively with Schistosoma mansoni, a bias reflecting the fact that the S. mansoni life cycle is the easiest to maintain in the laboratory, away from endemic areas, and most antigens were first identified in this species. In reality, there is now a genuine interest in developing vaccines against the other common causes of human schistosomiasis (S. japonicum and S. haemotobium). Although somewhat further down the road of vaccine development, it should be appreciated that the ultimate vaccine for each of these might have to be a combination of two or more antigens. The possibility of synergistic action would increase by incorporating antigens from different developmental stages of the parasite3 and the progress of research on the larval stage therefore needs complementary work on antigens emanating from other stages, for example, cercarial proteases. In addition, the design of a successful vaccine will not be based solely on the most effective way of inducing immunity but must also consider the technical feasibility of vaccine production, the prospects of passage through existing regulatory bodies, and the ease of incorporation into immunization delivery programmes. On mice and men Based on the need for an assessment of potentially protective immune responses, which might also be of importance in human immunity, the antigens depicted in Table 1 were subjected to independent testing in mice. In parallel, determination of cell-mediated and humoral responses against the same antigens in humans living in endemic areas was carried out with the aim of perhaps narrowing down the range of potentially protective antigens. The path towards clinical trials was initiated by contracting two laboratories with recognized experience in experimental schistosomiasis to undertake independent mouse studies in parallel, using both
Copyright © 1998, Elsevier Science Ltd All rights reserved 0169–4758/98/$19.00 PII: S0169-4758(97)01207-6
99
Why Don’t We Have a Schistosomiasis Vaccine? R.A. Wilson and P.S. Coulson Over the past 30 years there has been a concerted effort to understand host immune responses to schistosomes, with the ultimate aim of producing a vaccine for human use. In this issue, Bergquist and Colley, in summarizing recent meetings in Cairo, provide a detailed appraisal of progress towards that goal. It seems an appropriate time to ask why, with reference to Schistosoma mansoni, the development of a vaccine has proved so difficult. This question is explored here by Alan Wilson and Pat Coulson. Mature schistosomes inhabit the bloodstream, potentially the most hostile immunological environment, yet they are long-lived parasites. They have evolved highly effective mechanisms1 for evading the consequences of the cellular and humoral immune responses which they provoke. Indeed, they apparently exploit those responses to assist the process of egg excretion from intestinal tissues2. Everything points to the evasion mechanisms being deployed by larval schistosomes in the first 24 h after skin penetration which, on the face of it, provides little opportunity for immune attack. In these circumstances, the development of a vaccine was always going to present a challenge. Do we have the right paradigms? Research on immunity to schistosomes has thrown up ideas which, at their inception, appeared to provide promising routes to an effective vaccine. In the event they have not proved fruitful and, with the benefit of hindsight, we can offer plausible explanations as to why. The phenomenon of concomitant immunity, first demonstrated in rhesus monkeys3 and later in mice4, dominated schistosome vaccine research from the 1960s to the 1980s. It described the situation where a primary worm burden persisted while the host was resistant to a secondary challenge. It seemed a simple matter to discover how the mature worms induced protection and reproduce this in a vaccine. Concomitant immunity could well hold true in the rhesus monkey, and merits reinvestigation, but in the infected mouse5, and more recently in the black rat6, it has proved to be an artifact of egg-induced pathology. The host appears immune due to an altered portal vasculature which prevents establishment of worms, an effect so dominant that it masks any potential contribution from immunologically specific mechanisms. Antibody-dependent cellular cytotoxicity (ADCC) was another major concept which followed on from, and complemented concomitant immunity. Stated succinctly, newly transformed schistosomula are susceptible to killing in vitro by various combinations of antibody isotypes and leukocytes (primarily from humans R. Alan Wilson and Patricia S. Coulson are at the Department of Biology, PO Box 373, The University of York, York, UK YO1 5YW. Tel: +44 1904 432830, Fax: +44 1904 432884, e-mail: [email protected] Parasitology Today, vol. 14, no. 3, 1998
