RESUMEN
Control of schistosomiasis depends on a single drug, praziquantel, with variable cure rates, high reinfection rates, and risk of drug resistance. A vaccine could transform schistosomiasis control. Preclinical data show that vaccine development is possible, but conventional vaccine efficacy trials require high incidence, long-term follow-up, and large sample size. Controlled human infection studies (CHI) can provide early efficacy data, allowing the selection of optimal candidates for further trials. A Schistosoma CHI has been established in the Netherlands but responses to infection and vaccines differ in target populations in endemic countries. We aim to develop a CHI for Schistosoma mansoni in Uganda to test candidate vaccines in an endemic setting. This is an open-label, dose-escalation trial in two populations: minimal, or intense, prior Schistosoma exposure. In each population, participants will be enrolled in sequential dose-escalating groups. Initially, three volunteers will be exposed to 10 cercariae. If all show infection, seven more will be exposed to the same dose. If not, three volunteers in subsequent groups will be exposed to higher doses (20 or 30 cercariae) following the same algorithm, until all 10 volunteers receiving a particular dose become infected, at which point the study will be stopped for that population. Volunteers will be followed weekly after infection until CAA positivity or to 12 weeks. Once positive, they will be treated with praziquantel and followed for one year. The trial registry number is ISRCTN14033813 and all approvals have been obtained. The trial will be subjected to monitoring, inspection, and/or audits.
RESUMEN
Despite mass drug administration programmes with praziquantel, the prevalence of schistosomiasis remains high. A vaccine is urgently needed to control transmission of this debilitating disease. As some promising schistosomiasis vaccine candidates are moving through pre-clinical and clinical testing, we review the immunological challenges that these vaccine candidates may encounter in transitioning through the clinical trial phases in endemic settings. Prior exposure of the target population to schistosomes and other infections may impact vaccine response and efficacy and therefore requires considerable attention. Schistosomes are known for their potential to induce T-reg/IL-10 mediated immune suppression in populations which are chronically infected. Moreover, endemicity of schistosomiasis is focal whereby target and trial populations may exhibit several degrees of prior exposure as well as in utero exposure which may increase heterogeneity of vaccine responses. The age dependent distribution of exposure and development of acquired immunity, and general differences in the baseline immunological profile, adds to the complexity of selecting suitable trial populations. Similarly, prior or concurrent infections with other parasitic helminths, viral and bacterial infections, may alter immunological responses. Consequently, treatment of co-infections may benefit the immunogenicity of vaccines and may be considered despite logistical challenges. On the other hand, viral infections leave a life-long immunological imprint on the human host. Screening for serostatus may be needed to facilitate interpretation of vaccine responses. Co-delivery of schistosome vaccines with PZQ is attractive from a perspective of implementation but may complicate the immunogenicity of schistosomiasis vaccines. Several studies have reported PZQ treatment to induce both transient and long-term immuno-modulatory effects as a result of tegument destruction, worm killing and subsequent exposure of worm antigens to the host immune system. These in turn may augment or antagonize vaccine immunogenicity. Understanding the complex immunological interactions between vaccine, co-infections or prior exposure is essential in early stages of clinical development to facilitate phase 3 clinical trial design and implementation policies. Besides well-designed studies in different target populations using schistosome candidate vaccines or other vaccines as models, controlled human infections could also help identify markers of immune protection in populations with different disease and immunological backgrounds.
