Despite decades of widespread chemotherapy use, schistosomiasis remains a major cause of morbidity and mortality in most of the world. Current control measures for schistosomiasis consist of mass drug treatment, but to sustain their effects, they must be applied periodically for long periods of time. Furthermore, high rates of reinfection in endemic areas after mass drug treatments limit their effectiveness. A vaccine may therefore be an ideal method for control of schistosomiasis.
There are other reasons why a vaccination campaign would be an ideal strategy to combat schistosomiasis. These include: the disease spreads harmfully and in a subtle manner, leading to high worm burdens in some individuals who then transition to severe and irreversible pathology that is unresponsive to chemotherapy [1]; continuing wide spread chemotherapy use will inevitably result in drug resistance [2]; Vaccines have been proven to be an excellent means of cost-effective control of many infectious diseases; and a control approach that would combine drugs followed by vaccination would integrate short-term effects with long-term eradication goals [1].
There are several mechanisms that may be targeted by vaccine candidates (Table I) such as interfering with the inter-parasite signaling system [3] or targeting cercarial antigens [4]. Whatever the strategy, an ideal vaccine would combine two or more antigen targets to induce a synergestic action against the parasite.
Table I
Approaches to Vaccine Development
Point of Intervention |
Targets and Mechanisms |
Skin Penetration |
Inhibition of cercarial transformatin |
Larval Growth (skin to portal system) |
Killing of schistosomula by membrane disruption |
Male/Female Pairing |
Interference with inter-parasite signaling system |
Reproduction |
Interference with egg production and delivery |
Embryonation |
Inhibition of miracidial maturation |
Granuloma Formation |
Induction of T cell tolerance or blocking of cytokine action |
DNA vaccination and recombinant protein formulation are now the preferred vaccine delivery option. DNA vaccination, essentially the injection of plasmids containing DNA sequences encoding production of antigens, has promise for it bypasses problems such as antigen purification and large-scale industrial production [4]. This method also allows for the inclusion of adjuvants or cytokine genes directly to the vaccine, making it more effective. Although safety and ethical issues do not seem to be a problem, questions on long-term DNA integration and risk of stimulating Anti-DNA responses warrant attention [4].
The Development of Schistosome vaccines seemed attainable in the early 1990`s due to two research findings: that humans develop some form of resistance to schistosomiasis reinfection [5] and that infective larvae attenuated with ionizing radiation of S. mansoni provide high levels of protection in rodents and primates [6]. Still, although these early findings brought great optimism to the search for a vaccine, its development has proven to be difficult.
The list of published schistosome antigens continues to increase. They all differ and they all come from the different stages in the parasite's life cycle. But to be considered a candidate antigen for a vaccine, NK Bergquist of the WHO Special Program for Research and Training in Tropical Diseases (TDR) recommends that the antigen meet the following seven criteria:
Considerable efforts have been made in the last 15 years in finding the relevant schistosome antigens that may provide the protective immune response needed for a vaccine candidate. Research has focused on six vaccine candidates (listed in Table II) selected by the WHO based on the criteria just mentioned, and due to their known protection in various experiments. They include GST, which is known to have an effect on worm fecundity [6], paramyosin [7], IrV-5 [8], Sm-14 [9], and TPI [10] and Sm23 [11], two transmembrane proteins. An independent study funded by the WHO on the six candidate antigens showed that protein-based vaccines achieved protection that did not exceed 40% [4]. Due to these disappointing results, further exploration of antigen formulation led to the development of DNA vaccines encoding these proteins and recombinant proteins of these molecules.
Table II
Schistosoma candidate vaccines
Candidate Antigen |
Acronym |
Stage Expressed |
Type of Molecule |
Institutional Origin |
Glutathione S-transferase |
GST |
Schistosomula and Adult stages |
Enzyme |
Institut Pasteur, Lille, France |
Paramyosin |
Sm-97 |
All Stages |
Muscle Protein |
Cornell/CWRU, NIAID |
Irradiated vaccine antigen #5 |
IrV-5 |
All stages |
Muscle Protein |
John Hopkins School of Med |
Triose phosphate isomerase |
TPI MAP4 |
All stages |
Enzyme peptide loops |
Harvard School of Public Health |
23kD membrane antigen/Tetraspanin |
Sm-23 MAP3 TSP |
All stages |
Transmembrane protein |
John Hopkins and Harvard |
14kD membrane antigen |
Sm-14 FABP |
Schistosomula stage |
Fatty-acid-binding protein |
Oswaldo Cruz Foundation, Brazil |
Recent Developments:
Just in the last two years, research groups throughout the world have developed five possibly successful candidate antigens. These include: Glutathone-S-transferase (Sm28GST), 28kDa enzyme used by Andre Capon at The Institut Pasteur in France; paramyosin (Sm-97), a myofibrillar protein being used by Donald McManus at the Queensland Institute of Medical Research against S. japonicum; tretaspanins (TSP), an integral membrane protein being used by Donald Harn at the Harvard School of Public Health and by Rodrigo Correa-Oliveira at the Oswaldo Cruz Institute in Brazil; a fatty acid binding protein (Sm-14FABP), a antigen being worked on by Jimmy Liu at the Shangai Institute of Animal Parasitology; and Sm-p80 (a large calpain subunit), an antigen being studied at Texas Tech Medical Center by Afzal Siddiqui.
