Therapeutic challenges of schistosomiasis: mechanisms of action and current limitations

Abstract

Schistosomiasis, a parasitic disease caused by Schistosoma species, affects millions of people worldwide. This review explores the therapeutic challenges of schistosomiasis, focusing on the mechanisms of action of current treatments and their limitations. Praziquantel, the standard therapy, induces lesions and muscle contractions in the parasites, thereby facilitating their clearance by the host immune system. However, the biological complexity of schistosomes and their ability to modulate the immune response present hurdles to sustained treatment efficacy. Challenges include the emergence of resistance, adverse side effects, and inconsistent cure rates. Additionally, the remarkable longevity of schistosomes—spanning years to decades—complicates the evaluation of treatment outcomes. Addressing these issues, requires ongoing surveillance, research into novel therapeutic agents, and an integrated approach that combines medical interventions with preventive measures. This paper underscores the importance of understanding schistosome biology and advocates for comprehensive strategies to improve the management and control of this debilitating parasitic infection.

Context of schistosomiasis

Schistosomiasis, also known as bilharzia, is a widespread parasitic disease prevalent in tropical and subtropical regions (Balahbib et al. 2017). It is caused by parasitic worms of the genus schistosoma and is transmitted to humans through contact with water contaminated by the larvae of the parasite, typically during activities such as swimming, laundry washing, or fishing (Amarir et al. 2011; Balahbib et al. 2020a, b). Schistosomiasis is closely linked to poverty, poor sanitation, and limited access to clean water, making it a major public health issue in many parts of the world (Fenwick et al. 2006; Karunamoorthi et al. 2018).

In 2021, the World Health Organization (WHO) estimated that 251.4 million people required preventive treatment for schistosomiasis, with over 75.3 million receiving treatment (WHO 2023). The consequences of infection can be severe, impacting both the short- and long-term health of affected individuals (King 2011; Colombe et al. 2018). Common complications include anemia, malnutrition, and stunted growth in children. Schistosomiasis can also result in more serious conditions such as portal hypertension, severe liver damage (including cirrhosis), and bladder cancer (Barsoum 2013; Elbaz and Esmat 2013; Salas-Coronas et al. 2020; Verjee 2020).

Beyond individual health impacts, schistosomiasis places a heavy socio-economic burden on affected communities (Bergquist et al. 2017; Neves et al. 2024). Productivity losses due to school absenteeism and job disruption, coupled with healthcare costs for diagnosis and treatment, significantly reduce the economic well-being of populations already vulnerable to poverty, thus perpetuating the cycle of disease and economic hardship (Adenowo et al. 2015; Rinaldo et al. 2021).

In light of this, effective management of schistosomiasis is essential to reduce the morbidity and mortality associated with the disease. Current treatments, particularly praziquantel (PZQ), have revolutionized the management of schistosomiasis by providing an effective means of eliminating parasitic worms (Keiser and Utzinger 2012; Useh 2012; Alwan et al. 2023). This drug is widely used in control programs globally and has significantly lowered the prevalence of the disease in many regions (Engels et al. 2002; Fenwick et al. 2006).

The objective of this review is to provide a detailed examination of the mechanisms of action of current schistosomiasis treatments. By exploring how these drugs interact with the parasites and impact their survival and reproduction, we aim to enhance our understanding of both their efficacy and limitations.

Schistosomiasis: overview of the disease

Pathogen and life cycle of schistosomes

Schistosomiasis, a devastating parasitic disease, is caused by worms of the genus Schistosoma, belonging to the class trematoda (Mahmoud 2001; Pamu et al. 2018; Santos et al. 2021). These parasites have a complex life cycle involving multiple stages and various hosts, facilitating their survival and propagation (Mawa et al. 2013; Verjee 2020). The life cycle begins when infected hosts, typically humans, release eggs containing embryos into freshwater environments through feces or urine (Lombardo et al. 2019; Nelwan 2019).

Once in the water, the eggs hatch and release swimming larvae known as miracidia. These miracidia infect freshwater snails, which act as intermediate hosts. Inside the snail, the miracidia undergo several transformations, first into sporocysts, then into free-swimming larvae called cercariae. These cercariae are released back into the water, where they actively seek new hosts (Dinnik and Dinnik 1954; Horák et al. 2002; Galaktionov and Dobrovolskij 2013; Loker et al. 2022).

