Schistosome vaccines: a critical appraisal

An effective schistosome vaccine is a desirable control tool but progress towards that goal has been slow. Protective immunity has been difficult to demonstrate in humans, particularly children, so no routes to a vaccine have emerged from that source. The concept of concomitant immunity appeared to offer a paradigm for a vaccine operating against incoming larvae in the skin but did not yield the expected dividends. The mining of crude parasite extracts, the use of monoclonal antibodies and protein selection based on immunogenicity produced a panel of vaccine candidates, mostly of cytoplasmic origin. However, none of these performed well in independent rodent trials, but glutathione-S-transferease from Schistosoma haematobium is currently undergoing clinical trials as an anti-fecundity vaccine. The sequencing of the S. mansoni transcriptome and genome and the development of proteomic and microarray technologies has dramatically improved the possibilities for identifying novel vaccine candidates, particularly proteins secreted from or exposed at the surface of schistosomula and adult worms. These discoveries are leading to a new round of protein expression and protection experiments that will enable us to evaluate systematically all the major targets available for immune intervention. Only then will we know if schistosomes have an Achilles' heel.

The identification and characterization of new immunogenic egg components: implications for evaluation and control of the immunopathogenic T cell response in schistosomiasis

In schistosomiasis, granuloma formation to parasite eggs signals the beginning of a chronic and potentially life-threatening disease. Granulomas are strictly mediated by CD4+ T helper (Th) cells specific for egg antigens; however, the number and identity of these T cell-sensitizing molecules are largely unknown. We have used monoclonal T cell reagents derived from egg-sensitized individuals as probes to track down, isolate and positively identify several egg antigens; this approach implicitly assures that the molecules of interest are T cell immunogens and, hence, potentially pathogenic. The best studied and most abundant egg component is the Sm-p40 antigen. Sm-p40 and its peptide 234-246 elicit a strikingly immunodominant Th-1-polarized response in C3H and CBA mice, which are H-2k strains characterized by severe egg-induced immunopathology. Two additional recently described T cell-sensitizing egg antigens are Schistosoma mansoni phosphoenolpyruvate carboxykinase (Sm-PEPCK) and thioredoxin peroxidase-1 (Sm-TPx-1). In contrast to Sm-p40, both of these molecules induce a more balanced Th-1/Th-2 response, and are relatively stronger antigens in C57BL/6 mice, which develop smaller egg granulomas. Importantly, Sm-p40 and Sm-PEPCK have demonstrated immunogenicity in humans. The findings in the murine model introduce the important notion that egg antigens can vary significantly in immunogenicity according to the host's genetic background. A better knowledge of the principal immunogenic egg components is necessary to determine whether the immune responses to certain antigens can serve as indicators or predictors of the form and severity of clinical disease, and to ascertain whether such responses can be manipulated for the purpose of reducing pathology

From allergy to schistosomes: role of Fc receptors and adhesion molecules in eosinophil effector function

The dual function of eosinophils has been evidenced in protective immunity against parasites as well as in pathological manifestations during allergic disorders. We have demonstrated that a new class of IgE receptors, Fc etha RII/CD23, was involved in the functional duality of eosinophils and other proinflammatory cells. More recently, we have shown that Fc etha RI, the high affinity IgE receptor thought to be only expressed by basophils and mast cells, was involved in eosinophil-mediated cytotoxity against schistosomes as well as in mediator release. These reults favour the view that both IgE and its receptors have been primarily associated to a protective immune response, rather than to pathology. Nor only IgE receptors but also members belonging to the family of adhesion molecules can participate as co-receptors in eosinophil effector function. The inhibitory role of monoclonal antibodies to Lewis X (Le X,CD15) or to selectins in eosinophil-mediated cytotoxicity towards schistosomes and the detection of Le X and 'selectin-like' molecules on schistosomula surface indicate a double interaction mediated by selectins and their carbohydrate ligands between eosinophils and schistosomula. These results suggest new functions for these adhesion molecules, previously known to be involved mainly in cell infiltration.