Since a significant anti-fecundity effect has been observed with a 28kDa GST from S. japonicum [12], Andre Capon from the Institut Pasteur has initiated pre-clinical studies with a 28kDa GST from S. Haematobium. By producing a recombinant form of the protein (rSh28GST), he has been able to test its safety and its ability to produce protective immunity. His preliminary studies showed that no systemic or local toxicity was observed in healthy humans (African and Caucasian males and children) and no adverse reactions were observed (Capron et al. unpublished). In addition, his preliminary studies show support that rSh28GST prompts the development of protective immunity in human subjects because rSh28GST appears to induce a T Helper cell type-2 immune response (Capron et al. unpublished). These optimistic results have opened the doors to evaluating the clinical efficacy of rSh28GST in infected patients. The study is currently in phase III clinical trials [31].
André Capron, Institut Pasteur, France
http://canalacademie.com/IMG/andre_capron_002bis.jpg
Another promising vaccine candidate is paramyosin, a myofibril protein. Like Andre Capron, Zhang et al. have used recombinant protein fragments of paramyosin to induce protection in immunized BALB/c mice. Zhang et al. in a study published in 2006, found a significant reduction in worm burden, worm-pair numbers and liver eggs in mice vaccinated with recombinant paramyosin fragments. The study also went on to show that the paramyosin fragments were highly immunogenic by inducing a high amount of antibody production [13].
Tetraspanins are another group of antigens that have great potential as a vaccine candidate. Although its function is not known, previous studies have found that it is a transmembrane protein. Some mammalian homologues of tetraspanin have been studied and have been found to be associated with domains on the plasma membrane, function in cell-cell interactions and maintenance of cell membrane integrity [14]. Since schistosomes have a unique outer syncytial surface, the tegument, which constitutes the host-parasite interface, some believe that schistosomes tetraspanins might function by maintaining cell integrity or cell-cell interactions in the tegument [15].
Donald Harn, from the Harvard School of Public Health, has recently developed a very successful tetraspanin plasmid DNA vaccine that has been found to prevent 52% transmission in waterbuffalo, one of the highest rates achieved thus far with a vaccine (Harn et al. unpublished data). This is a very important finding for it is believed that waterbuffalo account for 75% of S. japonicum transmission in Asia [16]. Through the use of a plasmid with 23kDa tetraspanin (TSP-1) and glycolytic enzyme cDNA, Harn’s group was able to provide protection in excess of the 40% benchmark set by the WHO for progression of schistosome vaccine antigens into clinical trials. To improve the vaccine, Donald Harn has now entered a partnership at the NIH to reach the goal of preventing 80% transmission, a goal they believe is possible [28].
Another successful tetraspanin vaccine is currently being developed in Brazil [30]. Although researchers in Brazil do not believe they have used the same tetraspanin molecule used by the Harvard group, they have published in Nature their results from vaccination of mice with a recombinant tetraspanin molecule (TSP-2) [17]. Tran et al. found that naturally resistant individuals contained IgG3 and IgG4 antibodies that strongly recognize TSP-2, but unexposed individuals and chronically infected persons did not contain these antibodies. In addition, this study also found that mice vaccination with the tetraspanin recombinant protein, Sm-tsp-2, followed with infection with S. mansoni had 57% and 64% reduction in mean adult worm burden and liver egg burden respectively. These results show the potential of tetraspanin as an effective recombinant vaccine for human schistosomiasis [28].
Donald Harn, Harvard University, USA
Researchers at the Shangai Institute of Animal Parasitology have studied the S. japonicum antigen referred to as fatty acid binding protein, SmFABP [9]. It has been shown that FABPs play a unique role in schistosome defense against immunological attack by driving the parasites ability to uptake and transport fatty acid chains [18]. Liu et al., in this study used a recombinant FABP protein from S. japonicum, rSj14FABP, to induce immunity in BALB/c mice and other mammals. After vaccination of mice with rSj14FABP and challenged with S. japonicum, Liu et al. was able to produce worm reductions of 48.8% compared to non-vaccinated mice. In addition, rSj14FABP was found to be immunogenic in rats, and sheep with 31.9% and 59.2% worm reduction respectively.