When humans come into contact with contaminated water, cercariae penetrate the skin, often through hair follicles or pores (Kopperstad 2017; Waldeland 2017; Pamu et al. 2018). After penetration, the cercariae shed their tails and become schistosomulae, which then migrate through the tissues and into the bloodstream. Once in the circulatory system, the schistosomulae migrate through the heart and lungs to the liver’s vasculature, where they mature into adult worms (Nelwan 2019). In the liver, male and female schistosomes pair and migrate to either the mesenteric vasculature (Schistosoma mansoni and Schistosoma japonicum) or the urogenital vasculature (Schistosoma haematobium) to lay eggs (McManus et al. 2018). The eggs then pass through the walls of the blood vessels and are excreted via feces or urine, completing the schistosome life cycle (Nation et al. 2020).

The continuous deposition of eggs causes a granulomatous immune response, which over time leads to chronic inflammation, fibrosis, and severe organ damage (Gobbi et al. 2020) (Fig. 1).

Fig. 1.

Life cycle stages of Schistosomes

This intricate life cycle allows schistosomes to thrive in diverse aquatic environments and survive under various conditions. Understanding the life cycle of schistosomes is critical for devising effective strategies for the prevention, control, and treatment of schistosomiasis, thereby mitigating its profound impact on human health.

Consequences of Schistosoma spp. infection

Infection with schistosomes can lead to a wide range of symptoms and complications, the severity of which is influenced by factors such as Schistosoma species involved, the parasite burden, and the duration of the infection. In the initial stages, acute schistosomiasis may present with non-specific symptoms such as skin itching, rashes (referred to as cercarial dermatitis), and febrile episodes, all characteristic of acute schistosomeasis (Carbonell et al. 2021). However, as the infection progresses to a chronic phase (typically beyond 12 weeks post-infection), more severe complications may arise, primarily driven by the host’s inflammatory and immune responses to the eggs deposited by the parasites (Barsoum 2013; Costain et al. 2018).

In chronic forms of the disease, Schistosoma eggs can trigger persistent inflammation and fibrosis in various internal organs, particularly the liver and bladder (Barsoum 2013; McManus et al. 2020). This fibrotic process can lead to serious health issues, including portal hypertension, liver cirrhosis, and, in severe cases, liver failure (Verjee 2020; Hudson et al. 2023). Additionally, Schistosoma-induced renal lesions, resulting from eggs becoming trapped in surrounding tissues, may cause kidney failure and other renal complications (Barsoum 2003; Verjee 2019; Duarte et al. 2020).

In the case of S. haematobium, which primarily infects the urinary tract, symptoms may include dysuria (painful urination), hematuria (blood in the urine), and other urological issues (Obonyo 1981; Bello et al. 2014; Zaghloul et al. 2020). Chronic infection by S. haematobium also increases the risk of developing bladder cancer, adding a serious oncological dimension to schistosomiasis complications (Zaghloul and Gouda 2012; Zaghloul 2012; Gaber et al. 2020).

These complications, both medical and physical, significantly impact the quality of life of those infected with schistosomes and carry major public health consequences.

Impact of schistosomiasis on public health

Schistosomiasis represents a significant burden on public health, particularly in endemic regions where socio-economic, environmental, and behavioral factors exacerbate transmission conditions (Adenowo et al. 2015; Kalinda et al. 2018). This parasitic disease affects millions of people worldwide, especially in tropical and subtropical areas where poverty, lack of access to clean water, and inadequate sanitation are prevalent (Karunamoorthi et al. 2018). The public health impact of schistosomiasis is multifaceted and complex, encompassing medical, economic, social, and environmental dimensions (Kloos et al. 2008; Janoušková et al. 2022).

Economically, the healthcare costs associated with schistosomiasis—including medical consultations, medications, and surgical interventions—impose a significant financial burden on infected individuals and their families, particularly in regions with limited access to healthcare services (Webster et al. 2014; Lee et al. 2015; Redekop et al. 2017). Furthermore, the disease leads to school absenteeism in children, job disruption, and decreased productivity in adults, primarily due to the physical weakness caused by the infection (Stephenson 1993; Kinung’hi et al. 2016). This loss of productivity can have long-lasting economic repercussions, fueling a vicious cycle of poverty and disease within affected communities.

Socially, schistosomiasis can lead to stigmatization and discrimination against infected individuals, often stemming from misconception associating the disease with uncleanliness or neglect (Anyolitho et al. 2022; Schuster et al. 2022). Such stigma can severely impact the mental health and psychosocial well-being of those affected, further exacerbating their overall burden.

Environmentally, schistosomiasis is closely linked to factors such as deforestation, unsustainable agricultural practices, climate change, and alterations in aquatic habitats, all of which can promote the spread of intermediate host snails and elevate the risk of human infection (Sutherst 2004; Patz et al. 2008).

