Schistosoma mansoni infection induces plasmablast and plasma cell death in the bone marrow and accelerates the decline of host vaccine responses

Schistosomiasis is a potentially lethal parasitic disease that profoundly impacts systemic immune function in chronically infected hosts through mechanisms that remain unknown. Given the immunoregulatory dysregulation experienced in infected individuals, this study examined the impact of chronic schistosomiasis on the sustainability of vaccine-induced immunity in both children living in endemic areas and experimental infections in mice. Data show that chronic Schistosoma mansoni infection impaired the persistence of vaccine specific antibody responses in poliovirus-vaccinated humans and mice. Mechanistically, schistosomiasis primarily fostered plasmablast and plasma cell death in the bone marrow and removal of parasites following praziquantel treatment reversed the observed cell death and partially restored vaccine-induced memory responses associated with increased serum anti-polio antibody responses. Our findings strongly suggest a previously unrecognized mechanism to explain how chronic schistosomiasis interferes with an otherwise effective vaccine regimen and further advocates for therapeutic intervention strategies that reduce schistosomiasis burden in endemic areas prior to vaccination.     

Schistosomiasis vaccine development — the current picture

Development of a vaccine for schistosomiasis, a parasitic disease currently affecting over 200 million people worldwide, has been targeted as a priority by the World Health Organisation. Research demonstrating the ability of humans to acquire natural immunity to schistosome infection, together with the successful use of attenuated vaccines in animals both under laboratory and field conditions, suggest that development of a human vaccine is feasible. Attenuated vaccines for schistosomiasis are considered neither safe nor practicable for human use, however, and therefore other approaches must be considered. This review examines progress currently being undertaken in a number of different areas towards achieving the goal of a safe and effective human vaccine for schistosomiasis.     

Developing vaccines to combat hookworm infection and intestinal schistosomiasis

Hookworm infection and schistosomiasis rank among the most important health problems in developing countries. Both cause anaemia and malnutrition, and schistosomiasis also results in substantial intestinal, liver and genitourinary pathology. In sub-Saharan Africa and Brazil, co-infections with the hookworm, Necator americanus, and the intestinal schistosome, Schistosoma mansoni, are common. The development of vaccines for these infections could substantially reduce the global disability associated with these helminthiases. New genomic, proteomic, immunological and X-ray crystallographic data have led to the discovery of several promising candidate vaccine antigens. Here, we describe recent progress in this field and the rationale for vaccine development.     

Cloning and partial nucleotide sequence of Schistosoma japonicum paramyosin: a potential vaccine candidate against schistosomiasis.

, , , and 1992. Cloning and partial nucleotide sequence of Schistosoma japonicum paramyosin: a potential vaccine candidate against schistosomiasis. International Journal for Parasitology 22: 1187–1191. Paramyosin from the blood fluke, Schistosoma mansoni, has shown promise as a vaccine candidate for schistosomiasis mansoni. Here we report the cloning and partial nucleotide sequence of a cDNA encoding paramyosin from the related human parasite, Schistosoma japonicum. Affinity purified antibodies to this clone recognized a S. japonicum antigen of molecular weight 97 kDa, equivalent to the reported size of S. mansoni paramyosin. Alignment of the cDNA sequence with that of S. mansoni paramyosin revealed 90% identity. Comparison of the predicted amino acid sequences revealed 95% identity. Although these two parasites differ in many characteristics, the substantial homology demonstrated here between S. mansoni and S. japonicum paramyosin could have important implications for the development of a S. japonicum vaccine.     