and rats)7; this vulnerability is lost from 24 h posttransformation. Clearly, a vaccine which replicates this process would be highly effective. Unfortunately, evidence for the efficacy of ADCC in vivo is sparse, and it is plausible that schistosomes have evolved a strategy to reduce their susceptibility. Newly penetrated parasites remain in peripheral epidermal locations for 48 h (Ref. 8), by which time their immune evasion mechanisms have developed; does this place them beyond the reach of lethal dermal inflammatory responses? Another contributory factor to the failure of ADCC in vivo may be the dominance of antibody isotypes which block rather than mediate the process9. In light of the above, there is presently little to suggest that a vaccine based on ADCC mechanisms is going to be feasible. Leaving aside the question of antifecundity effects10, there are two contrasting strategies to develop a vaccine that minimizes worm burden11. One is to demonstrate protection in a host which has been exposed to a schistosome infection and then seek to replicate its mechanisms by vaccination; analysis of acquired immunity in humans falls into this category. The second strategy is to invoke by vaccination a novel response not normally encountered by the parasite and against which it has no defence; the radiation-attenuated vaccine may be such an example. In human schistosomiasis, the decreased prevalence and intensity of infection with age (particularly noticeable around/after puberty12), provide the strongest evidence for acquired immunity. Genetic analysis of human populations has also highlighted the presence of a co-dominant major gene controlling the intensity of schistosome infection, which has been localized to a region of chromosome 5 encoding immunological molecules13. If we accept that immunity occurs in humans, then the nature of protection remains problematic, with an IgE-mediated mechanism as one of the strongest candidates14. This in itself poses dangers since a vaccination regime to promote IgE production may well elicit undesirable side-effects such as exacerbation of allergy. More pertinent is the lack of evidence for immunity in children before puberty12. As these are the individuals most in need of protection, it is presently difficult to envisage how a vaccine strategy based on human responses after natural exposure to schistosomes could work for them. There is one paradigm that has stood the test of time; the radiation-attenuated schistosome vaccine, which protects both rodents and primates15. In mice, cell-mediated mechanisms operating against lung-stage parasites appear highly effective and immunity can be augmented to very high levels by co-administration of radiation-attenuated cercariae with interleukin 12 (IL-12) as an adjuvant16. Clearly this model is a cause for optimism that a schistosome vaccine is a realistic goal. However, a live attenuated schistosome vaccine is not a practical proposition for use in humans; it can only serve as a precursor for a defined recombinant vaccine.
Copyright © 1998, Elsevier Science Ltd All rights reserved 0169–4758/98/$19.00 PII: S0169-4758(97)01198-8
97
The Search for a Schistosomiasis Vaccine Do we have the right antigens? It is axiomatic that a schistosome vaccine will comprise one or more recombinant antigens in an appropriate formulation or live vector. The selection of six candidate vaccine antigens by WHO for independent evaluation (see Bergquist and Colley, this issue) was something of a mixed blessing. On the one hand it raised expectations that a vaccine was within reach. On the other, the existence of the WHO programme, together with reported successes by the antigen donors, inhibited the search for new vaccine candidates. For a variety of reasons, none of the six candidates performed to the required standard in trials with mice. The human studies now under way may reveal whether the intensity of responses to these candidates, resulting from preceding exposure to schistosomes, correlates with resistant status. What is surprising about the vaccine candidates is that five of them are intracellular, and only one a membrane protein. The five intracellular antigens are abundant constituents of adult worms and turn up frequently when cDNA libraries are screened with antischistosome serum. Intuitively, they are not the kind of molecules one would expect a parasite to release into its environment unless it was first damaged by some non-immune process, and so they would not be available to the immune system under normal circumstances. Exceptions are the holocrine secretion of cercarial acetabular gland contents during skin penetration, and the shedding of the cercarial tegument plasmamembrane during transformation, where natural release might occur; these early events would implicate the newly penetrated parasite as a target for protective mechanisms. In this context, Gobert (this issue) attempts to rationalize, in terms of schistosome biology, the choice of S. japonicum paramyosin as a vaccine candidate. Latest estimates suggest that the schistosome genome contains 1.5 to 2.03104 genes, so that pinpointing the antigens mediating protection is obviously going to be difficult. Sher17 credits Waksman with the postulate that ‘we should focus on molecules against which little or no response was (normally) directed’. Furthermore, ‘it would be a mistake to expect antibodies (or T cells) from infected laboratory or human hosts to identify these potentially effective immunogens’. For schistosomes, with the exception of