Current treatments for schistosomiasis

Historically, PZQ and oxamniquine (OXA) were the two most important schistosomicidal drugs used in clinical practice (Ferrari et al. 2003).

Praziquantel

PZQ is a widely used antiparasitic medication medicine that has proven to be highly effective against a variety of parasitic infections caused by flatworms, including both trematodes and cestodes (Nogueira et al. 2021; Norbury et al. 2022; Mengarda et al. 2022). It is particularly known for its efficacy in treating all forms of human schistosomiasis, including those caused by S. mansoni, S. haematobium, and S. japonicum (Levecke et al. 2020; Tesfie et al. 2020; Summers et al. 2022; Shao et al. 2023). Beyond schistosomiasis, PZQ is also used to treat other trematode infections, such as clonorchiasis (Qian et al. 2022), opisthorchiasis (Phung et al. 2022; Probst 2023), and paragonimiasis (Mahanta 2022; Richter 2022). It is equally effective against cestode infections, such as taeniasis and cysticercosis (Lalthanpuii et al. 2020; Lightowlers et al. 2021).

PZQ’s applications extend beyond human health; as it is also used in veterinary medicine to treat parasitic infections in domestic and livestock animals, underscoring its importance in both public and animal health (Paliy et al. 2021; Vermaak and Boshoff 2022; Borhani et al. 2024).

PZQ is an effective anthelmintic drug used to treat infections caused by flatworms (Redman et al. 1996).

PZQ is administered orally in tablet form and is generally well-tolerated by patients. It is rapidly absorbed, widely distributed throughout the body, primarily metabolized in the liver, and excreted via the kidneys (Kogiannou et al. 2021). It has a broad safety margin (Gupta et al. 2021; Ghazy et al. 2021) and exhibits low toxicity (Pica-Mattoccia and Cioli 2012; Borrego-Sánchez et al. 2020). PZQ is considered safe, even in vulnerable populations, and poses no genotoxic risk (Montero and Ostrosky 1997; Prinsloo et al. 2019), making it the preferred treatment option for parasitic infections.

PZQ is often administered as a single-dose treatment, making it a convenient choice for schistosomiasis control programs in endemic areas (Doenhoff et al. 2009; da Paixão Siqueira et al. 2017; Kirubi 2020). However, in cases of severe or chronic infections, prolonged dosing regimens may be required. In addition to treating active infections, PZQ is also utilized in mass drug administration (MDA) programs aimed at reducing the overall parasite burden in at-risk populations (Ndeffo Mbah et al. 2014; Hotez and Lo 2020).

Despite its undeniable success of PZQ, concerns have been raised about the potential emergence of resistance in schistosome populations. While PZQ remains a cornerstone in the global fight against schistosomiasis, ongoing efforts are needed to monitor its long-term efficacy and to develop new therapeutic alternatives to combat emerging resistance challenges.

Oxamniquine

Oxamniquine (OXA), a derivative of 2-aminomethyl-tetrahydroquinoline, is an older medication used in the treatment of schistosomiasis, particularly for infections caused by S. mansoni (Pica-Mattoccia et al. 1989; Ferrari et al. 2003). Similar to PZQ, OXA is an antiparasitic drug that disrupts the metabolism of parasitic worms (Mukherjee et al. 2016; da Silva et al. 2017). Despite its decades-long success, the use of OXA is limited by several issues, including restricted availability in some countries, potentially high cost, and concerns about resistance development (Li et al. 2018).

OXA is administered orally, usually in tablet form, and is well tolerated by patients (Ahmad et al. 1991; Bartley 2017). However, it is important to note that its effectiveness is limited to S. mansoni infections and is not recommended for treating infections caused by other schistosome species, such as S. haematobium or S. japonicum (Ahmad et al. 1991; Bartley 2017).

Despite these limitations, OXA remains a useful therapeutic tool in certain regions where S. mansoni is endemic, although its role is less central than that of PZQ, which is more widely effective against multiple schistosome species.

Challenges of schistosomiasis treatment: mechanism of action and longevity

In the absence of effective vaccines for human helminth infections, repeated rounds of mass treatment with drug monotherapies, such as PZQ, are typically used for control in most developing countries.

