Comment
Schistosomiasis Vaccines: A Response to a Devils’ Advocate’s View P. Hagan, M.J. Doenhoff, R.A. Wilson, M. Al-Sherbiny and R. Bergquist We thank Bruno Gryseels1 and Parasitology Today for continuing the discussion on the merits of vaccination against schistosomiasis. However, some of the questions raised can only be addressed by the very studies under scrutiny1. We highlight aspects of special significance, such as feasibility and safety, countering the suggestion that human trials are being initiated without proper care. Some argue that benefits of vaccination must be substantial to justify the high costs and strains on health services. Surely, this is true for any intervention, and is precisely the reason why vaccines have remained a priority for so long. A vaccination programme would be cheaper in the long term, and would produce less strain on services than would drugs, which must be constantly redistributed to counteract morbidity. However, one key issue is potential resistance to praziquantel. While limited evidence of resistance exists to date2, resistance can be produced experimentally3,4 . After 20 years of large-scale use, there are worrying reports from the field5 and concern remains that resistance might appear. Also, the relatively limited availability of oxamniquine in much of the world leaves us effectively with only one drug, with no potential candidates in the pipeline. In our opinion, swift action is needed, as resistance could rapidly close the window of opportunity for testing vaccines under the umbrella of safe and effective drugs. Feasibility Problems posed by the long-term relationship helminths and protozoa tend to establish with their hosts clearly complicate vaccine development, but the successful use of defined molecular vaccines against parasites of livestock6 is encouraging. Further support is provided by the exceptionally effective, practical vaccines7 developed against cystocercosis in sheep and cattle, and the prospects for introduction of a Fasciola vaccine8 for veterinary use. With regard to schistosomiasis, the existence of effective immune responses, both in experimental animals and humans, has been conclusively demonstrated. However, human trials are still necessary as the mechanisms of protection differ and further 322
work, even on non-human primates, will not improve our knowledge of human protective immune reactions. While humans should not be subjected to harmful experimentation, it is equally important not to delay efforts to alleviate the problem of schistosomiasis in endemic areas. We feel that schistosomiasis cannot be defeated with chemotherapy alone, but rather than arguing the advantages of drugs versus vaccines, we suggest that these approaches are not mutually exclusive, as drugs provide short-term reduction of morbidity, while vaccines hold the promise of long-term prevention. The development of a human vaccine is a long-term endeavour, but there are reasons to be optimistic. The strong protection reached with irradiated cercariae in experimental animals is the proof of principle, while practice is supported by studies showing human protective immune responses resulting in various degrees of resistance to infection. Gryseels feels that antigens eliciting natural immune responses are unlikely vaccine candidates and remains unimpressed by the notion of protective immunity. His first objection may well be correct, but it is also possible that the immune system is modulated in some general way, or by the schistosomes themselves, not to overreact to any antigen. The point is, however, that the mouse data was only one factor leading to the decision to recommend moving forward, when appropriate, towards human trials. Numerous studies in other animals and in humans provide support for the contended trials. Gryseels is critical of the imprecision of the measurements of the immunological, parasitological and behavioural parameters in investigations of age-related resistance, but the methodologies used were not any less precise than those employed in Burundi9, Senegal10 and Kenya11, which he uses to support his case. Without denying that behavioural, hormonal and physiological factors might play a role, decades of field research have produced irrefutable evidence that people living in endemic areas do develop various degrees of immunological protection against re-infection. The crucial protective immunological mechanisms that contribute to resistance in humans may