Asunto(s)
Desarrollo de Medicamentos , Enfermedades Endémicas/prevención & control , Vacunas Antiprotozoos/uso terapéutico , Schistosoma/inmunología , Esquistosomiasis/prevención & control , Animales , Coinfección , Diseño de Fármacos , Interacciones Huésped-Parásitos , Humanos , Inmunogenicidad Vacunal , Praziquantel/uso terapéutico , Vacunas Antiprotozoos/efectos adversos , Vacunas Antiprotozoos/inmunología , Schistosoma/patogenicidad , Esquistosomiasis/epidemiología , Esquistosomiasis/inmunología , Esquistosomiasis/transmisión , Esquistosomicidas/uso terapéuticoRESUMEN
Recent advances in systems biology have shifted vaccine development from a largely trial-and-error approach to an approach that promote rational design through the search for immune signatures and predictive correlates of protection. These advances will doubtlessly accelerate the development of a vaccine for schistosomiasis, a neglected tropical disease that currently affects over 250 million people. For over 15 years and with contributions of over 120 people, we have endeavored to test and optimize Sm-p80-based vaccines in the non-human primate model of schistosomiasis. Using RNA-sequencing on eight different Sm-p80-based vaccine strategies, we sought to elucidate immune signatures correlated with experimental protective efficacy. Furthermore, we aimed to explore the role of antibodies through in vivo passive transfer of IgG obtained from immunized baboons and in vitro killing of schistosomula using Sm-p80-specific antibodies. We report that passive transfer of IgG from Sm-p80-immunized baboons led to significant worm burden reduction, egg reduction in liver, and reduced egg hatching percentages from tissues in mice compared to controls. In addition, we observed that sera from Sm-p80-immunized baboons were able to kill a significant percent of schistosomula and that this effect was complement-dependent. While we did not find a universal signature of immunity, the large datasets generated by this study will serve as a substantial resource for further efforts to develop vaccine or therapeutics for schistosomiasis.
Asunto(s)
Anticuerpos Antihelmínticos/farmacología , Antígenos Helmínticos/inmunología , Helmintiasis Animal/prevención & control , Inmunización Pasiva , Vacunas/inmunología , Animales , Anticuerpos Antihelmínticos/inmunología , Modelos Animales de Enfermedad , Helmintiasis Animal/inmunología , Ratones , Ratones Endogámicos C57BL , Papio , Schistosoma mansoni , Esquistosomiasis mansoniRESUMEN
Vaccination has greatly reduced the burden of human diseases caused by infectious pathogens. Systematic development of vaccine targets requires established protocols to assess immunogenicity and efficacy of such vaccine candidates. Using a leading schistosomiasis vaccine candidate, Sm-p80, as an example, we describe standardized approaches for testing the immunogenicity and efficacy of Schistosoma mansoni vaccine targets. Unlike other parasite systems in which sterile immunity is required, the goal of S. mansoni vaccine targets is overall reduction in morbidity. Methods related to the parasitological parameters described in this chapter allow for the testing of the prophylactic (reduction in adult worm burden), anti-pathology (liver and intestine egg retention), and transmission blocking (fecal egg expulsion and egg hatching rates) efficacies for the vaccine target. The RNA sequencing approaches provide basis for identification of molecular signatures predictive of desirable outcomes for schistosomiasis vaccines.
Asunto(s)
Schistosoma mansoni/inmunología , Vacunas/inmunología , Animales , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Heces/parasitología , Femenino , Inmunidad Celular , Inmunidad Humoral , Ratones Endogámicos C57BL , Óvulo/fisiología , Parásitos/inmunología , Perfusión , PrimatesRESUMEN
BACKGROUND: Schistosomiasis continues to inflict significant morbidity and mortality in the tropical and subtropical regions of the world. The disease endemicity overlaps with the transmission of other parasitic diseases. Despite the ubiquity of polyparasitism in tropical regions, particularly in rural communities, little is known about the impact of multiple helminth infections on disease progression. In this pilot study, we describe the influence of chronic Trichuris trichiura infection on Schistosoma mansoni egg-induced hepatopathology in infected baboons. METHODS: Baboons with or without underlying whipworm infection were challenged with S. mansoni cercariae to establish schistosomiasis. Adult S. mansoni worms were recovered by perfusion and enumerated, hepatic granulomas were quantified via light microscopy, and transcriptional profiling of tissues were completed using RNA sequencing technologies. RESULTS: Co-infection with both S. mansoni and T. trichiura resulted in higher female schistosome worm burden and significantly larger liver granuloma sizes. Systems biology analyses of peripheral blood mononuclear cells (PBMC) revealed pathways associated with increased liver damage in co-infected baboons. CONCLUSIONS: Underlying chronic whipworm infection intensified schistosome egg-induced liver pathology in infected baboons. RNA-Seq analysis provided insight into pathways associated with increased liver damage, corroborating histological findings.