Mechanism of action of current treatments on schistosomiasis

The mechanism of action of praziquantel

The mechanism of action of PZQ in the treatment of schistosomiasis involves several key physiological effects on the parasites. A major aspect is its ability to increase membrane permeability in schistosomes. Early studies by Shaw and Erasmus revealed structural alterations in the membrane of adult S. mansoni worms, showing the formation of desmosomes and invaginations, thus indicating the disruptive effect of PZQ on the integrity of the parasite’s membrane (Shaw and Erasmus 1983). These findings are corroborated by Liang et al. (2010), who demonstrated that PZQ induces a rapid increase in membrane permeability, causing calcium leaks and prolonged muscle contractions, ultimately leading to paralysis in the parasites. This membrane disruption triggers a cascade of cellular events that leaves the parasites vulnerable to the host’s immune response, thereby enhancing treatment effectiveness (Liang et al. 2010).

Another core mechanism of PZQ’s action is the disruption of calcium homeostasis. Voltage-dependent calcium channels (Cav) have been identified as critical targets of PZQ. Research by Chen et al. (2004) underscores the vital role these channels play in the neuromuscular system of schistosomes. By regulating calcium entry into muscle cells, Cav channels are important for muscle contraction and movement. Salvador-Recatalà and Greenberg (2012) further explain that PZQ modulates these channels, leading to dysregulation of intracellular calcium concentration, disturbing muscular function in the parasites (Salvador-Recatalà and Greenberg 2012).

The interaction between PZQ and the host’s immune system also plays an essential role in the drug’s efficacy. Aragon et al. (2009) observed that PZQ stimulates the production of cytokines and inflammatory mediators, which strengthens the host’s immune response and creates an inhospitable environment for the parasites. This immune activation is critical, as it facilitates the recognition and elimination of the parasites. Brindley and Sher (1987) and Doenhoff et al. (1987) also highlight that PZQ’s effectiveness depends largely on the host’s ability to develop a Th1 immune response, which is vital for eradicating the treated parasites. PZQ also impacts the reproductive capacity of schistosomes, particularly their eggs (Brindley and Sher 1987); (Doenhoff et al. 1987).

PZQ treatment also impacts the genetic diversity of schistosomes, which can have implications for their evolution. Coeli et al. (2013) observed a reduction in allelic diversity following PZQ administration. This decrease may compromise the long-term efficacy of treatments, as a less diverse population is more vulnerable to selective pressures, potentially facilitating the emergence of resistant strains.

the other hand Lamberton et al. (2017), also observed a significant decrease in the fertility of treated adult worms, leading to a reduction in the long-term transmission of the disease. These results underscore the importance of PZQ in combating the spread of the disease by altering the life cycle of the parasites. Xiao et al. (1985) demonstrated that PZQ inhibits the development of mature eggs, reducing their ability to hatch and infect intermediate hosts (Xiao et al. 1985).

The neurogenic effects of PZQ are manifested through notable modifications in neurogenic pathways. Chan et al. (2014) highlighted the impact of PZQ on dopaminergic and serotonergic pathways, which are essential for regulating the formation of the “axis” in planarians (Chan et al. 2014). These interactions reveal unexpected links between calcium and neuronal pathways, suggesting that PZQ may alter the motility and behavior of the parasites, thereby contributing to their paralysis and elimination. Furthermore, the identification of new target ion channels, particularly TRP channels, as indicated by the work of Park et al. (2021), opens new perspectives for researching the mechanisms of action of PZQ. The discovery of a TRPM channel specific to schistosomes as a potential target of PZQ enhances our understanding of the interactions between the drug and the ionic systems of schistosomes, providing opportunities for developing new therapeutic strategies (Park et al. 2021a).

Other potential drug targets of PZQ have been suggested. It has been proposed that the anti-schistosomal action of PZQ is mediated by binding to myosin light chain (Gnanasekar et al. 2009), glutathione transferase (McTigue et al. 1995), inhibition of sphingomyelinase activity (Vale et al. 2017), inhibition of phosphoinositide turnover (Cupit and Cunningham 2015), inhibition of nucleoside absorption, and reduction of schistosome glutathione concentration (Cupit and Cunningham 2015), or antagonism with the allergen-like tegument protein 1 of S. mansoni (SmTAL1) (Thomas et al. 2015). However, these suggested targets require rigorous investigation beyond the initial reports, and it is unclear whether these targets facilitate the two pillars of PZQ’s action against schistosomes (paralysis and tegument damage) (Cupit and Cunningham 2015; Park and Marchant 2020).

PZQ exerts its antiparasitic effects against schistosomiasis through a complex combination of physiological modifications at the cellular level in the parasites, interactions with the host’s immune system, and effects on the reproduction and regeneration of the parasites (Fig. 2). This multifactorial understanding could guide the development of new therapeutic strategies to enhance treatment efficacy and limit the evolution of resistance.

Fig. 2.

