The development of a vaccine against schistosomiasis has been underway since the turn of the century. Usually when developing a vaccine researchers look at the lifecycle of the parasite to determine a possible target for vaccine development. In the past years research has focussed on developing recombinant antigens found on the adult schistosome. In the following post we will discuss the four main antigens that have been identified on the schistosome. These antigens are most interesting to discuss because they made it the furthest in development and have been or will be tested in humans. They have been chosen for further development because these antigens seemed to have played a role in the immune response of previously infected people. After we have discussed the antigens, we will discuss whether the approach taken to develop a vaccine against schistosomiasis is still durable or whether a different approach should be considered.
Sh28GST (Schistosoma Haematobium 28-kDa Glutathione S-Transferase)
Antigen
The first vaccine we will discuss is recombinant 28-kDa glutathione S-transferase (rSh28GST) or Bilhvax. This vaccine is targeted against P28GSTs. These are enzymes secreted by both Schistosoma Mansoni (Sm28GST) and Schistosoma haematobium (Sh28GST)(1). Effectiveness for a vaccine against Sh28GST was found in non-human primates (2) and therefore progressed to the human trial phases.
Mechanism
Sh28GST is an enzyme secreted by the schistosome and plays a significant role in the modulation of the host immune system. It inhibits the epidermal Langerhans cells to migrate to the draining lymph nodes when the cecaria travel through the skin. Because of the lack of interaction between the innate and adaptive immune system no adaptive immune response to the cecaria can be mounted. This gives them the chance to develop into adult schistosomes. On top of that it plays a role in the detoxification of the environment for the schistosome helping it survive inside the host (3). The vaccine aims to block Sh28GST by inducing the presence of antibodies against Sh28GST by injecting recombinant antigen and thereby stopping the modulation of the immune system by the helminths so the helminths can be cleared by the host.
Trials
The previous phase 3 trial for this vaccine was conducted between 2009 and 2012 (4). This trial found that the vaccine was immunogenic but not sufficiently protective. The study advised that for further studies a different approach to the administration of the vaccine should be taken which could instead of blocking the IgG4, induce a protective IgG3 response which would lead to a more effective immune response (1).
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| Figure 1: Structure of Sh28GST, Figure credits: rscb.org |
Next, we will discuss the vaccine targeted at the antigen 4kDa S. mansoni (Sm14). The vaccine is again a recombinant antigen (rSm14). Sm14 is a Fatty Acid-Binding Protein (FABP) expressed by Schistosoma mansoni in all life cycle stages (3). It was found that people with a natural resistance to S. mansoni showed a strong Th1-type response to Sm14 and it was therefore considered to be a prime target for a vaccine.
Mechanism
FABPs are used by schistosomes to take up fatty acids and sterols produced by the host. This is necessary because they lack the required oxygen pathways to make these essential nutrients themselves (5). The vaccine aims to reduce the amount of Sm14 that can take up these nutrients for the helminths by targeting them with rSm14 and therefore starving them to death in all different stages of the life cycle.
Trials
The last trial conducted was a phase-2b trial from 2018 to 2019 (6) from which the results are not yet published, but in the phase 1 trial the vaccine was found to be safe and strongly immunogenic (7).
Sm-TSP-2 (Schistosoma mansoni Tetraspanin)
Antigen
Another identified antigen is Schistosoma mansoni Tetraspanin 2 (Sm-TSP-2). This protein is expressed on the surface of adult schistosomes. Sm-TSP-2 was seen to be strongly recognized by IgG1 and IgG3 in people with an assumed immunity against S. mansoni (8). This made it a target for further vaccine development
Mechanism
The Sm-TSP-2 protein is membrane protein with four transmembrane groups and four extracellular loops. It is a regulatory protein that facilitates the formation and trafficking of the tegument of the schistosome. Due to the extracellular loops, it is recognizable for the immune system of the host primary for IgG1 and IgG2 which are able to opsonize or neutralize pathogens (3).
Trials
A phase I/II trial into the Immunogenicity and efficacy of this vaccine is still ongoing until 2024/2025 (9).
Sm-p80 (Schistosoma Mansoni Calpain)
Antigen
This vaccine is targeted against Calpain. This is expressed on adult schistosomes and in other stages of the life cycle (3) Calpain is a cysteine protease consisting of a large, catalytic and a small, proteolytic subunit. The large subunit of Calpain (Sm-p80) is accessible for the immune system and can be targeted by vaccines. Trials for the Sm-p80 vaccine are currently being conducted.
Mechanism
Sm-p80 is involved in the biogenesis and regeneration of the tegument of the helminths. This is an immune evasion technique used by helminths found in blood. Other evasion techniques used by Schistosomes are also likely to be aided by Sm-p80 (10). The Sm-p80 vaccination aims to mitigate these evasion tactics and seems to have a lot of different effects on both the adult worms and the developing stages in between as depicted in figure 2 below (11).
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| Figure 2: Sm-p80 vaccine efficacy on different levels of infection, disease and transmision. Figure credit: (11) |
Trials
Trials on primates have been conducted and will progress on to humans the trials will be discussed in further detail in the critical appraisal post. In figure 3 below you see the roadmap of development for the Sm-p80 vaccine
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| Figure 3: Roadmap to SM-p80 vaccine. Figure credit: (11) |
Discussion The past years research has mainly focussed on developing recombinant antigens to induce antibodies and an effective immune response against this antigen. Until now this approach has not delivered the desired result in humans. Therefore other approaches should be explored for instance the possibility to combine antigens in a multivalent chimeric vaccine (12) which could be achieved using newly developed vaccine techniques like mRNA used for the Covid-19 vaccines (3).
Innovative approaches could also be found by revisiting the first step of helminth vaccine development mentioned in the beginning of the post. Most of the research has focussed on attacking the already developed or matured helminth in the body, but it might be more effective to attack the helminth before it can deploy its wide array of immune evasion tactics. For instance, when penetrating the body, the Cercaria will migrate through the skin as schistosomula. A schistosomula is more susceptible to the immune system of the host therefore it could be an effective target for vaccines (13). These future possibilities are further discussed in the post about innovative therapies.
References