Lastly, Afzal Siddiqui and others are studying another potentially successful vaccine candidate called Sm-p80 at Texas Tech Medical Center. Sm-p80 is a larger subunit of calpain that is believed to play a role in surface membrane biogenesis in schistosomes [19]. The importance of Smp-80 for schistosomes stems from the fact that membrane renewal is a major phenomenom used by schistosomes to evade the immune system. Afzal Siddiqui believes that an immune response against Sm-p80 would make the parasite vulnerable to immune attack and clearance and also prevent membrane biogenesis. Afzal Siddiqui has found, through the use of a DNA vaccine, that vaccination of mice with plasmids encoding Sm-p80 and interleukin-2 (IL-2) provides a 59% protection while vaccination with plasmid formulated with Sm-p80 and interleukin-12 (IL-12) provides a 45% protection [29]. Although research is currently on halt, Siddiqui believes that Sm-p80 has great potential towards the development of a schistosomiasis vaccine [29].
Afzal Siddiqui, Texas Tech, USA
http://www.ttuhsc.edu/amarillo/som/im/faculty/images/afzai_a_siddiqui.jpg
There are many other vaccine candidates that have recently brought excitement to the schistosomiasis vaccine research world. Donald Harn from the Harvard School of Public Health published in 2005 a study using a triose-phosphate isomerase (TPI) plamid DNA vaccine that was used to vaccinate pigs in China. They found in that study that pigs vaccinated with SjCTPI DNA had adult worm burdens reduced by 48.3% and granuloma size was reduced by 42% [16]. Another vaccine candidate that has great potential but has not been thoroughly studied is SmIrv-1. After initial trials in the early 1990s at John Hopkins Medical School, the research dwindled down due to a senior researchers death. Since this candidate is also patented, little progress has been made in its development.
Economic Challenges and Impact
Introducing a schistosomiasis vaccine would introduce significant economic benefit to countries impacted by the parasitic illness, including Brazil, China, Egypt, the Phillipines and several countries in Sub-Saharan Africa. Improving the quality of life of many young children and working-age people in these areas has the potential to offer far-reaching benefits to the host countries. As the World Health Organization attests, it is important to remember these end-goals when considering the cost of what many researchers consider the final stages towards development of a Schistosomiasis vaccine [20].
Although several groups have started clinical trial testing, the most difficult and costly portion of vaccine development is yet to come. As already mentioned, current work in France, Egypt, and Brazil is being conducted under Phase I and Phase II clinical trials to study glutathione-S-transferase (GST) and other vaccine candidates [21]. However, the burden of cost is far from complete. Phase I and Phase II trials are usually done on a smaller scale to test safety and basic efficacy of vaccines, whereas Phase III clinical trials include construction and validation of manufacturing capacity and licensure, which are both very expensive. From Phase I and II trials to Phase III, costs rise dramatically, often including 50-60% of all costs incurred during vaccine development research [22]. For example, just in 2002, costs to develop pharmaceutical products and vaccine licensure were in the ranged of $500 million based on historical information [22]. Therefore, present-day estimates to develop a vaccine range from $750 million to about $1 billion.
Another major contributor to cost, as well as a logistical difficulty with vaccination efficacy, is the fact that these clinical studies will have to be performed in rural endemic areas where medical and healthcare facilities are often inadequate [23]. This suggests that a significant investment in both infrastructure and training of personnel will be needed in rural areas, further increasing expenses. In addition, to monitoring the duration of protection of the vaccine and assessing any possible immunopathologic effects, these groups may have to remain in the areas for several years [23]. In summary, administering the vaccine alone is very expensive, but in the end it will only be a fraction of the overall vaccination program.
There are, however, significant human, national and international economic benefits associated with vaccine development. For one, introducing an effective vaccine has the potential to eliminate disease and morbidity-related paralysis in millions of people [24]. The reduction in morbidity and disease will result in healthier populations that may contribute to society economically as workers, and socially as community leaders, and more.
Vaccination would provide a significant human benefit by improving the health and productivity of young populations, thus having positive effects on national economic productivity in countries already suffering financially. Many vaccine researcher express the thought that the initial target group for vaccination may be infants and children who have never been infected or who have only recently become exposed to the threat of eggs. This strategy has the potential of cutting costs, especially if studies continue to show that adults exhibit some or very strong immunity with current drug treatments. More importantly, it provides children with the possibilities of becoming economically and infrastructurally-productive teens and adults.
