Anti-Schistosome Vaccine Development - Assignment Example

Blood Fluke (Schistosomiasis) Vaccine Development Summary Reducing the number of worms is the standard for anti-schistosome vaccine development but because schistosome eggs are responsible for both pathology and transmission, a vaccine targeted on parasite fecundity and egg viability are also seems relevant. Researchers have been trying to isolate and characterise antigen of schistosomes with potential as vaccine candidates. Different models of immunisation and anti-infection are being use to achieve identification of candidate vaccine molecules. These antigens include Glutathione S-Transferases, 23-kDa Integral Membrane Proteins, and Radiation Attenuated Cercariae. However, although some of these antigens are successful in immunising domestic livestock, there is still no test have been made to man. The relationship between egg production, egg-directed immune response and disease, the anti-infection approach were developed to induce a parasite-eliminating immune response that acts against penetrating schistosomules. A vaccine from irradiated S. bovis cercariae was reported to protect cattle from infection. Another approach is the use of crude parasite extracts based on the cell-mediated immune response. Here, newly transformed schistosomula are being killed by freezing and thawing and provide reproducible levels of protection against a cercarial challenge. Since it has the potential for human use, the most promising so far is the approach to combine DNA vaccine and chemotherapy. 1. Introduction Schistosomiasis is an incapacitating disease affecting millions of people around the globe and rank second to malaria among the major parasitic disease of humans. Infection is distinguished by the existence of adult worms in the entrance and mesenteric veins of humans and various mammalian species as a result of complex migratory cycle instigated by cutaneous infiltration of infective larvae or cercariae. The female worm disposes in mucosae and tissues millions of eggs that are accountable for the pathology and disease allied with schistosomiasis. For this reason, various vaccines are being developed to control schistosomiasis. The following section is a literature review of different strategies that has been attempted to develop a vaccine that could control schistosomiasis. These includes include strategies such development of vaccine antigens, anti-infection, and mining crude parasite extracts. 2. Literature Review Schistosomiasis or blood fluke is an unbearable disease (Van Oss & Van Regenmortel p.501). A prominent attribute of schistosomiasis is the mysterious nature of the infection and associated diseases. For most people, the direct manifestations are minor or indeterminate so that the infected person is unaware of the amassing worm burden. It can take five to ten years after first exposure before severe pathology becomes evident, and interventions can do little to overturn the late-stage disease (Levine et al. 2004, p. 915). Moreover, schistosomes can live on a hostile environment of the mammalian bloodstream for thirty years thus developing a vaccine is not a simple task. (Maule & Marks p.304). There have been many effort but the results have been inadequate and as a result, since there is no comprehensible theory on which to base a vaccine. Some have researchers have focused their efforts on immune responses in animal models. Diverse routes have been followed, based on strategies that have succeeded with other pathogens. These include using crude parasite preparations and individual components purified from them. As an alternative schistosome cercariae have been attenuated with radiation or chemicals rather than repeated passage in culture. There is no logical sequence, but there is an underlying rationale for each of the various lines of work that have often progressed in parallel. 2.1 Vaccine Antigens Over the past decades, scientists in many laboratories were trying to isolate and characterise antigens of schistosomes with potential as vaccine candidates. In general, antigens have identified using models of immunisation and challenge infection, the identification of antigens uniquely recognized by naturally resistant hosts, and the targets of protective MAbs. Enormous progress has been achieved in the identification of candidate vaccine molecules and some of these antigens are Glutathione S-Transferases, Paramyosin, the 23-kDa Integral Membrane Proteins, and Radiation-Attenuated Cercaria. However, the majority of these antigens have been only tested in experimental animals for their anti-worm potential as judged by decreased worm burdens in immunized compared to control mice, but others may have ‘antifecundity’ or ‘antipathology’ effects (Mahmoud 2001, p.183). By far the best-characterised schistosome antigen is the 28kDa glutathione S-transferase of S. Mansoni or (Sm28GST), although work has also been carried out on GST from other schistosome species and on the 26kDa forms of this molecule. Triose Phosphate Isomerase or TPI is a candidate vaccine molecule that was first identified using mAb that conferred passive protection when administered to naive mice. The molecule is a 28kDa enzyme involved in the glycolytic pathway and has been located in all stages of parasite development. Sm14 is another molecule identified from a mixture of antigens released by adult worms cultured in PBS which can induce up to 75% protection when administered to outbreed mice in conjunction with CFA. Moreover, the recombinant form of Sm14 is reported to induce significant and high levels of protection in mice, even in the absence of adjuvant (Mahmoud 2001, p.184). 