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British Medical Bulletin 62:139-148 (2002)
© 2002 The British Council

Vaccine development against schistosomiasis from concepts to clinical trials

André Capron, Monique Capron and Gilles Riveau

INSERM U 547, Institut Pasteur de Lille, Lille, France


   Abstract
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 Abstract
Introduction
 Effector mechanisms and clinical...
 From concepts to vaccine...
 From concepts to clinical...
 References
 
Schistosomiasis is still a major helminth infection at the beginning of the 21st century and an important public health problem in many non-industrialised countries. As the second major parasitic disease in the world after malaria, schistosomiasis affects 200 million people, 800 million being exposed to the risk of infection. It is also estimated that 20 million individuals suffer from severe consequences of this chronic and debilitating disease responsible for at least 500,000 deaths per year.


   Introduction
Top
 Abstract
 Introduction
Effector mechanisms and clinical...
 From concepts to vaccine...
 From concepts to clinical...
 References
 
Infection is characterized by the presence of adult worms in the portal and mesenteric veins of humans and various mammalian species, as part of a complex migratory cycle initiated by cutaneous penetration of infective larvae (cercariae) shed by infected fresh water snails. The infective larvae transform into schistosomula in the skin of appropriate hosts and over several weeks develop into sexually mature, egg laying worms. It is agreed that in this long lasting infection (worms can survive up to 15 years) marked by a considerable female worm fecundity, the deposition of millions of eggs in mucosae and tissues (in particular liver) is the essential source of pathology and disease.

In spite of undeniable chemotherapeutic progress and the existence of active molecules such as praziquantel (PZQ), there is a considerable spreading of endemic disease, in particular in West Africa. The construction of dams and the development of important irrigation schemes are often followed by impressive epidemic outbreaks as for instance observed in the region of St Louis in Senegal. After some 20 years experience, it is generally agreed that chemotherapy shows numerous limitations. In particular, mass treatment does not affect re-infection which rapidly occurs in infected populations in most endemic areas; within a period of 6–8 months following chemotherapy, prevalence has returned to its initial level. Efficient drug delivery thus requires a substantial infrastructure to cover regularly all parts of an endemic area which makes chemotherapy an expensive approach1. In addition, although there is not yet clear evidence of the existence of PZQ resistant strains, decreased susceptibility to the drug has been observed in several countries2–4.

Vaccine strategies represent, therefore, an essential component of the control of this major helminth disease. Vaccination can be either targeted towards the prevention of infection or to the reduction of parasite fecundity. Schistosome eggs being responsible for both pathology and transmission, a vaccine targeted toward parasite fecundity and egg viability appears, therefore, entirely relevant.


   Effector mechanisms and clinical expression of immunity
Top
 Abstract
 Introduction
 Effector mechanisms and clinical...
From concepts to vaccine...
 From concepts to clinical...
 References
 
Research developed in our laboratory for over 20 years has led in a first phase to the identification in animal models and in man of in vitro mechanisms of protective immunity against infection or re-infection. At present, six vaccine candidates have been selected by the World Health Organization (WHO)1. Among them, the 28 kDa glutathione-S-transferase (GST) appears the best characterized and the most promising molecule, already under test in phase II clinical trials5.

The most significant contributions of these studies have been the demonstration in vivo of the protective role of IgE6 and eosinophils7. In humans, epidemiological correlations supporting our experimental observation arising from seven different studies in various parts of the world strongly suggest that IgE may be one of the keys to protective immunity8.

Together with IgE, high levels of IgG4 are produced during helminth infection. Preliminary evidence was first reported of a significant correlation between susceptibility to re-infection by Schistosoma mansoni in humans and increased production of IgG4 to defined schistosome antigens.9 In fact, in the following studies, elevated production of IgG4 and IgG2 antibodies was consistently associated with increased susceptibility to re-infection10. From these studies, it was concluded that immunity to re-infection was more closely related to the IgE/IgG4 balance than to the absolute level of each isotype.