ADCC, proposed immune effector mechanisms require the release (ie. secretion) of antigens from the intact parasite into its environment to invoke a response. However, an examination of DNA databases (excluding expressed sequence tags), has revealed that out of 300 schistosome cDNAs so far sequenced, only nine code at the 5' end for a signal peptide characteristic of membrane/ secreted proteins (B. Shah, pers. commun.). Clearly, there is enormous scope for identification of new vaccine candidates. In this issue, Doenhoff addresses the point by reviewing other antigens which may have such merits; in addition, Mountford and Harrop focus attention on the lung-stage schistosomulum as a source of antigens capable of stimulating protective Th1-mediated responses. These approaches do not exhaust the possibilities for antigen identification. To take just one example, secretions of the head gland, which the schistosomulum uses to penetrate the blood vessel wall during migration out of the skin8, are completely uncharacterized but represent a potential target for immune attack. 98
Do we need a schistosomiasis vaccine? In view of the manifold obstacles, it is worth asking ‘Why develop a vaccine?’, particularly when the efficacy of chemotherapy apparently makes one unnecessary. There appear to us two potent arguments. The first is that the clinical course of disease is insidious18; in the minority of individuals with a high worm burden transition to severe and irreversible pathology is usually diagnosed at too late a stage for chemotherapy to affect the outcome. In those individuals who acquire low to moderate worm burdens, the rationale for vaccination or chemotherapy appears to be similar, provided that the two therapies are equally effective. Arguably, in that situation a vaccine would be preferred because of its capacity to limit worm accumulation whereas chemotherapy removes worms after they have accumulated. The second reason is that with continuing chemotherapy it seems almost inevitable that drug resistance will appear. Indeed, seven laboratory passages of the life cycle with subcurative chemotherapy were sufficient to select for resistance to praziquantel19. Furthermore, there are already reports of low efficacy of the drug in Egypt20 and Senegal21. The multiple drug resistance acquired by helminth parasites of livestock, which has compromised control measures22, provides a salutary warning in this respect. In summary, we suggest that a schistosome vaccine is both desirable and feasible. However, not only are new protective antigens needed, but they must be developed in the context of defined effector responses. Only then can we address the complex question of antigen formulation to manipulate immune priming in a specific direction which will maximize parasite elimination. References 1 Pearce, E.J. and Sher, A. (1987) Mechanisms of immune evasion in schistosomiasis. Contrib. Microbiol. Immunol. 8, 219–232 2 Doenhoff, M.J. et al. (1985) Does the immunopathology induced by schistosome eggs potentiate parasite survival? Immunol. Today 6, 203–206 3 Smithers, S.R. and Terry, R. (1969) Immunity in schistosomiasis. Ann. New York Acad. Sci. 160, 826–840 4 Doenhoff, M. et al. (1978) Factors affecting the acquisition of resistance against Schistosoma mansoni in the mouse. J. Helminthol. 52, 173–186 5 Wilson, R.A. (1990) Leaky livers, portal shunting and immunity to schistosomes. Parasitol. Today 6, 354–358 6 Imbert-Establet, D. et al. Schistosome-induced portacaval haemodynamic changes in Rattus rattus are associated with translocation of adult worms to the lungs. Parasitology (in press) 7 Butterworth, A.E. (1984) Cell-mediated damage to helminths. Adv. Parasitol. 23, 143–235 8 Crabtree, J.E. and Wilson, R.A. (1985) Schistosoma mansoni: an ultrastructural examination of skin migration in the hamster cheek pouch. Parasitology 91, 111–120 9 Grzych, J.M. et al. (1984) Blocking activity of rat monoclonal antibodies in experimental schistosomiasis. J. Immunol. 133, 998–1004 10 Capron, A. et al. (1995) Development of a vaccine strategy against human and bovine schistosomiasis. Background and update. Mem. Inst. Oswaldo Cruz 90, 235–240 11 Wilson, R.A. and Sher, A. (1993) Vaccines against schistosomiasis: an alternative view. Trans. R. Soc. Trop. Med. Hyg. 87, 237 12 Fulford, A.J.C. et al. (1998) Puberty and age-related changes in susceptibility to schistosome infection? Parasitol. Today 14, 23–26 13 Marquet, S. et al. (1996) Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33. Nat. Genet. 14, 181–184 14 Dunne, D.W. et al. (1997) The isolation of a 22kDa band after SDS-PAGE of Schistosoma mansoni adult worms and its use to demonstrate that IgE responses against antigen(s) it contains are associated with human resistance to reinfection. Parasite Immunol. 19, 79–89
Parasitology Today, vol. 14, no. 3, 1998
The Search for a Schistosomiasis Vaccine 15 Coulson, P.S. (1997) The radiation-attenuated vaccine against schistosomes in animal models: paradigm for a human vaccine? Adv. Parasitol. 39, 272–323 16 Wynn, T.A. et al. (1996) IL-12 enhances vaccine-induced immunity to schistosomes by augmenting both humoral and cell-mediated immune responses against the parasite. J. Immunol. 157, 4068–4078 17 Sher, A. (1988) in The Biology of Parasitism (Englund, P.T. and Sher, A., eds), pp 169–182, Alan R. Liss 18 von Lichtenberg, F. (1987) in The Biology of Schistosomes (Rollinson, D. and Simpson, A.J.G., eds), pp 185–232, Academic Press