Summary of the different mechanisms of action of praziquantel

The mechanism of action of oxamniquine

OXA, a pro-drug, plays a crucial role in the treatment of schistosomiasis through several interconnected mechanisms of action. First, it requires enzymatic activation by the sulfotransferase enzyme SULT-OR, which is present in susceptible parasites. This activation transforms OXA into an active metabolite capable of interacting with the DNA of schistosomes, disrupting their cellular replication and leading to parasite death (Valentim et al. 2013). Furthermore, OXA directly interferes with the DNA synthesis mechanisms, causing genetic damage that inhibits cell division and compromises the viability of schistosomes (replication (da Silva et al. 2017; Kannigadu and N’Da 2020). Once inside the parasite, OXA is metabolized into an active compound that modifies essential processes for schistosome reproduction. This metabolite binds to the parasitic DNA, resulting in alterations that disrupt critical replication mechanisms (Valentim et al. 2013). Additionally, OXA is particularly effective against both immature and adult forms of the worms, allowing for the eradication of developing schistosomules and limiting the spread of the infection (Ferrari et al. 2003; da Silva et al. 2017). Thus, the action of OXA relies on a series of complementary mechanisms, ranging from enzymatic activation to interference with DNA, contributing to its antiparasitic efficacy.

The limitations of current treatments for schistosomiasis

Limitations of praziquantel

PZQ remains, to this day, the recommended first-line treatment for schistosomiasis, a parasitic disease that affects millions of people worldwide, primarily in tropical and subtropical regions. However, although PZQ is widely used due to its effectiveness against adult worms, it presents several significant limitations that compromise its long-term efficacy and pose major challenges for disease control programs.

Firstly, the low sensitivity of juvenile forms of the parasites to PZQ represents a significant barrier to the complete eradication of the infection. Indeed, PZQ is ineffective against schistosomula, the immature forms of the parasites, which evade treatment (Kaji 2020; Pillay 2022). This inefficacy is particularly problematic in the fight against schistosomiasis, as schistosomula, once inside the host’s body, continue to mature into adult worms. These adult parasites produce eggs that are responsible for the most severe clinical complications of the disease, such as liver damage, urinary infections, and kidney disorders (Horák et al. 2002; Skelly and Wilson 2006). Furthermore, the accumulation of eggs in tissues can lead to chronic inflammation and scarring, exacerbating morbidity in infected individuals.

Secondly, the lack of protection against reinfections is another notable limitation of praziquantel. Although this drug is effective in eliminating adult worms present in the body at the time of treatment, it does not provide lasting immunity against new infections (Molehin 2020a; Asuming-Brempong et al. 2022) Additionally, Tetteh-Quarcoo et al. (2020). This means that in regions where schistosomiasis transmission is endemic, treated individuals can quickly become reinfected after being re-exposed to the parasites. This issue makes disease control particularly challenging, especially in areas where access to clean water and adequate sanitation facilities is limited.

A third major challenge in the use of PZQ is the emergence of drug resistance. Indeed, the repeated distribution of PZQ in mass treatment programs, used for decades in many endemic countries, has exerted selective pressure on parasite populations, promoting the emergence of strains resistant or tolerant to the drug (Fallon and Doenhoff 1994; Fallon et al. 1995; Ismail et al. 1996; Jaoko et al. 1996; Stelma et al. 1997; Cioli 2000). Nogueira et al. (2022; Couto et al. 2011; Tetteh-Quarcoo et al. 2020; Botros and Bennett 2007). This resistance has been documented in several regions, notably in Egypt (Ismail et al. 1996), Senegal (Gryseels et al. 2001), and various parts of sub-Saharan Africa (Doenhoff and Pica-Mattoccia 2006), Kenya (Melman et al. 2009), Uganda(Stothard et al. 2013), Sichuan Province (Seto et al. 2011). Studies have also reported cases of PZQ resistance in several species of Schistosoma, such as S. mansoni, S. japonicum, and S. haematobium, as well as in other species of cestodes (Cioli 2000). Mutations in drug targets can affect the drug’s binding ability and interfere with the target’s activity. Potential resistance to PZQ may arise from genetic mutations in SmTRPM, which could reduce PZQ efficacy in S. mansoni (Park et al. 2021b). Additionally, ABC transporters involved in the transmembrane transport of toxins and xenobiotics may also contribute to this resistance (Lespine et al. 2008). Furthermore, voltage-gated calcium channels are implicated in this phenomenon. Indeed, Kohn et al. (2001) observed that cells expressing the structurally unusual beta subunit of voltage-gated calcium channels exhibit novel sensitivity to PZQ (Kohn et al. 2001).