Asunto(s)
Coinfección/patología , Coinfección/veterinaria , Parasitosis Hepáticas/patología , Parasitosis Hepáticas/veterinaria , Esquistosomiasis/patología , Esquistosomiasis/veterinaria , Tricuriasis/patología , Tricuriasis/veterinaria , Enfermedades de los Animales/parasitología , Enfermedades de los Animales/patología , Animales , Enfermedad Crónica , Coinfección/parasitología , Femenino , Granuloma/patología , Humanos , Hígado/metabolismo , Hígado/parasitología , Hígado/patología , Parasitosis Hepáticas/parasitología , Masculino , Papio , Recuento de Huevos de Parásitos , Proyectos Piloto , Primates , Schistosoma mansoni , Esquistosomiasis/parasitología , Transcriptoma , Tricuriasis/parasitología , TrichurisRESUMEN
For decades, mass drug treatment with praziquantel (PZQ) has been utilized to treat schistosomiasis, yet reinfection and the risk of drug resistance are among the various factors precluding successful elimination of schistosomiasis. Tractable models that replicate "real world" field conditions are crucial to effectively evaluate putative schistosomiasis vaccines. Herein, we describe the cellular immune responses and cytokine expression profiles under field conditions that include prior infection with schistosomes followed by treatment with PZQ. Baboons were exposed to Schistosoma mansoni cercariae through trickle infection over 5 weeks, allowed for chronic disease to develop, and then treated with PZQ. Peripheral blood mononuclear cells (PBMCs) were monitored for cellular immune response(s) at each disease stage and PZQ therapy. After initial infection and during chronic disease, there was an increase in non-classical monocytes, NK and NKT cells while the CD4:CD8 T cell ratio inverted from a 2:1 to 1:2.5. The cytokine expressions of PBMCs after trickle infections were polarized more toward a Th2 response with a gradual increase in Th1 cytokine expression at chronic disease stage. Following PZQ treatment, with the exception of an increase in B cells, immune cell populations reverted back toward naïve levels; however, expression of almost all Th1, Th2, and Th17 cytokines was significantly increased. This preliminary study is the first to follow the cellular immune response and cytokine expression profiles in a non-human primate model simulating field conditions of schistosomiasis and PZQ therapy, providing a promising reference in predicting the immune response to future vaccines for schistosomiasis.
Asunto(s)
Antihelmínticos , Esquistosomiasis , Animales , Antihelmínticos/uso terapéutico , Leucocitos Mononucleares , Praziquantel/uso terapéutico , Primates , Esquistosomiasis/tratamiento farmacológico , Esquistosomiasis/veterinariaRESUMEN
Asiatic schistosomiasis caused by Schistosoma japonicum is a neglected tropical disease resulting in significant morbidity to both humans and animals - particularly bovines - in endemic areas. Infection with this parasite leads to less healthy herds, causing problems in communities which rely on bovines for farming, milk and meat production. Additionally, excretion of parasite eggs in feces perpetuates the life cycle and can lead to human infection. We endeavored to develop a minimally purified, inexpensive, and effective vaccine based on the 80 kDa large subunit of the calcium activated neutral protease (calpain) from S. japonicum (Sj-p80). Here we describe the production of veterinary vaccine-grade Sj-p80 at four levels of purity and demonstrate in a pilot study that minimally purified antigen provides protection against infection in mice when paired with a low-cost veterinary adjuvant, Montanide™ ISA61 VG. Preliminary data demonstrate that the vaccine is immunogenic with robust antibody titers following immunization, and vaccination resulted in a reduction of parasite eggs being deposited in the liver (23.4-51.4%) and intestines (1.9-55.1%) depending on antigen purity as well as reducing the ability of these eggs to hatch into miracidia by up to 31.6%. We therefore present Sj-p80 as a candidate vaccine antigen for Asiatic schistosomiasis which is now primed for continued development and testing in bovines in endemic areas. A successful bovine vaccine could play a major role in reducing pathogen transmission to humans by interrupting the parasitic life cycle and improving quality of life for people living in endemic countries.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Antígenos Helmínticos/farmacología , Desarrollo de Medicamentos , Vacunas Antiprotozoos/farmacología , Schistosoma japonicum/patogenicidad , Esquistosomiasis Japónica/prevención & control , Drogas Veterinarias/farmacología , Adyuvantes Inmunológicos/economía , Animales , Anticuerpos Antihelmínticos/sangre , Antígenos Helmínticos/economía , Antígenos Helmínticos/inmunología , Bovinos , Análisis Costo-Beneficio , Modelos Animales de Enfermedad , Costos de los Medicamentos , Femenino , Interacciones Huésped-Patógeno , Inmunogenicidad Vacunal , Ratones Endogámicos C57BL , Recuento de Huevos de Parásitos , Proyectos Piloto , Vacunas Antiprotozoos/economía , Schistosoma japonicum/inmunología , Esquistosomiasis Japónica/parasitología , Esquistosomiasis Japónica/transmisión , Vacunación , Drogas Veterinarias/economíaRESUMEN