Aluminum hydroxide associated to Schistosoma mansoni 22.6 kDa protein abrogates partial protection against experimental infection but not alter interleukin-10 production

The need to develop a vaccine against schistosomiasis led several researches and our group to investigate proteins from Schistosoma mansoni as vaccine candidates. Sm22.6 is a protein from S. mansoni that shows high identity with Sj22.6 and Sh22.6 (79 and 91%, respectively). These proteins are associated with high levels of IgE and protection to reinfection. Previously, we have shown that Sm22.6 induced a partial protection of 34.5% when used together with Freund's adjuvant and produced a Th0 type of immune response with interferon-g and interleukin-4. In this work, mice were immunized with Sm22.6 alone or with aluminum hydroxide adjuvant and high levels of IgG, IgG1, and IgG2a were measured. Unfortunately, no protection was detected. Since IL-10 is a modulating cytokine in schistosomiasis, we also observed a high level of this molecule in splenocytes of vaccinated mice. In conclusion, we did not observe the adjuvant effect of aluminum hydroxide associated with rSm22.6 in protective immunity.     

Distribution of Peripheral Memory T Follicular Helper Cells in Patients with Schistosomiasis Japonica

Background

Schistosomiasis is a helminthic disease that affects more than 200 million people. An effective vaccine would be a major step towards eliminating the disease. Studies suggest that T follicular helper (Tfh) cells provide help to B cells to generate the long-term humoral immunity, which would be a crucial component of successful vaccines. Thus, understanding the biological characteristics of Tfh cells in patients with schistosomiasis, which has never been explored, is essential for vaccine design.

Methodology/Principal Findings

In this study, we investigated the biological characteristics of peripheral memory Tfh cells in schistosomiasis patients by flow cytometry. Our data showed that the frequencies of total and activated peripheral memory Tfh cells in patients were significantly increased during Schistosoma japonicum infection. Moreover, Tfh2 cells, which were reported to be a specific subpopulation to facilitate the generation of protective antibodies, were increased more greatly than other subpopulations of total peripheral memory Tfh cells in patients with schistosomiasis japonica. More importantly, our result showed significant correlations of the percentage of Tfh2 cells with both the frequency of plasma cells and the level of IgG antibody. In addition, our results showed that the percentage of T follicular regulatory (Tfr) cells was also increased in patients with schistosomiasis.

Conclusions/Significance

Our report is the first characterization of peripheral memory Tfh cells in schistosomasis patients, which not only provides potential targets to improve immune response to vaccination, but also is important for the development of vaccination strategies to control schistosomiasis.     

Towards a vaccine for onchocerciasis

In 1985, the Edna McConnell Clark Foundation initiated a 15-year program to support immunologic and molecular biology approaches to onchocerciasis research. This research extended the previous support provided by the Edna McConnell Clark Foundation towards a vaccine for schistosomiasis and initiated research that would have direct relevance to >2 billion people infected with filaria or other parasitic helminthes. This report describes the strategy and structuring of this program, and introduces a series of articles highlighting recent scientific achievements towards a vaccine for onchocerciasis.     

An Immunomics Approach to Schistosome Antigen Discovery: Antibody Signatures of Naturally Resistant and Chronically Infected Individuals from Endemic Areas

Schistosomiasis is a neglected tropical disease that is responsible for almost 300,000 deaths annually. Mass drug administration (MDA) is used worldwide for the control of schistosomiasis, but chemotherapy fails to prevent reinfection with schistosomes, so MDA alone is not sufficient to eliminate the disease, and a prophylactic vaccine is required. Herein, we take advantage of recent advances in systems biology and longitudinal studies in schistosomiasis endemic areas in Brazil to pilot an immunomics approach to the discovery of schistosomiasis vaccine antigens. We selected mostly surface-derived proteins, produced them using an in vitro rapid translation system and then printed them to generate the first protein microarray for a multi-cellular pathogen. Using well-established Brazilian cohorts of putatively resistant (PR) and chronically infected (CI) individuals stratified by the intensity of their S. mansoni infection, we probed arrays for IgG subclass and IgE responses to these antigens to detect antibody signatures that were reflective of protective vs. non-protective immune responses. Moreover, probing for IgE responses allowed us to identify antigens that might induce potentially deleterious hypersensitivity responses if used as subunit vaccines in endemic populations. Using multi-dimensional cluster analysis we showed that PR individuals mounted a distinct and robust IgG1 response to a small set of newly discovered and well-characterized surface (tegument) antigens in contrast to CI individuals who mounted strong IgE and IgG4 responses to many antigens. Herein, we show the utility of a vaccinomics approach that profiles antibody responses of resistant individuals in a high-throughput multiplex approach for the identification of several potentially protective and safe schistosomiasis vaccine antigens.     

