The specific IgA antibody responses to the protective recombinant Schistosoma mansoni 28-kDa glutathione-S-transferase (Sm28GST) Ag and to derived synthetic peptides have been evaluated before and 6 mo after chemotherapy in S. mansoni-infected patients from Kenya. These studies revealed a parallelism between the age-dependent evolution of IgA antibody levels to Sm28GST and to one synthetic peptide (115-131) and the acquisition of resistance to reinfection. Functional analysis revealed that IgA antibodies to Sm28GST displayed a potent neutralizing effect on the enzymatic properties of the molecule, and also markedly impaired schistosome fecundity, by limiting both the egg laying of mature worms and the hatching capacity of schistosome eggs into viable miracidia. These results suggest that, in addition to IgE, IgA antibodies might participate in the protective immune response against schistosomiasis.

IgA Antibodies to a Protective Antigen in Human Schistosomiasis Mansoni

Schistosomiasis, caused mainly by S. mansoni, S. haematobium and S. japonicum, continues to be a serious tropical disease and public health problem resulting in an unacceptably high level of morbidity in countries where it is endemic. Praziquantel, the only drug currently available for treatment, is unable to kill developing schistosomes, it does not prevent re-infection and its continued extensive use may result in the future emergence of drug-resistant parasites. This scenario provides impetus for the development and deployment of anti-schistosome vaccines to be used as part of an integrated approach for the prevention, control and eventual elimination of schistosomiasis. This review considers the present status of candidate vaccines for schistosomiasis, and provides some insight on future vaccine discovery and design.

/pdf/schistosomiasis-vaccines-where-do-we-stand-3cfx0odhr3.pdf

Schistosomiasis vaccines: where do we stand?

Schistosomes: the road from host–parasite interactions to vaccines in clinical trials

Background 
Treatment of urinary schistosomiasis by chemotherapy remains challenging due to rapid re-infection and possibly to limited susceptibility to praziquantel treatment. Therefore, therapeutic vaccines represent an attractive alternative control strategy. The objectives of this study were to assess the safety and tolerability profile of the recombinant 28 kDa glutathione S-transferase of Schistosoma haematobium (rSh28GST) in healthy volunteers, and to determine its immunogenicity.


Methodology 
Volunteers randomly received 100 µg rSh28GST together with aluminium hydroxide (Alum) as adjuvant (n = 8), or Alum alone as a comparator (n = 8), twice with a 28-day interval between doses. A third dose of rSh28GST or Alum alone was administered to this group at day 150. In view of the results obtained, another group of healthy volunteers (n = 8) received two doses of 300 µg of rSh28GST, again with a 28-day interval. A six-month follow-up was performed with both clinical and biological evaluations. Immunogenicity of the vaccine candidate was evaluated in terms of specific antibody production, the capacity of sera to inhibit enzymatic activity of the antigen, and in vitro cytokine production.


Principal Findings 
Among the 24 healthy male participants no serious adverse events were reported in the days or weeks after administration. Four subjects under rSh28GST reported mild reactions at the injection site while a clinically insignificant increase in bilirubin was observed in 8/24 subjects. No hematological nor biochemical evidence of toxicity was detected. Immunological analysis showed that rSh28GST was immunogenic. The induced Th2-type response was characterized by antibodies capable of inhibiting the enzymatic activity of rSh28GST.


Conclusions 
rSh28GST in Alum did not induce any significant toxicity in healthy adults and generated a Th2-type immune response. Together with previous preclinical results, the data of safety, tolerability and quality of the specific immune response provide evidence that clinical trials with rSh28GST could be continued in humans as a potential vaccine candidate against urinary schistosomiasis.

/pdf/safety-and-immunogenicity-of-rsh28gst-antigen-in-humans-xjpxd5zqlx.pdf

Safety and immunogenicity of rSh28GST antigen in humans: phase 1 randomized clinical study of a vaccine candidate against urinary schistosomiasis.

Protection of cattle against Fasciola hepatica infection by vaccination with glutathione S-transferase

A member of the glutathione S-transferase family, Sm28GST has previously demonstrated a good ability to protect rodents against experimental infection with Schistosoma mansoni. In order to evaluate its efficacy in a model closer to man, two different protocols of immunization with recombinant Sm28GST were tested on baboons in a large-scale trial. Three injections in the presence of aluminium hydroxide as adjuvant resulted in a significant 38% reduction in the adult worm burden together with a trend for a lower percentage of inflammatory tissue in the liver. Individual levels of protection, ranging from 0 to 80%, underlined the heterogeneity of the immune response to this purified molecule in outbred primates. On the other hand, two injections of Sm28GST in the presence of aluminium hydroxide and Bordetella pertussis reduced female schistosome fecundity by 33%, with a more pronounced effect (66%) on faecal egg output; there was also a trend, in this protocol, for decrease of the mean granuloma surface in the liver. Individual anti-Sm28GST IgG antibodies were apparently unrelated to levels of immunity, but there was partial evidence that cytophilic IgE might play a role in the immune mechanisms affecting worm viability, but not fecundity. In the mouse model, Sm28GST vaccination resulted in a lower hatching ability of tissue eggs recovered from immunized mice whereas passive transfer of specific anti-Sm28GST T-lymphocytes, one day before infection, significantly reduced the number of eggs in the liver of mice. We propose that different protocols of immunization with a recombinant molecule can impede Schistosoma mansoni worm viability and fecundity, but can also affect miracidium physiology, with important consequences for disease transmission and granuloma-derived pathology.

Immunization of mice and baboons with the recombinant Sm28GST affects both worm viability and fecundity after experimental infection with Schistosoma mansoni.

Reactivating the phototransduction cascade with a mutation agnostic gene therapy preserves vision in rod-cone dystrophies


 Rod-cone dystrophy (RCD), also known as retinitis pigmentosa, is a group of inherited disorders characterized by rod degeneration followed by degeneration of peripheral cones, leaving patients with tunnel vision in mid stages and blindness in the latest stages. Previous studies expressed microbial chloride pumps, in degenerating cone photoreceptors to restore these cells’ activity and prolong vision. Microbial opsins lack intracellular signal amplification, requiring high light intensities. To develop a more sensitive strategy; we examined the phototransduction cascade in degenerating cones, in two RCD mouse models. We found that opsin and arrestin expression is maintained in the soma during outer segment degeneration. We thus hypothesized that cone reactivation based on cone opsin signaling may be feasible by expressing a target channel activated by G proteins recruited by cone opsin. Adeno-associated viral (AAV) mediated expression of G protein coupled inwardly rectifying K (GIRK) channel provided improvements in visual function in two RCD mouse models with mutations in two distinct genes. Importantly, we confirmed cone opsin and cone arrestin expression in cones of late-stage RCD patients, validating the rationale of GIRK-mediated gene therapy in humans. We propose GIRK channel expression in cones as a new approach to maintain high acuity, high sensitivity, color vision in RCD independently of the underlying mutation.

/pdf/reactivating-the-phototransduction-cascade-by-universally-2kpli4v5.pdf

Reactivating the phototransduction cascade by universally applicable gene therapy preserves retinal function in Rod-Cone dystrophy

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Immunization of mice and baboons with the recombinant Sm28GST affects both worm viability and fecundity after experimental infection with Schistosoma mansoni.

Reactivating the phototransduction cascade with a mutation agnostic gene therapy preserves vision in rod-cone dystrophies

Reactivating the phototransduction cascade by universally applicable gene therapy preserves retinal function in Rod-Cone dystrophy