Opposing effects of IgE and IgG4 were not dissociable in the analysis, indicating that these isotypes were probably antagonising each other in terms of protection. Although both IgE and IgG4 responses initially depend on IL-4 and IL-13 production, it has recently been shown that the production of IgG4 antibodies is regulated in an antigen specific context by IL-10 and IFN-{gamma} produced by Th0 cells10. This supports the view that IgE and IgG4 can be dissociated in spite of their reported dependence on IL-4. The putative role of IL-10 in the preferential induction of an IgG4 response should be placed in the broader perspective of the general properties of this cytokine. Indeed it is now well established that IL-10 prevents APC-dependent IgE synthesis and IgE-dependent cytokine release from host cells, activation of eosinophils as well as IL-5 release12.

The evidence that IL-10 has an inhibitory function toward several essential effector arms of the immune response should prompt further studies on its production profile and biological activity in human schistosomiasis.

The clinical expression of immunity to schistosome infection is obviously not simply determined by the mere balance between IgE and IgG4 antibodies. The participation of additional mechanisms observed in experimental models cannot be excluded.

Evidence for additional protective mechanisms operating in man has been provided by the recently observed relationship between IgA responses to the protective antigen Sm28GST and acquired resistance. Initial studies in the rat first indicated a potential protective role for IgA antibodies produced after vaccination with Sm28GST as well as the synergistic association of IgA and IgE antibodies in rat eosinophil-dependent cytotoxicity13.

A significant association between IgA antibodies to Sm28GST and age-dependent decrease in egg excretion in infected humans was demonstrated14. The potential protective role of IgA antibodies in human schistosomiasis, including Schistosoma haematobium and Schistosoma japonicum infection, has now been supported by a series of convergent correlation studies in several parts of the world. Within the limits of our current knowledge, the effector function of IgA antibodies appear to be associated with a decrease in female worm fecundity and egg viability15.

Confirming initial observations made in Kenyan populations,14 recent studies in Senegal have shown a significant association between the IgA response to Sm28GST and a decrease in egg excretion, whereas neutralisation of GST enzymatic activity by antibodies appears closely related to inhibition of female worm fecundity16.

IgA does not appear to be the only isotype with such neutralizing properties as IgG antibodies have also demonstrated this activity in cattle (Schistosoma mattheei), primates (S. haematobium)17 and man16. In the latter case, IgG3 to Sh28GST especially in male populations seems to be correlated with the age-dependent decrease in egg output in S. haematobium infection18. Indeed, before any treatment, a specific IgG3 response was predominant in the male population with low intensity of infection and was associated with maximal GST inhibition. In contrast, the neutralizing activity of serum samples from women with a low intensity of infection was correlated with a high specific IgA response especially directed toward a peptide constituting part of to the GST enzyme site (Fig. 1).



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  		Fig 1. Association of specific isotype response in males (in black) and females (in grey) with the Sm28GST enzymatic inhibition. Kendall's test has been used to evaluate individual correlation of the presence of specific IgG3 and IgA in male volunteers (n = 76) and female volunteers (n = 79) with the neutralizing activity of the serum. Each population has been divided into two levels of infection intensity (high and low) according to the geometric mean for both sexes and the WHO Technical Report Series, no. 830. The value of correlation coefficient r and the significance are indicated. These results have been published in Remoué et al18.

 
The potential role of IgA in immunity to schistosomes and in particular its antifecundity effect has led over the past 3 years to the development of novel strategies of mucosal immunization. Multiple vectors (synthetic or recombinant live vectors have been used in the mouse model) have now established for the first time the feasibility of inducing a protective response associated with IgA production against a systemic parasitic disease19,20 This will probably lead to second generation vaccines once the optimal delivery conditions have been defined. Another question arising from these observations concerns the regulation of the IgA response in the general framework of antischistosome immunity. Although our current knowledge of the regulation of the IgA response (notably secretory IgA production) in man remains fragmentary, there are convincing pieces of evidence which involve both Th1 and Th2 cytokines. There is also evidence that IL-10 and TGF-ß positively regulate IgA production. It has been postulated that Th3 cells which produce high amounts of TGF-ß participate significantly in IgA regulation18. This suggests that the overall cytokine pattern expressed in the context of human schistosomiasis might result from a simple (Th1/Th2) to a more sophisticated (Th0/Th3) model. Indeed, a continuously changing cytokine profile according to the different developmental stages together with a continuum of different combinations of cytokines is the most likely possibility.