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well be diverse but [while not excluding a potential role for T helper cell type 1 (Th1) responses], the evidence favouring a role for Th2-type responses in protection is accumulating and is consistent with both epidemiological and biological observations (Ref. 12, M. Al-Sherbiny et al., unpublished). An early report of the role of IgE in the development of protective immunity, for example, showed that humans with high specific IgE levels remained negative despite continued water contact in an endemic area13; recent work confirms that human susceptibility to Schistosoma mansoni infection is genetically controlled14. This showed that humans who are homozygous for genes in the SM1 locus on chromosome 5, which encodes the cytokines regulating the development of Th-cell responses, show increased levels of interleukin (IL)-4 and IL-5 and have generally lower egg outputs14. Further support for the importance of the Th2-cell cytokine profiles comes from studies in the Philippines demonstrating an anti-paramyosin IgA antibody associated with protection15. But we should retain an open mind – there is no necessity for a schistosome vaccine to replicate the immune responses generated in naturally exposed humans. Indeed, it can be argued that the stimulation of a response to which the parasite has not evolved a successful evasion strategy might lead to enhanced protection. Safety Clearly, safety is a vital issue. No vaccinations are carried out without appropriate risk assessment and the procedure is no more different or more harmful than the way industry assesses the safety and efficacy of new drugs. The development of the anti-schistosomiasis drug Oltipraz is well known for showing great promise during animal testing, only to be stopped due to side effects in humans which, incidentally, emphasizes the absolute necessity for clinical trials. Likewise, all vaccine candidates must pass rigorous safety testing with no molecule being advanced if it carries a perceivable risk. Although the first trials (Phase Ia, Ib etc.) provide data on immunogenicity, they are designed primarily to assess potential health hazards. Recent Phase Ia Parasitology Today, vol. 16, no. 8, 2000
Comment and Phase Ib trials [supported by the European Union (EU) and with independent observers provided by WHO] of Bilhvax, the first schistosomiasis vaccine to be tested in humans, have demonstrated its safety and its excellent immunogenicity (A. Capron pers. commun.). The Phase II trials (and those beyond) focus on protection, but this does not mean that the safety aspect is disregarded. Individuals who opt for selection and participation in vaccine trials are well aware of what is involved, and appreciate the advantage of access to careful medical examination and treatment. Schistosomiasis vaccines pose many problems, but the basic ground rules for their testing are common to all vaccines. Assessment of Efficacy As Gryseels describes, vaccine trials will be based on follow-up after reinfection. The rate of any re-infection cannot be predicted easily in advance of a vaccine trial. Nevertheless, the knowledge gained from many treatment and re-infection studies suggests that the rate of re-infection will not pose severe restrictions on the likelihood of success of the trials. Similarly, vaccine studies can be designed to allow treatment of eggpositive individuals without undermining the end point of the trials. Gryseels correctly indicates that egg counts and detection of circulating antigens do not distinguish between protection from infection and anti-fecundity. While such measurements will be central to the vaccine trials, a successful vaccine must reduce pathology, and it can be argued that, from a practical point of view, the mechanism matters less than the result. If a vaccine reduces egg counts, then it might reduce diagnostic possibilities; however, praziquantel might do the same16, yet no serious medical or ethical issues have been raised against the use of drugs. With respect to the impact of vaccination on morbidity, data from Tanzania suggest that chemotherapy may not always have a lasting impact on egg counts and pathology17. Although they will be difficult to perform, there is no reason why schistosomiasis vaccine trials should not be done. The available diagnostic techniques will offer a valuable insight into the impact of vaccination on egg excretion, worm burdens and pathology. While the trials are not perfect, they are the best we are likely to have for the foreseeable future. In any case, in the early vaccine trials, egg excretion can be measured with more sensitivity than in routine diagnostics by relying on more and larger samples. Parasitology Today, vol. 16, no. 8, 2000
Development and Vaccines Schistosomiasis may be considered as one indicator of a lack of the basic requirements of safe water, sanitation education and health care. A schistosomiasis vaccine is not intended to solve the problems of social, economic and political inequity. It is designed simply to deal with the disease; other problems have to be addressed elsewhere. It is likely that an effective schistosomiasis vaccine can be made more easily and speedily (and more cheaply) than the problem of social injustice can be remedied. The development of a schistosomiasis vaccine will neither mask important underlying social issues nor influence political commitment to basic human needs, any more than did the introduction of praziquantel.