Schistosomiasis is of public health importance to an estimated one billion people in 79 countries. A vaccine is urgently needed. Here, we report the results of four independent, double-blind studies of an Sm-p80-based vaccine in baboons. The vaccine exhibited potent prophylactic efficacy against transmission of Schistosoma mansoni infection and was associated with significantly less egg-induced pathology, compared with unvaccinated control animals. Specifically, the vaccine resulted in a 93.45% reduction of pathology-producing female worms and significantly resolved the major clinical manifestations of hepatic/intestinal schistosomiasis by reducing the tissue egg-load by 89.95%. A 35-fold decrease in fecal egg excretion in vaccinated animals, combined with an 81.51% reduction in hatching of eggs into the snail-infective stage (miracidia), demonstrates the parasite transmission-blocking potential of the vaccine. Substantially higher Sm-p80 expression in female worms and Sm-p80-specific antibodies in vaccinated baboons appear to play an important role in vaccine-mediated protection. Preliminary analyses of RNA sequencing revealed distinct molecular signatures of vaccine-induced effects in baboon immune effector cells. This study provides comprehensive evidence for the effectiveness of an Sm-p80-based vaccine for schistosomiasis.
Asunto(s)
Vacunas Antiprotozoos , Esquistosomiasis , Animales , Femenino , Masculino , Anticuerpos Antiprotozoarios/biosíntesis , Anticuerpos Antiprotozoarios/inmunología , Método Doble Ciego , Perfilación de la Expresión Génica , Papio , Recuento de Huevos de Parásitos , Proteínas Protozoarias/inmunología , Vacunas Antiprotozoos/administración & dosificación , Vacunas Antiprotozoos/genética , Vacunas Antiprotozoos/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los Resultados , Schistosoma mansoni/inmunología , Esquistosomiasis/prevención & control , Esquistosomiasis/transmisión , Esquistosomiasis/veterinaria , Transcripción GenéticaRESUMEN
Sm-p80, the large subunit of Schistosoma mansoni calpain, is a leading candidate for a schistosomiasis vaccine. The prophylactic and antifecundity efficacy of Sm-p80 has been tested in three animal models (mouse, hamster and baboon) using a multitude of vaccine formulations and approaches. In our continual effort to enhance the vaccine efficacy, in this study, we have utilized the adjuvant, synthetic hexa-acylated lipid A derivative, glucopyranosyl lipid A (GLA) formulated in aluminum (GLA-Alum) with recombinant Sm-p80. The rSm-p80+GLA-Alum immunization regimen provided 33.33%-53.13% reduction in worm burden in the mouse model and 38% worm burden reduction in vaccinated baboons. Robust Sm-p80-specific immunoglobulin (Ig)G, IgG1, IgG2a and IgM responses were observed in all immunized animals. The rSm-p80+GLA-Alum coadministration induced a mix of T-helper (Th) cells (Th1, Th2 and Th17) responses as determined via the release of interleukin (IL)-2, IL-4, IL-18, IL-21, IL-22 and interferon-γ.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Compuestos de Alumbre/farmacología , Antígenos Helmínticos/inmunología , Glucósidos/inmunología , Lípido A/inmunología , Schistosoma mansoni/inmunología , Receptor Toll-Like 4/agonistas , Vacunas/inmunología , Animales , Proliferación Celular , Citocinas/biosíntesis , Citocinas/genética , Femenino , Inmunidad Humoral , Ratones Endogámicos C57BL , Papio , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Recombinantes/metabolismo , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/parasitología , Linfocitos T Colaboradores-Inductores/inmunología , VacunaciónRESUMEN
Sm-p80-based vaccine efficacy for Schistosoma mansoni was evaluated in a baboon model of infection and disease. The study was designed to replicate a human vaccine implementation scenario for endemic regions in which vaccine would be administered following drug treatment of infected individuals. In our study, the Sm-p80-based vaccine reduced principal pathology producing hepatic egg burdens by 38.0% and egg load in small and large intestines by 72.2% and 49.4%, respectively, in baboons. Notably, hatching rates of eggs recovered from liver and small and large intestine of vaccinated animals were significantly reduced, by 60.4%, 48.6%, and 82.3%, respectively. Observed reduction in egg maturation/hatching rates was supported by immunofluorescence and confocal microscopy showing unique differences in Sm-p80 expression in worms of both sexes and matured eggs. Vaccinated baboons had a 64.5% reduction in urine schistosome circulating anodic antigen, a parameter that reflects worm numbers/health status in infected hosts. Preliminary analyses of RNA sequencing revealed unique genes and canonical pathways associated with establishment of chronic disease, praziquantel-mediated parasite killing, and Sm-p80-mediated protection in vaccinated baboons. Overall, our study demonstrated efficacy of the Sm-p80 vaccine and provides insight into some of the epistatic interactions associated with protection.
