Schistosomiasis Vaccines: The Need for More Research before Clinical Trials

Techniques The flexibility of branching processes allows them to be applied in many scientific disciplines, from population genetics to subatomic particle physics. Branching processes provide a versatile tool for parasitologists who would like to construct simple quantitative models of their system, or derive parameters for use in statistical analysis. We hope that our brief introduction might also serve as a first step in understanding more complex stochastic processes. Acknowledgements We thank Chris Tofts, Margaret Mackinnon and two anonymous reviewers for helpful comments. DET is supported by NERC (PDRA grant GR3/10261); AMD by a NERC Fellowship (GT5/F/92/ALS/1); and MJH by a Royal Society Dorothy Hodgkin Research Fellowship (502008.K505). References 1 Kermack, W.O. and McKendrick, A.G. (1927) Contributions to the mathematical theory of epidemics, Part I. Proc. R. Soc. Edinburgh A 115, 700–721 2 Anderson, R.M. and May, R.M. (1991) Infectious Diseases of Humans, Dynamics and Control, Oxford University Press 3 Hethcote, J. (1994) Frontiers in Theoretical Biology. Lecture Notes in Biomathematics 100 (Levin, S., ed.), Springer-Verlag 4 Anderson, R.M. and May, R.M. (1979) Population biology of infectious diseases: Part I. Nature 280, 361–367 5 Bailey, N.J.T. (1975) The Mathematical Theory of Infectious Diseases and Its Application, Griffin 6 Rigaud, T., Mocquard, J.P. and Juchault, P. (1992) The spread of parasitic sex factors in populations of Armadillidium vulgare Latr. (Crustacea, Oniscidea): effects on sex ratio. Gen. Sel. Evol. 24, 3–18 7 Watson, H.W. and Galton, F. (1874) On the probability of extinction of families. J. Anthropol. Inst. Great Britain and Ireland 4, 138–144 8 Dobson, A. and Grenfell, B. (1995) in Ecology of Infectious Diseases in Natural Populations (Grenfell, B. and Dobson, A., eds), pp 1–19, Cambridge University Press 9 Barbour, A.D. (1994) in Probability, Statistics and Optimization (Kelly, F.P., ed.), pp 101–116, John Wiley 10 Barbour, A.D., Heesterbeek, J.A.P. and Luchsinger, C.J. (1996) Thresholds and initial growth rates in a model of parasitic infection. Ann. Appl. Prob. 6, 1045–1074

11 Diekmann, O., Heesterbeek, J.A.P. and Metz, J.A.J. (1990) On the definition and the computation of the basic reproduction rate R0 in models for infectious diseases in heterogeneous populations. J. Math. Biol. 28, 365–382 12 Schaffer, H.E. (1970) in Mathematical Topics in Population Genetics (Kojima, K., ed.), pp 317–336, Springer-Verlag 13 Mackinnon, M.J. (1997) Survival probability of drug resistant mutants in malaria parasites. Proc. R. Soc. London Ser. B 264, 53–59 14 Quinn, B.G. and MacGillivray, H.L. (1986) Normal approximations to discrete unimodal distributions. J. Appl. Prob. 23, 1013–1018 15 Kemp, A.W. and Newton, J. (1990) Certain state-dependent processes for dichotomised parasite populations. J. Appl. Prob. 27, 251–258 16 Griffiths, D.A. (1973) Multivariate birth-and-death processes as approximations to epidemic processes. J. Appl. Prob. 10, 15–26 17 Dunn, A.M. et al. (1995) Evolutionary ecology of vertically transmitted parasites: transovarial transmission of a microsporidian sex ratio distorter in Gammarus duebeni. Parasitology 111, S91–S109 18 Hatcher, M.J. and Dunn, A.M. (1995) Evolutionary consequences of sex ratio distortion by cytoplasmically inherited feminizing factors. Proc. R. Soc. London Ser. B 348, 445–456 19 Dunn, A.M, Terry, R.S. and Taneyhill, D.E. (1998) Within-host transmission strategies of transovarial, feminizing parasites of Gammarus duebeni. Parasitology 117, 21–30 20 Smith, J.E. and Dunn, A.M. (1991) Transovarial transmission. Parasitol. Today 7, 146–148 21 Werren, J.H. (1997) Biology of Wolbachia. Annu. Rev. Entomol. 42, 587–609 22 Daley, D.J. (1968) Extinction conditions for certain bisexual Galton– Watson branching processes. Zeitschrift Wahrscheinlichkeitstheorie 9, 315–322 23 Athreya, K.B. and Ney, P.E. (1971) Branching Processes, SpringerVerlag 24 Harris, T.E. (1963) The Theory of Branching Processes, Springer-Verlag 25 Karlin, S. and Taylor, H. (1975) A First Course in Stochastic Processes, Academic Press 26 Resnick, S. (1992) Adventures in Stochastic Processes, Birkhäuser 27 Mollison, D., Scalia-Tomba, G. and Jacquez, J.A., eds (1991) Spread of epidemics: stochastic modelling and data analysis. Math. Biosci. 107 (Special issue) 28 Rigaud, T. and Juchault, P. (1993) Conflict between feminizing sex ratio distorters and an autosomal masculinizing gene in the terrestrial isopod Armadillidium vulgare Latr. Genetics 133, 247–252