Humoral and cell mediated immune responses against Schistosoma spindale in BALB/c mice.

(BALB/c mice were infected with cercariae of Schistosoma spindale by tail immersion technique and by dropping some cercariae from a pipet onto the outer surface of the pinna of the ears. Groups of mice were removed on Days 10, 20 and 30 and tested for humoral and cell mediated immune responses using either adult worm or cercarial antigen. On Day 50 the mice were sacrificed and the worm burden was determined for each mouse. This method resulted in an infectivity rate of 89.7%. There was a significant increase in antibody titer to the adult worm antigen while no significant increase was observed for cercarial antigen over the period of the study. Results obtained for cell mediated immunity were more dramatic. There was a significant increase in foot pad swelling for adult worm antigen compared to a significant decrease for cercarial antigen during the course of the infection.

The susceptibility of adult schistosomes to immune attrition

Mouse infection models are described that demonstrate reduction of egg production in Schistosoma haematobium infections and both worm loss and reduced fecundity in S. bovis infections. Neither phenomenum could be shown in S. mansoni infected mice. The immunological basis for these anti-adult responses was inferred by comparison with infections in T-cell deprived mice and by the serum transfer of the ability to reduce a S. bovis worm burden into immunocompromised hosts. Vaccination with irradiation attenuated parasites was also shown to have consequences for the adults of a challenge infections of S. haematobium and S. bovis specifically. Prior vaccination resulted in an abrogation of the anti-fecundity and adult worm elimination that occurred in non-vaccinated similary infected mice. hese models are being used to define the targets and mechanisms involved in anti-adult attrition. A serological assay, quantitation of a circulating antigen (CAA) has been assessed for its ability to measure worm burdens of different species of schistosome in mice. This assay will be used to question whether anti-adult immunity contributes to the pattern of infection with S. mansoni and S. haematobium in man

Serodiagnosis of parasitic infections by ELISA with different antigens.

An enzyme-linked immunosorbent assay is described in which four antibodies (amoebiasis, schistosomiasis, echinococcosis and filariasis) can be tested at once. Because of the sensitivity, specificity, reproducibility and practicability this test system can be recommended as a quantitative routine test.

Serological evidence of schistosomiasis among Orang Asli from three areas of Peninsular Malaysia.

Using ELISA and COPT diagnostic tests, serological evidence of Malaysian schistosomiasis was discovered among Orang Asli populations from three areas in Peninsular Malaysia. Serum samples collected in 1975 indicated an ELISA-positive prevalence of 25% and a COPT prevalence of 11% from Pos Iskandar, Pahang and an ELISA prevalence of 13% and a COPT of 4% from Bukit Lanjan, Selangor. Resurveys at these site in 1982-1984 showed a continued presence of serological positive individuals but prevalence rates were markedly lower: 7% and 1% for ELISA and 4% and 2% for COPT at Pos Iskandar and Bukit Lanjan respectively. Snail hosts were not found at either site. The source of infection for persons living in these lowland areas remains unknown. In a third area, Kuala Tahan, Pahang, located in the foothills of the central mountain range, foci of transmission have been found near to Orang Asli settlements. The serological prevalence rate among Negrito Orang Asli in that study area was 9% for ELISA and 4% for COPT. Thirty-three of 36 COPT-positive sera produced vacuolated bleb precipates and in 31 these were the only reactions seen. The high percentage of positives producing only these precipates suggests that among Orang Asli schistosomiasis patients such reactions are not an indication of recently acquired infection as has been reported for schistosomiasis patients in the Philippines.

The circumoval precipitin test in early experimental schistosomiasis japonica.

The time of the appearance of circumoval precipitins by testing weekly blood samples of rabbits infected with light, moderate and heavy doses of cercariae of Schistosoma japonicum as well as their titers were determined. In heavy infections, circumoval precupitins appeared as early as the end of the 4th week or 28th day after cercarial penetration while the appearance of detectable levels in light infections was delayed only up to the 7th week after infection. In view of these observations, the circumoval precipitin test should be used for detection of early schistosomal infection before eggs are demonstrable in the faeces.