Asunto(s)
Praziquantel/uso terapéutico , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Vacunación/métodos , Vacunas/inmunología , Animales , Antihelmínticos/uso terapéutico , Anticuerpos Antihelmínticos/inmunología , Antígenos Helmínticos/inmunología , Enfermedad Crónica , Femenino , Humanos , Masculino , Recuento de Huevos de Parásitos , Schistosoma mansoni/efectos de los fármacos , Schistosoma mansoni/fisiología , Esquistosomiasis mansoni/parasitología , Esquistosomiasis mansoni/terapia , Resultado del Tratamiento , Vacunas/administración & dosificaciónRESUMEN
Schistosomiasis remains a serious chronic debilitating hepato-intestinal disease. Current control measures based on mass drug administration are inadequate due to sustained re-infection rates, low treatment coverage and emergence of drug resistance. Hence, there is an urgent need for a schistosomiasis vaccine for disease control. In this study, we assessed the anti-pathology efficacy of Schistosoma mansoni large subunit of calpain (Sm-p80)-based vaccine against schistosomiasis caused by infections with Schistosoma mansoni in baboons. We also evaluated the disease transmission-blocking potential of Sm-p80 vaccine. Immunisations with Sm-p80-based vaccine resulted in significant reduction of hepatic egg load in vaccinated baboons (67.7% reduction, p = 0.0032) when compared to the control animals, indicative of reduction in pathology. There was also a significant reduction in sizes of egg-induced granulomas in baboons immunised with Sm-p80 vaccine compared to their control counterparts. Egg hatching rate analysis revealed an overall 85.6% reduction (p = 0.0018) in vaccinated animals compared to the controls, highlighting the potential role of Sm-p80 vaccine in disease transmission. The findings on anti-pathology efficacy and transmission-blocking potential presented in this study have formed the basis for a large-scale double-blinded baboon experiment that is currently underway.
Asunto(s)
Hígado/inmunología , Hígado/patología , Esquistosomiasis/inmunología , Vacunas/inmunología , Animales , Humanos , Inmunoglobulina G/inmunología , Papio , Schistosoma mansoni/inmunología , VacunaciónRESUMEN
A reduction in the burden of schistosomiasis is potentially achievable by integrating a schistosomiasis vaccine with current control measures. Here, we determine parasite-specific in vitro responses of B, T, and NK cells from naive uninfected rhesus macaques to Schistosoma mansoni (Sm) egg (SmEA) and worm antigen (SmWA) preparations isolated from infected baboons. Pronounced B cell responses to SmEA and NK cell responses to both SmEA and SmWA were observed. High levels of IL-2 and IL-21 responses against Sm antigens were observed in T and non-T cells of lymph nodes (LNs) and gut lamina propria-derived lymphocytes (LPLs). Data analysis showed multifunctionality of LN-derived CD4+ , CD8+ , and CD4+ CD8+ double positive T cells against either SmWA or SmWA+SmEA antigen preparations. Distinct SmEA-specific multifunctional responses were observed in gut LPLs, suggesting simultaneous responses against egg antigens. These data provide insight into the immune effectors involved in schistosome responses by rhesus macaques.