It is also important to note that the quality of life of patients treated with PZQ can be affected by the side effects associated with this drug. Although the adverse effects of PZQ are generally mild, some patients experience abdominal pain, headaches, nausea, and other uncomfortable symptoms nausea (Jaoko et al. 1996). These side effects, while not severe, may hinder treatment adherence, especially in contexts where treatments need to be repeated due to the high risk of reinfection.

Furthermore, epidemiological factors can influence the efficacy of praziquantel. Studies conducted in certain endemic regions have shown a decrease in treatment effectiveness, notably in new foci of S. mansoni in Senegal (Fallon et al. 1995). This decline in efficacy can be attributed to environmental factors, genetic variations in the parasites, or prolonged use of PZQ in these areas, raising concerns about the sustainability of control efforts in hyperendemic settings (Cioli and Pica-Mattoccia 2003). This underscores the complexity of combating schistosomiasis, which must take into account not only the biology of the parasite but also local transmission dynamics and the specific characteristics of affected populations. However, Cioli et al. (2000), address the limitations of current treatments for schistosomiasis, highlighting that the low cure rates observed with PZQ in some schistosomiasis foci may be attributable to epidemiological factors rather than parasite resistance to the drug (Cioli 2000).

Finally, genetic variations among different parasitic strains must also be considered. Research by Cioli et al. (2004) revealed differences in PZQ sensitivity between S. mansoni isolates, suggesting that resistance may result from selective pressures in regions where the drug has been widely used. Understanding these genetic variations is crucial to anticipate the evolution of resistance and to adjust control strategies accordingly.

In conclusion, the current limitations of PZQ use in the fight against schistosomiasis highlight the complex challenges faced by public health programs. It is essential to adopt a proactive approach that combines research on new therapeutic targets, the development of alternative treatments, and the implementation of integrated disease control strategies. Only such an approach will help overcome the present obstacles and achieve the long-term goal of eradicating schistosomiasis.

Limitations of oxamniquine

Despite its decades-long success, OXA’s use is limited by a number of problems, including limited availability and efficacity, a potentially high cost, and concerns about resistance development (Li et al. 2018).

The resistance to OXA in S. mansoni poses a significant challenge in the treatment of schistosomiasis, particularly in South America, where this medication has been predominantly used since the 1970s. Studies, such as those by Valentim et al. (2013), have identified a quantitative trait locus (QTL) on chromosome 6 associated with this resistance, indicating a genetic basis for the emergence of resistant strains. Furthermore, mutations identified in the sulfotransferase gene (SULT-OR), which is essential for the activation of OXA, contribute to rendering some parasites insensitive to this treatment (Valentim et al. 2013). Notably, the mutation (p.E142del) has been closely linked to resistance to OXA, illustrating the importance of genetic variations in treatment response (Rogers and Bueding 1971). Another mutation, designated (p.C35R), has also been observed in strains from incurable patients in Brazil (Pica-Mattoccia et al. 1992).

Indeed, the efficacy of OXA now appears inferior to that of other treatments, particularly PZQ. Studies indicate that PZQ achieves cure rates exceeding 90% among patients, while OXA manages only a cure rate of 42% in certain regions (Ferrari et al. 2003). This situation emphasizes the clinical limitations of OXA in treating schistosomiasis, especially in endemic areas where resistant strains are more prevalent.

Another concerning aspect of OXA’s use relates to potential side effects. Studies have reported adverse effects such as abdominal pain, nausea, and vomiting, which limit its use, particularly among children and individuals with comorbidities (Li et al. 2018).

The recommended dosage of OXA, set at 20 mg/kg per day, is also more complex than that of PZQ, which is typically administered at a dose of 60 mg/kg per day for three days. This complexity in dosing can lead to adherence issues and complicate treatment follow-u (Ferrari et al. 2003).

While OXA has shown some efficacy in reducing morbidity related to schistosomiasis, its use is complicated by the emergence of resistant strains, making it difficult to treat severe forms of the disease, particularly those associated with hepatic and splenic complications, such as hepatic fibrosis and portal hypertension (Li et al. 2018).

Finally, despite ongoing research aimed at developing OXA derivatives, the lack of long-term studies on their efficacy and safety raises concerns regarding their clinical use. It is essential to strengthen ongoing clinical trials to thoroughly evaluate these new compounds and their potential to overcome the observed resistance (LoVerde et al. 2021). These discoveries have facilitated the development of new OXA derivatives capable of targeting the three main schistosome species responsible for schistosomiasis. One of these derivatives, CIDD-0149830, proved to be extremely promising, showing 100% efficacy against parasites in just five days (LoVerde et al. 2021). This approach also aims to combine these new derivatives with PZQ to combat increasing resistance and improve treatment efficacy.