2.2 Anti-Infection Immunity Since there is a relationship between egg production, egg-directed immune response, and disease, a vaccine against schistosomiasis might take several forms (Mahmoud 2001, p.470). However, the most likely vaccine is one that would target protective immune response against the infective or migratory stages of parasite larvae, which would reduce their numbers before they were able to mature into egg-laying adult worms. The anti-infection approach is inducing a parasite-eliminating immune response that acts against penetrating schistosomules, lung-stage schistosomules, pre-adults, or fully mature male and female worms. In laboratory animals, high levels of resistance to schistosomiasis can be consistently induced by exposure to normal cercariae that would result in development of an egg-laying worm population and by vaccination with highly irradiated cercariae which die before reaching maturity (Liew 1989, p.153). Anti-infective vaccines are usually assessed by portal perfusion and counting of the actual number of adult parasites developing from a quantitative challenge infection. For instance, a 50% protection indicates that on average the vaccinated group harbours half as many parasites as the appropriate unvaccinated control group. A vaccine made from irradiated S. bovis cercariae which was developed for cattle, was reported to confer a significant degree of protection against infection. Although the use of a similar live vaccine would not be suitable for human population, the success of the animal vaccine has provided clues to potential immune-protective mechanisms in human schistosomiasis (Ryan et al. 2003, p.813). However, there is a general disagreement on the immunogenic effect of these irradiated cercariae as a result of different groups of workers studying different parasites in different hosts (Dawes 1999, p.56). The situation with regard to the stimulation of immunity in mice by means of irradiated cercariae of S. Mansoni is perplexed. For instance, some researcher agrees that exposure to irradiated cercariae induced resistance in mice. Others claim that repeated exposures give better degree of immunity while some argues that one or three exposures are enough (Dawes 1999, p.57). 2.3 Crude parasite extracts and DNA Vaccines The use of crude parasite extracts was based on the cell-mediated immune response associated with the murine attenuated vaccine model. In an attempt to replicate these responses, newly transformed schistosomula, killed by freezing and thawing, were administered intradermally to C57BL/6a strain mice together with live BCG as adjuvant. This non-living vaccine elicited significant, reproducible levels of protection against a cercarial challenge that correlated with sensitization for delayed type hypersensitivity rather than a humoral response (Maule & Marks 2006, p.306). To identify candidate vaccine molecules, establishment of protective vaccine regimens using a crude parasite extract or non-living attenuated parasites is required. Then the immune response to the vaccine components should be analysed using the reductionist approach to purify or clone the protective molecules present in the crude vaccine (Yong 1992, p.205). The advantage of this strategy is that it is theoretically possible to develop a vaccine using subfractionation techniques. Two approaches similar to this have been successful in schistosomiasis. A crude extract of infective schistosome larvae was used to demonstrate a vaccinating effect in mice using adjuvants designed to elicit CMI, a known mechanism of immunity in schistosomiasis. Fractionation of this protective extract identified a soluble, protective high molecular weight fraction from which a 97-Kda antigen was purified and shown to be protective. Cloning of the 97-kDa antigen has shown it to be homologous to paramyosin, a myofibrillar protein of invertebrates. Recombinant paramyosin was used in vaccine studies in mice and shown to be similar to the native antigen in eliciting only partial protection. Depletion of paramyosin does not abolish the protective effect with this extract, suggesting that other protective antigens exist in the crude vaccine (Yong 1992, p.205). The finding of large and significant heritabilities for levels of antibody isotype responses to crude and defined schistosome antigens indicates that additive genetics play an important role in the humoral immune response to infection (Secor & Colley 2004, p.182). The emergence of ‘DNA vaccines’ provided another potential vaccination strategy to protect experimental hosts against schistosomiasis. It has been used successfully in the development of viral vaccines where neutralizing antibodies and CD8 immune responses are important. DNA vaccination in combination with chemotherapy seems a promising approach as the pathology in mice immunised with a Sm28GST DNA construct in combination with treatment of infected mice with Praziquantel was reported almost completely prevented and there was a large reduction in the number of eggs in the tissues. In this approach, anti-GST antibodies induced by DNA vaccination would bind to native GST on the surface of the schistosome worms after being unmasked by the Praziquantel treatment. This is a form of dual chemotherapy and vaccination to treat both humans and animals in endemic regions where prior exposure to schistosome is highly probable (Levine et al. 2004, p.916). 3. Conclusion Developments of vaccines against schistosomiasis were attempted but there is still no clear paradigm on which to base a vaccine. Different strategies have been developed and one of them is identification of candidate vaccine molecules. Another is the anti-infection approach where parasite-eliminating immune response is being developed to act against penetrating schistosomules. The use of crude parasite extracts that was based on cell-mediated immune response associated with the murine attenuated vaccine model. Finally, the recent advent of DNA vaccines that could treat both animals and humans. In view of the varying strategies, conflicting results of experiments, and limitations of vaccines to animals, researchers of schistosomiasis vaccines should consider combining their efforts and follow the same route in pursuing their purpose. Since DNA vaccines have a better potential for human use, research on schistosomiasis vaccines should focus their efforts on studying DNA vaccination with chemotherapy. 4. Bibliography Dawes B., 1999, Advances in Parasitology, Academic Press, UK Levine M., Kaper J., Rappuoli R., & Good M., 2004, New generation vaccines, Informa Health Care, US Liew F.Y., 1989, Vaccination strategies of tropical diseases, CRC Press, US Maule A. G. & Marks N. J., 2006, Parasitic flatworms: molecular biology, biochemistry, immunology and physiology, CABI, UK Mahmoud A., 2001, Schistosomiasis, World Scientific, UK Ryan K. J., Ray C. G. & Sherris J.C., 2003, Sherris medical microbiology: an introduction to infectious diseases, McGraw-Hill Professional, US Secor W. E. & Colley D. G., 2004, Schistosomiasis, Springer, US Van Oss C. & Van Regenmortel H., 1994, Immunochemistry, CRC Press, US Yong W. K., 1992, Animal Parasite Control Utilizing Biotechnology, CRC Press, US Read More