Asunto(s)
Antígenos Helmínticos/inmunología , Enfermedades de los Monos/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/veterinaria , Animales , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Interleucina-2/inmunología , Interleucina-2/metabolismo , Interleucinas/inmunología , Interleucinas/metabolismo , Células Asesinas Naturales/inmunología , Ganglios Linfáticos/inmunología , Macaca mulatta , Enfermedades de los Monos/parasitología , Papio , Remisión Espontánea , Schistosoma mansoni/fisiología , Esquistosomiasis mansoni/parasitologíaRESUMEN
Schistosomiasis remains a major global health problem. Despite large-scale schistosomiasis control efforts, clear limitations such as possible emergence of drug resistance and reinfection rates highlight the need for an effective schistosomiasis vaccine. Schistosoma mansoni large subunit of calpain (Sm-p80)-based vaccine formulations have shown remarkable efficacy in protecting against S. mansoni challenge infections in mice and baboons. In this study, we evaluated the cross-species protective efficacy of Sm-p80 vaccine against S. japonicum and S. haematobium challenge infections in rodent models. We also elucidated the expression of Sm-p80 and Sm-p80 ortholog proteins in different developmental stages of S. mansoni, S. haematobium, and S. japonicum. Immunization with Sm-p80 vaccine reduced worm burden by 46.75% against S. japonicum challenge infection in mice. DNA prime/protein boost (1 + 1 dose administered on a single day) resulted in 26.95% reduction in worm burden in S. haematobium-hamster infection/challenge model. A balanced Th1 (IFN-γ, TNF-α, IL-2, and IL-12) and Th2 (IL-4, IgG1) type of responses were observed following vaccination in both S. japonicum and S. haematobium challenge trials and these are associated with the prophylactic efficacy of Sm-p80 vaccine. Immunohistochemistry demonstrated that Sm-p80/Sm-p80 ortholog proteins are expressed in different life cycle stages of the three major human species of schistosomes studied. The data presented in this study reinforce the potential of Sm-p80-based vaccine for both hepatic/intestinal and urogenital schistosomiasis occurring in different geographical areas of the world. Differential expression of Sm-p80/Sm-p80 protein orthologs in different life cycle makes this vaccine potentially useful in targeting different levels of infection, disease, and transmission.
Asunto(s)
Antígenos Helmínticos/inmunología , Vacunas Antiprotozoos/inmunología , Schistosoma haematobium/inmunología , Schistosoma japonicum/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis Urinaria/prevención & control , Esquistosomiasis Japónica/prevención & control , Esquistosomiasis mansoni/prevención & control , Animales , Anticuerpos Antihelmínticos/inmunología , Calpaína/inmunología , Cricetinae , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunoglobulina G/inmunología , Interleucina-12/biosíntesis , Interleucina-2/biosíntesis , Interleucina-4/biosíntesis , Masculino , Ratones , Ratones Endogámicos C57BL , Papio , Schistosoma haematobium/crecimiento & desarrollo , Schistosoma japonicum/crecimiento & desarrollo , Schistosoma mansoni/crecimiento & desarrollo , Esquistosomiasis Urinaria/inmunología , Esquistosomiasis Urinaria/parasitología , Esquistosomiasis Japónica/inmunología , Esquistosomiasis Japónica/parasitología , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/parasitología , Factor de Necrosis Tumoral alfa/biosíntesis , Vacunación , Vacunas de ADN/inmunologíaRESUMEN
Schistosomiasis is a neglected parasitic disease of major public health concern as it affects over 250 million people in developing countries. Currently there is no licensed vaccine available against schistosomiasis. The Schistosoma mansoni calpain protein, Sm-p80, is a leading vaccine candidate now ready to move to clinical trials. In order to better assess Sm-p80 vaccine immunogenicity; here we used a systems biology approach employing RNA-sequencing to identify gene signatures and epistatic interactions following Sm-p80 vaccination in mouse and baboon models that may predict vaccine efficacy. Recombinant Sm-p80 + CpG-oligodeoxynucleotide (ODN) vaccine formulation induced both cellular and humoral immunity genes with a predominant TH1 response as well as TH2 and TH17 gene signatures. Early gene responses and gene-network interactions in mice immunized with rSm-p80 + ODN appear to be initiated through TLR4 signaling. CSF genes, S100A alarmin genes and TNFRSF genes appear to be a signature of vaccine immunogenicity/efficacy as identified by their participation in gene network interactions in both mice and baboons. These gene families may provide a basis for predicting desirable outcomes for vaccines against schistosomiasis leading to a better understanding of the immune system response to vaccination.