Letters Schistosomiasis Vaccines: The Need for More Research before Clinical Trials Recently, Bergquist and Colley presented a rationale for schistosomiasis vaccine development (Box 1 in Ref. 1). However, for each of their five topics, at least one alternative justification might come out. The first rationale, that vaccines are unparalleled in providing cost-effective control of many infectious diseases, cannot be extrapolated for a parasitic disease with such a complex epidemiology, transmission, host biologic and immune variability. The second one, that high-level protection is consistently realized with irradiated cercariae, is true, but the actual vaccine candidates were selected by other strategies, not related to the irradiated cercariae experiments. The third topic states that rapid reinfection following treatment makes chemotherapy expensive. In fact, rapid reinfection is an Parasitology Today, vol. 15, no. 4, 1999

awkwardly chosen term, because it is hard to define what period of time is ‘rapid’ for reinfection for a determined endemic area. For example, in an endemic area in Brazil, with a prevalence of 40%, 5–10% of the adult population and 30–40% of the children were reinfected after two years2. This might be considered ‘rapid’ when transmission control is the target. Nevertheless, when reducing morbidity is the aim (following the guidelines of WHO), one single treatment can be sufficient to prevent the hepatosplenic form. In one endemic area this was observed for at least six years after treatment (Caatinga do Moura, Bahia)3, and in other areas even larger periods of time were reported: 14 or 20 years (Peri-Peri and Comercinho, Minas Gerais State) (N. Katz, R.S. Rocha and P. Coura Filho, unpublished). One single treatment appears to be an effective

‘vaccine’ for the prevention of hepatosplenic form of schistosomiasis. Do we need a better one? Will we be able to find it? The fourth rationale, ‘drug delivery requires a substantial infrastructure to cover all parts of an endemic area regularly’ will also be necessary for the vaccine delivery unless a single-dose vaccine gives lifelong protection. For the time being, there is not enough evidence to believe so. Moreover, regular chemotherapy administration is required only when the objective is transmission control. In addition, it is well known that for transmission control, any isolated measure does not suffice. Even effective tools, such as, chemotherapy, sanitation, water supply, sewage draining, health education and vaccine, if and when available, must be implemented in a reasonable combined way. The last statement, that expanded chemotherapy programs carry with them the spectre of drug resistance is correct, in theory. However, until now, there is no clear-cut evidence that drug resistance

0169-4758/99/$ – see front matter © 1999 Elsevier Science. All rights reserved.

165

Letters These issues must be taken into account when considering a vaccine against schistosomiasis.

occurs in significant numbers in treated (and many times re-treated) populations. The same concern can be raised against the use of vaccine. Up to now, the foremost results gained with the actual vaccine candidates is a decrease in the number of worms. Can we prevent the reoccurrence of a second generation of worms that are ‘resistant’ to vaccination? Will vaccines do better than praziquantel, which induced resistance after seven laboratory passages4? The Talmud, the Jewish book of the rabbi’s commentaries on the Bible, says that a glass half filled with water, can be seen considering the full or the empty part. Let us consider the schistosomiasis vaccine empty glass. The best six antigens selected by WHO for development produce only a decrease of 50–60% in the number of worms, and only if the experiments were performed in their

original laboratories. In two independent laboratories sponsored by the WHO, these same levels of protection could not be confirmed5. Also, the in vitro immunological responses elicited by most of the candidate antigens using human samples, cannot be presumed to represent successful protective mechanisms. If, instead of first establishing the facts, the scientific community moves to clinical trials, we may have to pay the price of experimenting on human volunteers. Much more research should be realized to answer important questions that have arisen with vaccine experiments. As Gryssels stated, ‘research should rather aim at further improving and understanding host–parasite relationships including the refinement and integration of available tools’ (quoted in Ref. 1).