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The Future Perhaps it is too optimistic to hope that all of the current schistosome vaccine candidate antigens will prove successful – only time will tell. Artificial immunization presents an awesome challenge, but this is matched by powerful technological advances in genomics and proteomics, which offer renewed hope for the development of novel chemotherapeutics and vaccines. We are at a critical stage and can only hope that Gryseels’ reservations will, to use his own words, ‘…not stop anybody from pursuing or funding research on the immunology or control of schistosomiasis’1. Acknowledgements The authors thank the many schistosomiasis researchers who offered comments on the early drafts of this text. References 1 Gryseels, B. (2000) Schistosomiasis vaccines: a Devil’s advocate view. Parasitol. Today 16, 46–48 2 Picquet, M. et al. (1998) Efficacy of praziquantel against Schistosoma mansoni in northern Senegal. Trans. R. Soc. Trop. Med. Hyg. 92, 90–93 3 Cioli, D. (1998) Chemotherapy of schistosomiasis: an update. Parasitol. Today 14, 418–422 4 Fallon, P.G. et al. (1994) Drug-resistant schistosomiasis: resistance to praziquantel and oxamniquine induced in Schistosoma mansoni in mice is drug specific. Am. J. Trop. Med. Hyg. 51, 83–88 5 Ismail, M. et al. (1999) Resistance to praziquantel: direct evidence from Schistosoma mansoni isolated from Egyptian villagers. Am. J. Trop. Med. Hyg. 60, 932–935 6 Smith, W.D. (1999) Prospects for vaccines of helminth parasites of grazing ruminants. Int. J. Parasitol. 29, 17–24 7 Lightowlers, M.W. (1999) Eradication of Taenia solium cysticercosis: a role for vaccination of pigs. Int. J. Parasitol. 29, 811–817 8 Muro, A. et al. (1997) Fasciola hepatica: vaccination of rabbits with native and
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recombinant antigens related to fatty acid binding proteins. Vet. Parasitol. 69, 219–229 Gryseels, B. (1994) Human resistance to schistosome infections: age or experience? Parasitol. Today 10, 380–384 Stelman, F.F. et al. (1993) Epidemiology of Schistosoma mansoni infection in a recently exposed community in northern Senegal. Am. J. Trop. Med. Hyg. 49, 701–706 Ouma, J.H. et al. (1998) The development of schistosomiasis mansoni in an immunologically naive immigrant population in Masongaleni, Kenya. Parasitology 117, 123–132 Ribeiro de Jesus, A. et al. Human immune responses to Schistosoma mansoni vaccine candidate ant gen. Infect. Immun. (in press) Hagan, P. et al. (1991) Human IgE, IgG4 and resistance to reinfection with Schistosoma haematobium. Nature 349, 243–245 Rodrigues, V. Jr et al. (1999) Genetic control of schistosome infections by the SM1 locus of the 5q31-q33 region is linked to differentiation of type 2 helper T lymphocytes. Infect. Immun. 67, 4689–4692 Hernandez, M.G. et al. (1999) Paramyosin is a major target of the human IgA response against Schistosoma japonicum. Parasite Immunol. 2, 641–647 Mutapi, F. et al. Chemotherapy accelerates the development of acquired immune responses to Schistosoma haematobium infection. J. Infect. Dis. 1998 178, 289–293 Hatz, C.F. et al. (1998) Evolution of Schistosoma haematobium – related pathology over 24 months after treatment with praziquantel among school children in southeastern Tanzania. Am. J. Trop. Med. 59, 775–781
Paul Hagan is at the Division of Infection and Immunity, IBLS, University of Glasgow, UK G12 8QQ. Mike Doenhoff is at the School of Biological Sciences, University of Wales, Bangor, Gwynedd, UK LL57 2UW. Alan Wilson is at the Department of Biology, University of York, York, UK YO1 5YW. Maged Al-Sherbiny is at the Egyptian Reference Diagnostics Centre, Cairo, Egypt. Robert Bergquist is at the World Health Organization, Geneva, Switzerland. Tel: +44 141 330 5765, Fax: +44 141 330 5765, e-mail:
[email protected]
NB see Letters, this issue.
Articles of interest from other Trends journals • Malaria sex ratios, by S.E. Reece and A.F. Read (2000) Trends in Ecology & Evolution 15, 259–260 • Common molecular mechanisms of symbiosis and pathogenesis, by U. Hentschel, M. Steinert and J. Hacker (2000) Trends in Microbiology 8, 226–231 • Sex in the worm: counting and compensating X-chromosome dose, by B.J. Meyer (2000) Trends in Genetics 16, 247–253 • Artificial chromosomes: ideal vectors? by W.R.A. Brown, P.J. Mee and M.H. Shen (2000) Trends in Biotechnology 18, 218–223 • Do antibiotics maintain antibiotic resistance? by J.A. Heinemann, R.G. Ankenbauer and C.F. Amàbile-Cuevas (2000) Drug Discovery Today 5, 195–204
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