Asunto(s)
Antígenos Helmínticos/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Vacunas/inmunología , Animales , Anticuerpos Antihelmínticos/inmunología , Epistasis Genética/genética , Epistasis Genética/inmunología , Femenino , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/inmunología , Inmunidad Celular/genética , Inmunidad Celular/inmunología , Inmunidad Humoral/genética , Inmunidad Humoral/inmunología , Masculino , Ratones Endogámicos C57BL , Oligodesoxirribonucleótidos/administración & dosificación , Oligodesoxirribonucleótidos/inmunología , Papio , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Schistosoma mansoni/metabolismo , Schistosoma mansoni/fisiología , Esquistosomiasis mansoni/parasitología , Esquistosomiasis mansoni/prevención & control , Transducción de Señal/genética , Transducción de Señal/inmunología , Transcriptoma/genética , Transcriptoma/inmunología , Vacunación/métodos , Vacunas/administración & dosificaciónRESUMEN
Mass antiparasitic drug administration programs and other control strategies have made important contributions in reducing the global prevalence of helminths. Schistosomiasis, however, continues to spread to new geographic areas. The advent of a viable vaccine and its deployment, coupled with existing control efforts, is expected to make significant headway towards sustained schistosomiasis control. In 2016, Science ranked the schistosomiasis vaccine as one of the top 10 vaccines that needs to be urgently developed. A vaccine that is effective against geographically distinct forms of intestinal/hepatic and urinary disease is essential to make a meaningful impact in global reduction of the disease burden. In this opinion article, we focus on salient features of schistosomiasis vaccines in different phases of the clinical development pipeline and highlight the Sm-p80-based vaccine which is now being prepared for human clinical trials.
Asunto(s)
Antígenos Helmínticos/inmunología , Ensayos Clínicos como Asunto , Salud Global/tendencias , Esquistosomiasis/prevención & control , Vacunas/normas , Salud Global/normas , HumanosRESUMEN
Schistosomiasis is a neglected tropical disease (NTD) of public health importance. Despite decades of implementation of mass praziquantel therapy programs and other control measures, schistosomiasis has not been contained and continues to spread to new geographic areas. A schistosomiasis vaccine could play an important role as part of a multifaceted control approach. With regards to vaccine development, many biological bottlenecks still exist: the lack of reliable surrogates of protection in humans; immune interactions in co-infections with other diseases in endemic areas; the potential risk of IgE responses to antigens in endemic populations; and paucity of appropriate vaccine efficacy studies in nonhuman primate models. Research is also needed on the role of modern adjuvants targeting specific parts of the innate immune system to tailor a potent and protective immune response for lead schistosome vaccine candidates with the long-term aim to achieve curative worm reduction. This review summarizes the current status of schistosomiasis vaccine development.
Asunto(s)
Descubrimiento de Drogas/tendencias , Esquistosomiasis/prevención & control , Vacunas/inmunología , Vacunas/aislamiento & purificación , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , PrimatesRESUMEN
Many chronic inflammatory diseases can be improved by helminth infection, but the mechanisms are poorly understood. Allergy and helminthiasis are both associated with Th2-like immune responses; thus, defining how infection with parasites leads to reduced allergy has been particularly challenging. We sought to better understand this conundrum by evaluating host-parasite interactions involved in Th2 immunity in human schistosomiasis. Immune cells were cultured with schistosomes and the effect on CD23, an IgE receptor associated with resistance in schistosomiasis, was evaluated. Cells treated with schistosomes demonstrated reduced surface CD23 levels with a parallel accumulation of soluble (s) CD23 suggesting this IgE receptor is proteolytically cleaved by the parasite. Consistent with this hypothesis, a schistosome-generated (SG)-sCD23 fragment of 15 kDa was identified. SG-sCD23 inhibited IgE from binding to CD23 and FcεRI, but lacked the ability to bind CD21. These results suggested that schistosomes target IgE-mediated immunity in immuno-evasive tactics. Based on its characteristics, we predicted that SG-sCD23 would function as an efficacious allergy preventative. Treatment of human FcεRI-transgenic mice with recombinant (r) SG-sCD23 reduced the ability of human IgE to induce an acute allergic response in vivo. In addition, an optimized form of rSG-sCD23 with an introduced point mutation at Asp258 (D258E)to stabilize IgE binding had increased efficacy compared to native rSG-sCD23. Schistosome infection may thus inhibit allergic-like protective immune responses by increasing soluble IgE decoy receptors. Allergy treatments based on this naturally occurring phenomenon may be highly effective and have fewer side effects with long-term use.