PAMAM-Lys,a Novel Vaccine Delivery Vector,Enhances the Protective Effects of the SjC23 DNA Vaccine against Schistosoma japonicum Infection

Background

Schistosomiasis japonica remains a major public-health concern in China. Praziquantel-based chemotherapy effectively reduces both infections and intensity; however, it can not prevent re-infection. Furthermore, there is an increasing concern about praziquantel resistance following long-term repeated use of the drug in endemic areas. Therefore, development of a schistosomiasis vaccine, as a strategy to prevent and control schistosomiasis japonica, has been given high priority. The present study was conducted to develop PAMAM dendrimers as a novel vaccine delivery vector for a schistosomiasis japonica DNA vaccine and evaluate its ability to enhance protective effects against Schistosoma japonicum infection.

Methodology/Principal Findings

Lysine was used to modify 4.0G PAMAM, and the modified product PAMAM-Lys was synthesized. PAMAM-Lys showed both high transfection and low cytotocity for gene delivery in vitro. DNA vaccines combined with PAMAM-Lys produced higher level of protection compare with naked DNA vaccines against S. japonicum infection in a mouse model. Futhermore,antibodies from mice immunized with PAMAM-Lys combined DNA vaccines were significantly higher than those of mice immunized with the naked DNA vaccines. The PAMAM-Lys vector elicited a predominantly IgG2a antibody response and a tremendously increase in the production of IL-2 and IFN-γ.

Conclusion/Significance

Lysine-modified PAMAM-Lys is an excellent vector. PAMAM-Lys may enhance the immunoreactivity of DNA vaccine and increase the protective effect of the SjC23 DNA vaccine against S. japonicum infection.     

Genetic control of vaccine-induced immunity against a parasitic helminth, Schistosoma mansoni

Schistosoma mansoni is one of several species of trematode helminths responsible for schistosomiasis, a major parasitic infection of man. Genetic analysis in mice has revealed that the protective immunity induced against this parasite by an attenuated larval vaccine is strongly influenced by genes regulating the activation of macrophage effector cells. The latter finding suggests that the induction of cell-mediated immunity may be a successful strategy for a non-living vaccine against the human infection.     

Schistosomiasis and hookworm infection in humans: Disease burden,pathobiology and anthelmintic vaccines

Helminth diseases are the ancient scourges of humans and their damages are ‘silent and insidious’. Of the helminth infections, schistosomiasis and hookworm infection have a great impact. This review covers information regarding vaccine candidates against schistosomiasis and hookworms that reached at least up to the phase-1 trial and literatures regarding other vaccine candidates have been excluded. For clinical manifestations, all available literatures were included, and for epidemiology and global burden of the diseases (GBD), literatures only within 2000–2019 were included. Literatures were searched surfing various databases including PubMED, Google Scholar, and Science Direct and overall over 150 literatures were identified. Globally ~250 million people are suffering from schistosomiasis, resulting 1430 thousand DALY (disability adjusted life year) per year. On the other hand, about 1.3 billion people are infected with hookworm (HW), and according to WHO, ~878 million school-age children (SAC) are at risk. HW is estimated to cause 65,000 deaths annually, accounts for 845 thousand DALYs as well as to cause 6–35.3% loss in productivity. Despite tremendous efforts, very few anthelmintic vaccine candidates such as Na-GST-1, Na-APR-1 and Na-ASP-2 against HW, and Sm28GST/Sh28GST, Sm-p80, Sm14 and Sm-TSP-1/SmTSP-2 against schistosomiasis reached up to the clinical trials. More efforts are needed to achieve the WHO targets taken against the maladies.     