Thus, it is clear that OXA, while having played a historical role in the treatment of schistosomiasis, must give way to more effective and safer therapeutic alternatives to meet the current challenges in the fight against this disease.

Innovative therapeutic and vaccine approaches in the fight against schistosomiasis

Future approaches to combat schistosomiasis are focusing on innovative avenues, ranging from improved treatments to vaccine research. The therapeutic optimization of PZQ has been the subject of extensive research over the past fifty years. According to D’Abbrunzo (D’Abbrunzo et al. 2023), various studies have been conducted to enhance the properties of PZQ through innovative formulation strategies. These include the preparation of solid dispersions incorporating excipients such as povidone, sodium starch glycolate, mesoporous silica, as well as complexes of calcium carbonate, mannitol, Gelucire, and clay minerals. Systems such as PZQ-β-cyclodextrins, PZQ liposomes, and solid polymeric and lipid nanoparticles have also been developed (D’Abbrunzo et al. 2023). Other approaches include the implementation of coground systems, rapidly dispersible granules, as well as techniques for melt granulation and ultrasonic spray freezing. More recently, the preparation of micro and nanocrystals has been explored. Today, promising new avenues are emerging to optimize the properties of PZQ, including: (i) deracemization through the formation of diastereomeric cocrystals (Devogelaer et al. 2021; Rodríguez-Ruiz et al. 2022; Gerard et al. 2024); (ii) identification of crystalline polymorphs (Zanolla et al. 2018; De Moraes et al. 2023); and (iii) development of multicomponent systems, such as solvates, hydrates, and cocrystals (D’Abbrunzo et al. 2023, 2024; Mureşan-Pop et al. 2024).

On the other hand, although OXA has been abandoned as a first-line treatment, recent research has demonstrated its potential. In 2021, LoVerde et al. developed new derivatives of OXA targeting the three main species of schistosomes responsible for schistosomiasis. One of these derivatives, CIDD-0149830, showed remarkable efficacy of 100% against the parasites within just five days (LoVerde et al. 2021). This approach aims to combine these new derivatives with PZQ to address the growing resistance and enhance treatment efficacy (LoVerde et al. 2021). However, limitations remain, including ineffectiveness against juvenile schistosomes and the risk of drug resistance, highlighting the urgent need for effective vaccination strategies (McManus et al. 2020).

The development of a vaccine against schistosomiasis presents significant challenges. Despite nearly four decades of research, no effective vaccine is currently available. To date, none of the existing immunogens or vaccination protocols have succeeded in inducing sufficient levels of resistance to significantly reduce human infection or disease (Sher et al. 1989; Abdel Aziz et al. 2019). The complexity of the schistosome life cycle and the host immune responses pose additional obstacles. Although several vaccine candidates have shown promising results in animal models, their transition to human application is hampered by the need to identify protective antigens capable of generating effective immune responses without causing adverse effects related to egg antigens (Lebens et al. 2004).

The current state of protein-based vaccine candidates against S. mansoni infection is showing promising developments, with several candidates in preclinical trials. These include Paramyosin, Sm29, and SmKI-1. Paramyosin, a protein crucial for the parasite’s structure and motility, has shown promising immune responses in animal studies(Deng et al. 2007; McManus and Loukas 2008). Sm29, a surface protein of S. mansoni, is being developed for its potential to induce immune protection and reduce parasite burden (Cardoso et al. 2008; Chura-Chambi et al. 2013). SmKI-1, a kallikrein inhibitor, aims to neutralize the parasite’s immune evasion mechanisms, thereby enhancing the host’s defenses (Ranasinghe et al. 2015).

The Recommendations for schistosomiasis vaccine development emphasize that an effective vaccine should significantly reduce morbidity and lower the burden of adult worms and egg excretion rates by 75% in immunized individuals (Siddiqui and Siddiqui 2017; Molehin 2020b).

The future perspectives for protein-based vaccine candidates against Schistosoma infection are promising, as current efforts focus on targeting S. mansoni while aiming for cross-protection against S. haematobium (Hotez and Bottazzi 2023). The candidate, Sm-TSP-2, is in Phase 2 clinical trials in Uganda and targets a surface protein of S. mansoni (Keitel et al. 2019; Li et al. 2021). The candidate, developed by the Oswaldo Cruz Institute, utilizes a fatty acid-binding protein and has shown promising results, including protection against other parasitic infections (Tendler et al. 2015, 2018). Lastly, Sm-p80, also effective against S. mansoni and offering protection against S. haematobium, has recently commenced clinical trials (Molehin et al. 2017; Siddiqui et al. 2018; Zhang et al. 2018).