Asunto(s)
Hipersensibilidad/prevención & control , Evasión Inmune , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Adulto , Animales , Interacciones Huésped-Parásitos , Humanos , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Masculino , Ratones , Ratones Transgénicos , Receptores de IgE/administración & dosificación , Receptores de IgE/genética , Receptores de IgE/inmunología , Schistosoma mansoni/genética , Esquistosomiasis mansoni/genética , Esquistosomiasis mansoni/parasitología , Células Th2/inmunología , Adulto JovenRESUMEN
Based on data obtained using vaccine efficacy studies in mice, hamsters, and baboons, the credentials of Sm-p80 as a first tier vaccine candidate for schistosomiasis have been well established. Sm-p80-based vaccine formulation(s) have consistently exhibited potent prophylactic efficacy in reducing adult worm burden following cercarial challenge and induce killing of established adult worms in chronic infection. This vaccine is protective against both intestinal and urinary schistosomiasis. In this study, the longevity of Sm-p80-specific antibody responses was studied in mice and in baboons. Robust antibody titers were detected in mice for up to 60 weeks following vaccination with Sm-p80 recombinant vaccine (Sm-p80 + GLA-SE). In the follow-up experiments to our published studies, Sm-p80-specific IgG was also detected in baboons 5-8 years following the initial vaccination with an Sm-p80 DNA vaccine. In one baboon, transfer of Sm-p80-specific antibody was detected in umbilical cord blood and in the baby. These long-lasting humoral immune response data coupled with the vaccine efficacy data in rodents and nonhuman primates further strengthens the case for Sm-p80 to be moved forward through development leading to human clinical trials.
Asunto(s)
Anticuerpos Antihelmínticos/sangre , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/prevención & control , Vacunas/inmunología , Animales , Antígenos Helmínticos/inmunología , Biomphalaria/parasitología , Cricetinae , Femenino , Sangre Fetal/química , Sangre Fetal/inmunología , Inmunidad Materno-Adquirida , Inmunoglobulina G/sangre , Ratones , Papio , Embarazo , Schistosoma mansoni/genética , Vacunación , Vacunas de ADN/inmunologíaRESUMEN
No vaccines are available for human use for any parasitic infections, including the helminthic disease schistosomiasis. Sm-p80, the large subunit of Schistosoma mansoni calpain, is a leading antigen candidate for a schistosomiasis vaccine. Prophylactic and antifecundity efficacies of Sm-p80 have been tested using a variety of vaccine approaches in both rodent and nonhuman primate models. However, the therapeutic efficacy of a Sm-p80-based vaccine had not been determined. In this study, we evaluated the therapeutic efficacy of Sm-p80 by using 2 different strategies and 3 Sm-p80-based vaccine formulations in baboons. Vaccine formulations were able to decrease established adult worms by 10%-36%, reduce retention of eggs in tissues by 10%-57%, and decrease egg excretion in feces by 13%-33%, compared with control formulations. Marked differences were observed in B and T cell immune correlates between vaccinated and control animals. This is the first report of killing of established adult schistosome worms by a vaccine. In addition to distinct prophylactic efficacy of Sm-p80, this study adds to the evidence that Sm-p80 is a potentially important antigen with both substantial prophylactic and therapeutic efficacies. These data reinforce that Sm-p80 should be moved forward along the path toward human clinical trials.