Schistosoma spp.: progress toward a defined vaccine

During the last 2 decades, much was learned concerning the nature of acquired immunity in schistosomiasis, under experimental as well as field conditions. The knowledge is being applied now to design of a defined vaccine against this major parasitic disease. Several Schistosoma spp. antigens have been purified and shown to potentially protect in vivo. Determination of a method for presenting these antigens that will induce an optimal combination of cellular and humoral immune responses remains a critical step in vaccine development.     

Human T cell epitope mapping of the Schistosoma mansoni 14-kDa fatty acid-binding protein using cells from patients living in areas endemic for schistosomiasis

The development of a defined anti-schistosomiasis vaccine would contribute to the current control strategy mainly because immunization provides long-lasting immunity to the disease. Sm14, one of the six Schistosoma mansoni antigens selected by WHO as a candidate to compose a subunit vaccine against schistosomiasis, has been associated with resistance to S. mansoni infection in human beings and is able to induce protection in the murine model. To identify human T cell epitopes in Sm14, we used the TEPITOPE algorithm to select peptides that would most likely bind to several HLA-DR molecules. In this study, three Sm14 epitopes were selected and produced as synthetic peptides. Human T cell responses from schistosomiasis patients living in endemic areas in Brazil were determined by proliferation assay and IL-5 and IFN-gamma measurements. Differential peptide recognition and cytokine production in response to Sm14 epitopes were observed in individuals resistant to S. mansoni infection versus susceptible individuals. Sm14(32-48) and Sm14(53-69) peptides were preferentially recognized by peripheral blood mononuclear cells (PBMCs) of S. mansoni-resistant individuals, and Sm14(53-69) induced significant production of IFN-gamma. Additionally, Sm14(32-48) and Sm14(53-69) were "promiscuous" peptides, since they were able to induce cellular immune responses in individuals carrying 10 and 8, respectively, of the 11 HLA-DR molecules expressed in the studied population. Among Sm14 synthetic peptides tested in this study, we identified Sm14(32-48) and Sm14(53-69) as promising candidates to compose an anti-schistosomiasis vaccine, since they seem to be related to resistance to human schistosomiasis.     

Higher Frequency of Circulating PD-1high CXCR5+CD4+ Tfh Cells in Patients with Chronic Schistosomiasis

The current knowledge of immunological responses to schistosomiasis is insufficient for the development of vaccine and therapies. The role of T follicular helper (Tfh) cells in schistosome infections is not fully defined. The frequency of circulating Tfh cells and serum cytokine levels were analyzed in 11 patients with chronic schistosomiasis and 10 healthy controls (HC), who reside in an endemic area for Schistosomiasis japonicum. Significantly higher frequencies of circulating CXCR5⁺ CD4⁺ Tfh cells and higher expression levels of ICOS and PD-1 in CXCR5⁺ CD4⁺ Tfh cells were observed in patients with chronic schistosomiasis compared to HC. The levels of IL-21 in serum and the expression of IL-21 mRNA were higher in chronic schistosomiasis patients than in HC. Moreover, the frequency of circulating PD-1^high CXCR5⁺ CD4⁺ Tfh cells positively correlated with the levels of IL-21 in serum from patients with chronic schistosomiasis. A positive correlation was also found between the frequency of PD-1^high CXCR5⁺ CD4⁺ Tfh cells and the levels of soluble egg antigen (SEA)-specific antibodies in serum samples from the patient group. Our study is the first regarding Tfh cells in chronic human schistosomiasis and the finding indicate that PD-1^high CXCR5⁺ CD4⁺Tfh cells might play an important role in the production of specific antibodies in schistosomiasis. This study contributes to the understanding of immune response to schistosomiasis and may provide helpful support in vaccine development.     

