• Malaria Vaccine
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Why a vaccine?

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].

Vaccine Targets and Approach

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

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 a Vaccine

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:

• Able to significantly reduce worm burdens and/or egg production compared to controls. This should be shown in consistently in two different experimental animals species.
• Demonstrate induction of cell-mediated and humoral immune responses
• It must include a sufficient number of epitopes to overcome MHC restriction in hosts and genetic variation of parasite strains.
• Be compatible with safe adjuvants and stability of vaccine
• Lack of side effects
• Ease incorporation into delivery vectors
• Ease of passage though regulatory authorities

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

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.

GST Vaccine

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

Paramyosin

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

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

Fatty Acid Binding Protein

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.

Sm-p80

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

Other Vaccine candidates

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.