These candidates represent various immunological approaches, ranging from protein-based vaccines to recombinant antigen formulations, aimed at stimulating protective immunity against S. mansoni (Molehin 2020b).

The importance of the lifespan of schistosomes in evaluating treatment effectiveness

The longevity of schistosomes, the parasitic worms responsible for schistosomiasis, is a fascinating subject that requires a multidisciplinary approach. Data collected to date reveal significant variability in the lifespan of these parasites, influenced by various factors such as parasite species, host, and environmental conditions.

For example, studies have shown that S. mansoni parasites have an average lifespan of 4 to 5 years in humans, while S. haematobium parasites have an average lifespan of 7 to 10 years in humans (King et al. 2005). Research by Fulford et al. (1995), provided more precise estimates, indicating worm lifespans ranging from 5.7 to 10.5 years with a 95% confidence interval. Conversely, Goddard and Jordan (1980) (Goddard and Jordan 1980), suggested an average lifespan of about 3.3 years, with approximate 95% confidence limits of 2.7 to 4.5 years. However, estimated average lifespans can vary considerably depending on the cohorts studied. For instance, Vermund et al. (1983), reported average lifespans of up to 37 years for some cohorts, highlighting the complexity of the life dynamics of these parasites. It’s also important to note that schistosome longevity can exceed several decades, as documented cases have shown these parasites persisting in patients for over 30 years for S. mansoni (Baron 1939), S. japonicum (Markel et al. 1978)and S. haematobium (Fairley 1931). The World Health Organization reports the average lifespan of schistosomes to be around 5 years for S. japonicum, S. mansoni, and S. haematobium (OMS 1985).

This exceptional longevity can be attributed to several evolutionary and adaptive mechanisms. Schistosomes have developed strategies to modulate the host’s immune response, allowing them to avoid destruction. Additionally, their continuous reproductive cycle, with females regularly laying eggs throughout their adult life, helps maintain a stable parasite population in the host.

Furthermore, these parasites have developed physiological adaptations to survive in various environments, including the vascular systems of mammalian hosts. Understanding the mechanisms of schistosome longevity is crucial for developing effective strategies to combat schistosomiasis, a disease that affects millions of people worldwide. By targeting these mechanisms, it’s possible to develop more effective prevention and treatment approaches to control this devastating disease.

The variability in schistosome lifespan raises important questions regarding the evaluation of treatment efficacy. To ensure complete elimination of adult parasites, treatments must be administered over a sufficiently long period. However, this duration must be carefully balanced to avoid undesirable side effects. Thus, follow-up of treated patients over several years is necessary to assess treatment efficacy and prevent long-term reinfection (Webster et al. 2014). It’s crucial to recognize that even in areas where schistosomiasis transmission is reduced, reinfection by adult parasites can occur several years after initial treatment. For this reason, adopting combined prevention strategies, such as improving hygiene and sanitation, in addition to drug treatments, is recommended (World health Organization 2021).

Conclusion

The newly introduced WHO NTD roadmap and guidelines set an ambitious control strategy to achieve the elimination of schistosomiasis as a public health problem by 2030. Despite the effectiveness of PZQ, its limitations, including the potential for resistance development and variable treatment outcomes, highlight the urgency for continued research into alternative treatments and preventive strategies. Understanding the complex mechanisms of schistosome longevity and their interaction with the host immune system is essential for developing more targeted therapies. At present, there are no anti-schistosomal drugs undergoing clinical trials in humans, thus we must strive to retain the usefulness of PZQ in the schistosomiasis control toolbox.

Author contributions

Conceptualization, A.B. (Abdelaaali Balahbib) and A.F.; methodology, A.B(Abddelhakim Bouyahya), A.B (Abdelaali Balahbib); software, A.B. (Abddelhakim Bouyahya)and A.B (Abdelaaali Balahbib); validation, A.B. (Abdelaaali Balahbib), N.E. and A.F; formal analysis, A.B. (Abddelhakim Bouyahya).; investigation, H.E, Y.E. K.H; resources,, H.E, Y.E. K.H, A.F; data curation, A.B (Abdelaali Balahbib), H.E; writing—original draft preparation,. A.B (Abdelaali Balahbib), K.H, Y.E; writing—review and editing, A.B (Abdelaali Balahbib), A.B (Abddelhakim Bouyahya), A.F.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Data availability

All data generated during the study are included in this article.

Declarations

Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.