Although the existence of highly complex networks of regulation does not allow any attempt at oversimplification, it is, by and large, still the case that clinical expression of protective immunity to schistosomes in human is largely associated with a Th2 profile of immune response among which distinct mechanisms (either IgE- or IgA-dependent) might be implicated in the control of infection or of egg-induced pathology.


   From concepts to vaccine development
Top
 Abstract
 Introduction
 Effector mechanisms and clinical...
 From concepts to vaccine...
From concepts to clinical...
 References
 
On the basis of these immunological studies, the identification and molecular cloning in our laboratory of a target antigen of the effector response has made it possible in the last 10 years to develop numerous approaches to exploit its vaccine potential.

At present, six vaccine candidates have been selected by the WHO (Table 1)1, among which the 28 kDa glutathione-S-transferase (28GST) is the best characterized and the most promising molecule already under test in phase II clinical trials.


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  		Table 1. Schistosome vaccine candidates

 
Identified as an enzyme, GST was initially cloned from a cDNA library from S. mansoni and named Sm28GST21. The molecule has been crystallized22 making the elucidation of its 3-dimensional structure possible. The gene encoding for Sm28GST has been fully sequenced leading to a series of studies concerning the control of protein expression23. Vaccination experiments performed with the recombinant protein (expressed in Saccharomyces cerevisiae) in various experimental models (rodents, primates and cattle) have not only led to the demonstration of the partial, but significant, protective effect of the molecule against schistosome infection (reduction of 40–60% of worm burden) but also to evidence of a very significant inhibitory effect on female worm fecundity and egg viability5. It has been further demonstrated that the inhibition of fecundity and of egg viability was associated with the inhibition of the enzymatic activity of the GST expressed in the N- (24–43) and C- (190–211) terminal regions of the molecule24. Research undertaken to identify immune mechanisms induced by vaccination and implied in the inhibition of parasite fecundity has led in animal models24 to the original demonstration of the potential role played by IgA antibodies. In infected human populations, schistosome antifecundity immunity is associated with IgA and IgG3 response together with neutralizing antibodies16.

The extension of these observations to various animal models and to several schistosome species was made possible thanks to the molecular cloning in our laboratory of the genes encoding 28GST from the various schistosome species, S. haematobium, S. japonicum, and S. bovis25. Notably, the C-terminal regions of the various schistosome GSTs, apart from S. japonicum, exhibit a remarkable degree of conservation and are very closely homologous.

Preclinical studies performed in primates by homologous and heterologous immunization26 as well as in cattle have confirmed the remarkable antiparasite fecundity or anti-egg effect achieved by vaccination, reaching 75–85% in primates and 94% in young calves27. Entirely consistent with the predictive comparison of the molecular structure of the various GSTs, although no cross protection against challenge could be induced by heterologous immunization (S. mansoni versus S. haematobium) a dramatic reduction in egg production and viability has been achieved. This effect correlated in all cases with the induction of antibodies capable of neutralizing GST after vaccination, leading to the concept of a cross-species specific antifecundity vaccine5.

It is particularly noticeable that a significant antiworm fecundity effect has now been observed in all experiments performed with GSTs of all schistosome species (including S. japonicum by homologous immunization) leading to a wider view of the function of these molecules in schistosomes.

In this context, the recent demonstration in our laboratory that schistosomes release significant amounts of prostaglandin D2 (PGD2), which regulates various stages of the immune response, and the demonstration that PGD2 synthase is an homologue of 28GST28, re-inforce our views of the key role played by this enzyme in schistosome biology29 and its relevance as a vaccine target.