The attention the vaccination effort will receive may help to finance the cost of the campaign and to introduce other economic investments to those countries. Philanthropic efforts, like those initiated and headed by the WHO, TDR, CDC and UNICEF [20, 24], may help to introduce infrastructure for basic clinics and healthcare facilities and to reinforce attention to eliminate other diseases, such as Leishmaniasis and Malaria [23]. Finally, although quantifying the amount of money earned from reducing morbidity and co-morbidities associated with schistosomiasis infection is beyond the scope of this project, there is no doubt that the individual, familial and national economies will benefit from the reduced burden of schistosomiasis.
Medical Challenges/Impacts
As mentioned above, because there are so many challenges encountered during new pharmaceutical and vaccine development, it is important to start with the end in mind. Todd and Colley clearly state this when saying that, “developing a licensed vaccine project for neither the underfunded nor the weak of heart” [23]. Several important challenges to vaccine success include stability, delivery and administration, and efficacy. There are, however, many medical benefits associated with the vaccination strategy. These include the ideal elimination of schistosomiasis; improved health and quality of life of the millions of people infected with this parasite, especially children; possible establishment of more healthcare facilities and access to medical care; better sanitation and health education; strengthening of departments of health in affected countries; and access to an immense library of research that may lead to future scientific and medical discoveries.
Stability of the vaccine, the delivery method and the administration of vaccination programs are difficult medical challenges in the search for an adequate schistosome vaccine because they are within the context of Phase III clinical trials that must be carried out largely in rural areas [25]. Stability of the vaccine, or viability and usability, will be very important in areas such as Egypt, Brazil, Sub-Saharan Africa and the Caribbean Basin [21]. If not stable at high temperatures, the vaccine will have to be stored at low centigrade temperatures. This will require refrigerators that may have to run on generator power in places without electricity. In summary, the stability of the vaccine is important to ensure that, in clinical trials and if licensure is acquired, a truly viable vaccine is administered.
The delivery method and administration of vaccination programs also pose several challenges. As mentioned above, delivering the vaccine to rural areas is a great challenge. Vehicles equipped to transport vaccines, medical personnel and researchers will be necessary. Administration of vaccination may pose difficult cultural/societal problems as well. There may be trust and cultural block issues between citizens and medical personnel. And training interpreters and staff will be necessary and costly, especially if the program is to last for months.
Further complicating the issue is the fact that the three main species of schistosomes targeted for vaccination—mansoni, japonicum and haematobium—all require separate vaccination programs because they have, at least until recently, shown to be different antigenically. This means that the problems encountered to develop a vaccine for one species, already medically daunting, will triple when creating a world-wide vaccination program [21].
Nothing, however, can be done without the end in sight. It is important to remember the why’s and the reasons to undertake the search for a schistosomiasis vaccine. Unlike present drug treatments, a successful vaccine will more fully protect against long-term reinfection, may allow for the creation and maintenance of healthcare facilities in countries who benefit from the program, will improve the health and quality of life of millions of people worldwide, especially young children, and may help to strengthen departments of health in target countries.
Finally, access to an immense library of research will be of great value because this may allow vaccine developers to improve the administration/efficacy of the vaccine and may also lead to unseen benefits, including future medical discoveries. For instance, when Ogilvie et al. studied experimental Schistosoma infection, they made observations about the production of reaginic antibodies during the experiments. This led to the notion that the antibodies may function during the immune defense against the parasites [26]. When immunoglobulin E was discovered, studies rapidly followed by the demonstration of elevated IgE levels in helminth infection. The discovery has since had several medical and scientific applications for treatments and research of parasitic and allergic illnesses [26]. Thus, the schistosome vaccination program may lead researchers to unknown medical and/or scientific discoveries and advancements.
Political Challenges
Getting local and national governments to join the vaccination effort is feasible, but maintaining interest and involvement will be difficult. Many countries, especially those in sub-Saharan Africa, will have greater difficulties implementing and sustaining a vaccination program due to the fact that governmental stability is lacking in many of the target areas. In addition, support for the vaccination programs will be difficult especially since political commitment most often relates to economic commitment.
The use of international loan programs, the lowering of poverty rates, and external political commitment from the international community is necessary for a successful campaign. Availability of economic resources has promoted greater political commitment for wide-scale chemotherapy in countries such as Egypt, China, Prazil, the Phillippines, Tunisia and Saudi Arabia. Key factors contributing to success of these programs were concurrent socioeconomic development, national commitment and continued economic support, in several cases through loans from the World Bank [27]. It follows that wide-scale chemotherapy campaigns in sub-Saharan countries and other third-world nations had greater difficulty economically. Pilot-programs showed promising results, only to flounder and often disappear when foreign assistance is ended [27]. An international vaccination campaign will be no different.