19 Fallon, P.G. and Doenhoff, M.J. (1994) Drug resistant schistosomiasis: resistance to praziquantel and oxaminiquine in Schistosoma mansoni in mice is drug specific. Am. J. Trop. Med. Hyg. 51, 83–88 20 Ismail, M. et al. (1996) Characterization of isolates of Schistosoma mansoni from Egyptian villagers that tolerate high doses of praziquantel. Am. J. Trop. Med. Hyg. 55, 214–218 21 Stelma, F.F. et al. (1995) Efficacy and side effects of praziquantel in an epidemic focus of Schistosoma mansoni. Am. J. Trop. Med. Hyg. 53, 167–170 22 Sangster, N. (1996) Pharmacology of anthelmintic resistance. Parasitology 113, S201–S216
Schistosomiasis Vaccines: Research to Development N.R. Bergquist and D.G. Colley In this article, Robert Bergquist and Dan Colley deal with the consolidated, international efforts to generate a schistosomiasis vaccine; in particular, they summarize the deliberations of a series of meetings, held in Cairo, Egypt, 21–25 May 1997, with the aim of reviewing the current status of affairs in this respect in order to make recommendations for the future course of schistosomiasis vaccine development. More than 600 million people in the tropics are at risk of schistosomiasis and the number of infected individuals worldwide is near 200 million. Contributing to its severity and spread is the inadequate attention paid to this snail-borne infection in the construction of man-made lakes, irrigation projects, etc. Chemotherapy remains the cornerstone of intervention but rapid reinfection demands frequent retreatment and emphasizes the need for a more long-term approach. The existence of at least partially protective immunity in exposed humans would make a vaccine a logical complement to drug therapy. Studies in experimental models have been highly productive and are still much needed but may not adequately represent the human situation. Preliminary results from coordinated in vitro laboratory and field epidemiological research regarding the protective potential of a set of well-researched, defined schistosome antigens (Table 1) support the initiation of clinical trials. After the selection of suitable vaccine candidates the logical next step would be to scale up antigen production according to good manufacturing practice (GMP) and plan for Phase I/II trials, first in adults and then in children. Since the slow maturation of natural resistance does not temper reinfection in time either to stop Robert Bergquist is the Coordinator of Strategic Research at the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, CH-1211 Geneva 27, Switzerland. Dan Colley is the Director of the Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC), Bldg 102, MS F-22, 4770 Buford Highway, NE, Atlanta, GA 30341, USA. Tel: +41 22 791 3864, Fax: +41 22 791 4854, e-mail: [email protected] Parasitology Today, vol. 14, no. 3, 1998
serious morbidity from developing or to hinder transmission, younger age groups are the prime target for vaccination. The efforts to develop a schistosomiasis vaccine1,2 described here deal exclusively with Schistosoma mansoni, a bias reflecting the fact that the S. mansoni life cycle is the easiest to maintain in the laboratory, away from endemic areas, and most antigens were first identified in this species. In reality, there is now a genuine interest in developing vaccines against the other common causes of human schistosomiasis (S. japonicum and S. haemotobium). Although somewhat further down the road of vaccine development, it should be appreciated that the ultimate vaccine for each of these might have to be a combination of two or more antigens. The possibility of synergistic action would increase by incorporating antigens from different developmental stages of the parasite3 and the progress of research on the larval stage therefore needs complementary work on antigens emanating from other stages, for example, cercarial proteases. In addition, the design of a successful vaccine will not be based solely on the most effective way of inducing immunity but must also consider the technical feasibility of vaccine production, the prospects of passage through existing regulatory bodies, and the ease of incorporation into immunization delivery programmes. On mice and men Based on the need for an assessment of potentially protective immune responses, which might also be of importance in human immunity, the antigens depicted in Table 1 were subjected to independent testing in mice. In parallel, determination of cell-mediated and humoral responses against the same antigens in humans living in endemic areas was carried out with the aim of perhaps narrowing down the range of potentially protective antigens. The path towards clinical trials was initiated by contracting two laboratories with recognized experience in experimental schistosomiasis to undertake independent mouse studies in parallel, using both
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