   From concepts to clinical trials
Top
 Abstract
 Introduction
 Effector mechanisms and clinical...
 From concepts to vaccine...
 From concepts to clinical...
References
 
All these results have encouraged the initiation of phase I human trials to evaluate the safety and immunogenicity of the schistosome GST vaccine. Although most of our research has been primarily based on the model of S. mansoni infection, we have decided to concentrate in this initial project on S. haematobium GST (Sh28GST), the rationale being based on the following considerations:

  • It has been established that resistance to S. haematobium is strongly associated with immune-mediated inhibition of parasite fecundity.
  • The methods of quantitative evaluation of eggs in urine through filtration procedures are reliable and easier to handle than stool examination.
  • Urinary schistosomiasis provides a unique opportunity to follow by non-invasive methods (bladder and urinary tract ultrasound tomography) the evolution of inflammatory lesions associated with infection.
  • It is now well established from various surveys that in adolescents there is a rapid normalization of these indicators following chemotherapy and a rapid re-appearance following re-infection. In addition, the existence of a demonstrated synergy between the immune response and praziquantel treatment provides a unique opportunity to evaluate, under strict ethical conditions, the efficacy of the vaccine in association with chemotherapy in comparison with chemotherapy alone.

It should finally be stressed that preclinical studies in primates have clearly shown that vaccination performed either with Sm28GST or Sh28GST leads to an identical decrease in egg excretion and egg viability after S. haematobium challenge.

Sh28GST has been produced under conditions of Good Manufacturing Practice by our industrial partner (Pharos, Eurogentec, Belgium) and named Bilhvax. Phase I clinical trials were initiated in September 1998 and performed in Lille at the Center for Clinical Investigation. The main objective of this study which involved 24 healthy volunteers (Caucasian men) was the evaluation of the safety of Sh28GST immunisation and, as a secondary objective, the evaluation of immunogenicity.

Consistently with toxicity studies performed in rats, rabbits and dogs, where no systemic or local toxicity was observed and no cross reactivity with rat and human GST was detected, no adverse reactions either local or systemic were observed in human volunteers. No cross reactivity with human GST(Pi) was detected in spite of high titres of specific antibody produced. The evaluation of immunogenicity led to interesting results. Following 3 injections of 100 µg of Bilhvax in alum hydroxide, a strong immune response was elicited in all immunized individuals. A specific and significant IgG response was induced after the first administration in 6/8 vaccinated adults; the mean IgG titre increased strongly after the second injection, and all vaccinated adults had positive responses. Analysis of isotypic profiles indicated that IgG1 response was predominant, low IgG2 and IgA responses were observed, whereas strikingly high IgG3 responses were observed in 7/8 adults.

During phase Ib trials performed in St Louis, Senegal, specific antibody responses observed in healthy children after vaccination (2 injections of 100 µg of Bilhvax) showed a similar profile to vaccinated adults and a high, specific IgG3 response was observed in 10 of 12 vaccinated children.

The most striking feature of the antibody response was the production of high titres of neutralizing antibodies. In the phase Ia study, all vaccinated adults demonstrated significant titres of neutralizing antibodies which were strongly boosted after the third injection reaching a concentration of 100-fold over the IC50 usually observed in infected patients.

It was noticeable that these antibodies were able to neutralize not only the recombinant but also the native GST enzymatic activity. During phase Ib trials, as observed in adults, two injections of Sh28GST induced a high titre of neutralizing antibodies in all vaccinated children.

As anticipated, no production of Th1 cytokines was observed in phase Ia and phase Ib studies. In contrast, there was a prominent production of IL-5 and IL-13 strongly boosted after the third injection in all vaccinated individuals. Identical cytokine profiles were observed in vaccinated children during phase Ib but the production of IL-5 and IL-13 was higher and significant production of IL-2 and IL-10 was observed.

The follow-up of vaccinated individuals (for 4 months after the first injection) indicated that Bilhvax induced a high and lasting specific immune response associated with a Th2 type profile generally regarded as associated with protective immunity in human schistosomiasis30.

It is also of particular interest to observe that the major features of the immune response induced by vaccination in humans are perfectly consistent with the concepts that we had derived from our studies of experimental models. In particular, if the close association between neutralizing antibodies and the inhibition of parasite fecundity already observed in experimental models and in human infected populations can be regarded, on the basis of our results, as a surrogate marker of vaccine efficacy, then we have undoubtedly moved a significant step toward the feasibility of a clinical vaccine against one of the major human parasitic diseases31.


   Footnotes
 
Correspondence to: Prof. André Capron, INSERM U 547, Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 245, 59019 Lille Cedex, France


   References
Top
 Abstract
 Introduction
 Effector mechanisms and clinical...
 From concepts to vaccine...
 From concepts to clinical...
 References
 

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