Naftale Katz Laboratório de Esquistossomose Centro de Pesquisas ‘René Rachou’ Fundação Oswaldo Cruz Av. Augusto de Lima, 1715 – Barro Preto Belo Horizonte, MG 30.190-002 Brazil

Reply

(4) The objection that resistance against vaccination could develop is possible in principle, but is regarded as remote. To our knowledge, this has not happened with any current commercial vaccine, and schistosomes are not known to exhibit antigenic variation. As hard-core issues of schistosome vaccinology have only occasionally been brought up for discussion, we are pleased that Katz points out that there are problems that must be solved before vaccination can become an integrated component of schistosomiasis control. With the notable exception of Basch4, no one has tackled these issues conceptually. So far, the emphasis has been only on vaccine discovery and initial experimental testing, and we must admit that nobody really knows the ‘proper’ way to produce a valid schistosome vaccine candidate for human use or how to evaluate it. In fact, even if the ideal vaccine were handed to us tomorrow, we would not know how to use it. The research needed to pose these types of questions must be started now, and it is therefore not too soon to begin asking questions regarding development. The clinical trials to be pursued in the USAID/Egyptian MOHP co-operation described in our report will require a good deal of development research before any clinical trials will be feasible. To be approved by the US Food and Drug Administration (FDA), the chosen candidate(s) will need to be produced in bulk under good manufacturing practice (GMP). They will then have to be evaluated in experimental model systems for toxogenicity and clinical grade purity and, assuming that this status is achieved, they will subsequently have to be tested for safety (and, to some extent, for immunogenicity) in Phase I clinical trials in both the USA and Egypt. It can be expected that a great deal will be learned from such activities in regard to the candidates and, perhaps just as importantly, in regard to how to run clinical trials. The

studies will first be carried out at an NIAID/NIH Vaccine Testing and Evaluation Unit (VTEU) with Egyptian participation, followed by the establishment of a national VTEU in Egypt, before any clinical trials are initiated. The ‘research aspect’ of such an undertaking may be difficult to grasp, but it will very definitely be a learning experience to develop and use a VTEU in a region that is currently lacking such a facility. In addition, this undertaking should greatly benefit the MOHP of the Government of Egypt in their push for national biotechnology and pharmaceutical industrial development. Beyond Phase I, clinical trials will require truly challenging research at the epidemiologic and immunologic frontiers of schistosomiasis such as, for example, searching for clinical correlates of immunity, deciding on case definitions that will hold up on a population basis, determining what ‘gold standard’ will be used for monitoring infection. Most currently commercially available vaccines required many Phase I clinical trials before a successful vaccine was marketed. Invariably those Phase I trials did not wait until the candidate in front failed before getting started, and it is not realistic to think that we should not do the same for schistosomiasis. If we wait until the perfect candidate is discovered, expressed and produced according to GMP before confronting the difficult problems and challenging questions that will surround the testing and use of a schistosomiasis vaccine, we will not have served our public health roles well. It serves as notice that a safe and effective veterinary vaccine, based on a recombinant antigen from the cestode sheep parasite Taenia ovis2, in spite of a decade of subsequent research and development has yet to be used routinely3. We are worried that science dedicated to producing vaccines, particularly vaccines against parasitic diseases, ends up against hurdles in the real world of commerce and politics that could arrest the use of potentially effective tools. To push ahead

In the title of his comment on our report1, Katz suggests that there is a need for more research on vaccines against schistosomiasis. We agree entirely with this, and would like to emphasize that the considerations he says cannot be neglected, have not been, nor will be, ignored. In fact, one of the meetings reported on, focused on these very issues. The intent is that research, and consequent development, will occur by heading down the road to clinical trials. The conclusions of the meetings in Cairo do not represent a move away from research but rather towards the practical aspects of vaccine studies that embrace continued research to fuel this development. We see it as a pivotal change that a group of schistosome investigators agreed that it is time to move from research only, to research and development. We would like to respond to the specific points raised. (1) The extrapolation can be made, as we expect the vaccine to be effective or it would not go forward in each respective stage of the evaluation. Naturally, an anthelmintic vaccine constitutes a challenge but there is evidence2,3 that the issues involved can be dealt with successfully at the research level. (2) Even if the majority of the candidates (with the exception of IrV-5) were not selected from antigens involved in the response against irradiated cercariae, they might still be as effective. The irradiated model represents no more than proof of principle. (3) Katz is right in pointing out that ‘rapid’ has not been defined in the context of reinfection. However, the issue is really the requirement of retreatment, be it three years, five years, or longer, between interventions. An effective vaccine could overcome such logistic and economic strains, especially as transmission would continue and booster-stimulation occur through water contact. 166

0169-4758/99/$ – see front matter © 1999 Elsevier Science. All rights reserved.

References 1 Bergquist, R.N. and Colley, D.G. (1998) Parasitol. Today 14, 99–104 2 Katz, N. et al. (1978) Rev. Inst. Med. Trop. São Paulo 20, 273–278 3 Bina, J.C. (1980) Rev. Méd. da Bahia 26, 9–14 4 Fallon, P.G. and Doenhoff, M.J. (1994) Am. J. Trop. Med. Hyg. 51, 83–88 5 WHO (1996) TDR News 50, 8–9

Parasitology Today, vol. 15, no. 4, 1999