Schistosome membrane proteins as vaccines

Schistosomes are parasitic blood flukes that infect approximately 200 million people and are arguably the most important human helminth in terms of mortality. The outermost surface of intra-mammalian stages of the parasite, the tegument, is the key to the parasite's success, but it is also generally viewed as the most susceptible target for vaccines and drugs. Over the past 2 years the proteome of the Schistosoma mansoni tegument has been investigated and these studies revealed surprisingly few proteins that are predicted to be accessible to the host immune response, namely proteins with at least one membrane-spanning domain. However, of this handful of proteins, some are showing great promise as recombinant vaccines against schistosomiasis at a pre-clinical level. In particular, the tetraspanin family of integral membrane proteins appears to be abundantly represented in the tegument, and convergent data using the mouse vaccine model and correlates of protective immunity in naturally exposed people suggests that this family of membrane proteins offer great promise for schistosomiasis vaccines. With the recent advances in schistosome genomics and proteomics, a new suite of potential vaccine antigens are presented and these warrant detailed investigation and appropriate funding over the next few years.     

A vaccine against Asian schistosomiasis

There is continued transmission of schistosomiasis japonica in China and Philippines despite highly effective control programs that focus on the application of the highly effective drug praziquantel (PZQ). The massive Three Gorges Dam across the Yangtze River in Southern China, soon to be completed, is expected to significantly increase schistosomiasis transmission and introduce the disease into areas currently unaffected. After long-term experience it is generally accepted that PZQ chemotherapy, although the cornerstone of current control programs, does have significant limitations. Furthermore, efficient drug delivery requires a substantial infrastructure to regularly cover all parts of an endemic area. Although there is not yet clear-cut evidence for the existence of PZQ-resistant schistosome strains, decreased susceptibility to the drug has been observed in several countries. As a result, a protective vaccine represents an essential component for the long-term control of schistosomiasis. This article briefly reviews aspects of anti-schistosome protective immunity that are important in the context of vaccine development. The current status in the development of vaccines against Schistosoma japonicum will then be discussed as will new approaches that may improve on the efficacy of available vaccines, and aid in the identification of new targets for immune attack. With new and extensive data becoming available from the S. japonicum genome project, the prospects for developing an effective vaccine are encouraging. The challenges that remain are many but it is crucial that the momentum towards developing effective anti-schistosome vaccines is maintained.     

The irradiated cercariae vaccine model: looking on the bright side of radiation

Schistosomes infect between 200 and 300 million people at any one time. A major strategy to reduce the impact of schistosomiasis on human health is the development of a defined antigen vaccine. Protective immunity induced in mice by irradiated cercariae may serve as a model for the development of a vaccine. In such vaccinated mice, worm burdens resulting from challenge infection can be reduced by more than 90% compared to non-vaccinated mice. During the past three decades, the irradiated-carcariae vaccine model has been dissected in the detail in order to determine factors that may be relevant to vaccination, such as the participating immune compartments, the site and kinetics of the immune response, and the antigens recognized. In this review, Dania Richter, Donald A. Harn and Franz-Rainer Matuschka highlight the research on the vaccine model, focusing on the murine model using gamma-irradiated cercariae of Schistosoma mansoni.     

Vaccination against Schistosomiasis: The case for Lung-stage Antigens

The development of an effective vaccine against human schistosomiasis remains a highly desirable yet elusive goal. In this article, Adrian Mountford and Richard Harrop focus attention on an approach that aims to identify proteins from Schistosoma mansoni that are capable of stimulating protective Th1 cell-mediated immune responses. They propose that the most likely source of such antigens is the lung-stage schistosomulum.     

The functional and immunological significance of some schistosome surface molecules

The molecules discussed in this review include some of the leading vaccine candidates in schistosomiasis: the glutathione S-transferases, triose-phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase and the 23 and 25 kDa surface integral membrane proteins. Mark Wright, Kathy Davem and Graham Mitchell highlight the possible biological roles and immunological relevance of these molecules.