Alok Kafle
Suvash Chandra Ojha- 1Department of Tropical Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- 2WHO Collaborating Centre for Research and Control of Opisthorchiasis, Khon Kaen University, Khon Kaen, Thailand
- 3Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, China
The liver fluke O. viverrini (Opisthorchis viverrini), a neglected tropical disease (NTD), endemic to the Great Mekong Subregion (GMS), mainly afflicts the northeastern region of Thailand. It is a leading cause of cholangiocarcinoma (CCA) in humans. Presently, the treatment modalities for opisthorchiasis incorporate the use of the antihelminthic drug praziquantel, the rapid occurrence of reinfection, and the looming threat of drug resistance highlight the urgent need for vaccine development. Recent advances in “omics” technologies have proven to be a powerful tool for such studies. Utilizing candidate proteins identified through proteomics and refined via immunoproteomics, reverse vaccinology (RV) offers promising prospects for designing vaccines targeting essential antibody responses to eliminate parasite. Machine learning-based computational tools can predict epitopes of candidate protein/antigens exhibiting high binding affinities for B cells, MHC classes I and II, indicating strong potential for triggering both humoral and cell-mediated immune responses. Subsequently, these vaccine designs can undergo population-specific testing and docking/dynamics studies to assess efficacy and synergistic immunogenicity. Hence, refining proteomics data through immunoinformatics and employing computational tools to generate antigen-specific targets for trials offers a targeted and efficient approach to vaccine development that applies to all domains of parasite infections. In this review, we delve into the strategic antigen selection process using omics modalities for the O. viverrini parasite and propose an innovative framework for vaccine design. We harness omics technologies to revolutionize vaccine development, promising accelerated discoveries and streamlined preclinical and clinical evaluations.
GRAPHICAL ABSTRACT | Sincere gratitude to Prof. Jennifer Keiser for generously granting permission for the use of tegument picture in this graphical abstract.
1 Introduction
Opisthorchiasis caused by O. viverrini (Opisthorchis viverrini; Ov) infection is a significant public health issue in many Southeast Asian countries, including Thailand, Lao PDR, Vietnam, and Cambodia, infecting more than 12 million people (Kaewpitoon et al., 2008; Sripa et al., 2021). The liver fluke infection is caused by eating raw or uncooked fish products, which is common in Thailand’s northeastern and northern regions, particularly in rural areas. Infection progression can result in cholangitis, obstructive jaundice, hepatomegaly, cholecystitis, cholelithiasis, and cholangiocarcinoma (CCA), among other hepatic disorders (Sripa et al., 2007). Biliary damage caused by O. viverrini examined in the hamster model showed that the parasite infection can solely cause CCA in the long term (Songserm et al., 2009). Hence, O. viverrini and C. sinensis liver fluke parasites have been classified as “Group 1” biological carcinogens (World Health Organization, 1994).
Upon ingesting raw infected fish, O. viverrini metacercariae excyst in the duodenum. The newly excysted juveniles (NEJs) start to migrate towards the ampulla of Vater, relying on chemotaxis and glycogen reserves for the movement (Tielens et al., 1982). Once within the bile duct, they mature into self-fertilizing adult flukes in the bile ducts, thereby acquiring the reproductive capabilities necessary to release eggs (Harinasuta and Harinasuta, 1984; Orido, 1990). The pathogenic mechanisms of O. viverrini-induced CCA (Ov-CCA) involve parasite-feeding-triggered inflammation, host-helminth interactions at the tegument interface, and immunopathology driven by secreted ES (Excretory Secretory products) products and EVs (Extracellular Vesicles) effector repertoire (Chaiyadet et al., 2019; Glaser, Gaudio et al., 2009; Sripa, 2003; Sripa et al., 2012).
Understanding parasite biology and host interactions better is imperative to identify new drug targets or potential vaccine candidates. The analysis of genomic (Laha et al., 2007; Young et al., 2014), transcriptomic (Jex et al., 2012), and proteomic (Mulvenna et al., 2010) data of O. viverrini has provided us with a deeper understanding of Ov-tegument and secreted proteins. These proteins may function both protectively and as immunogens in host-specific interactions. Despite substantial research efforts and omics advancement, no vaccine conferring efficacious protection against trematode infections has achieved the level of effectiveness required for commercial deployment (McManus, 2020). Furthermore, the lack of interest from pharmaceutical industries and attention from health agencies and policies is related to the fact that no vaccine against opisthorchiasis is available for clinical use. This can also be attributed partially to the abundance of proteomics data and findings, yet relatively less focus on filtering and analysing these datas for wet lab and translational investigations. Hence, incorporating immunoproteomics is essential in this context, as it facilitates a filter in the rigorous validation of potential markers, thereby bridging the gap between discovery and clinical verification (Pedersen et al., 2005; Ejazi et al., 2018). Moreover, previous investigations exploring antibody responses in the context of parasitic infections have demonstrated the value and feasibility of such immunoproteomics-based studies (Jedlina-Panasiuk, 2002; Pleasance et al., 2011; Zhang et al., 2015; Driguez et al., 2016).
Antigens identified through immunoproteomics analysis spanning from the tegument to ES molecules and EVs of O. viverrini can be computationally evaluated. Furthermore, assessing vaccine solubility, antigenicity, immunogenicity, and allergenicity predictions informs the selection of epitopes optimally suited to activating robust host defences (Kapuganti et al., 2022). For the last few years, advanced Artificial intelligence (AI) and Machine Learning (ML) algorithms to predict protein structures and modelling have permitted structural prediction with about 90% accuracy in silico (Stevens and He, 2022). Moreover, molecular docking simulations yield insights into projected binding dynamics between prioritised epitopes and immune receptors (Sahoo et al., 2022; Che et al., 2023). Access to these two web-based servers alone holds immense potential to significantly streamline academic research efforts and lead to substantial cost savings. We believe it is now imperative to incorporate immunoinformatics in the prioritisation process before in vitro and in vivo studies, thereby propelling the progression toward clinical trials more efficiently (Figure 1). Hence, this review highlights the initial phases in vaccine design, which involves the integration of immunoproteomics utilising omics data and computational bioinformatics tools for the systematic studies on helminthic parasites. This integration has the potential to identify numerous protein marker candidates suitable for clinical investigations and to advance the rational design of multi-epitope vaccines against opisthorchiasis.
Figure 1. Translational progression by integrating Omics, Immunoproteomics, and in vitro and in vivo studies seamlessly accelerates vaccine development from discovery to clinical application.
2 Current knowledge of the biology and -omics of Opisthorchis viverrini parasite
The multi-omics journey for O. viverrini started over 15 years ago by generating and analysing so-called expressed sequence tags (EST) that profiled the first description of gene discovery for the liver fluke O. viverrini (Laha et al., 2007). Since 2010, the integration of multi-omics strategies and methodologies, including liquid chromatography-mass spectrometry (LC-MS), next-generation sequencing, and various -omics based technologies, has significantly enhanced our understanding of trematode biology-spanning across the field of genomics, transcriptomics, proteomics, metabolomics, and glycomics (Table 1) (Mulvenna et al., 2010; Jex et al., 2012; Talabnin et al., 2013; Young et al., 2014; Prasopdee et al., 2019; Kokova et al., 2020). Therefore, research efforts focused on the genomes, transcriptomes, and proteomes of O. viverrini isolates at a global level hold great potential to significantly advance our understanding of the molecular pathogenesis of O. viverrini associated CCA. Such investigations are expected to lay the groundwork for identifying critical targets for designing new interventions.
Table 1. Overview of omics methods and technologies in Opisthorchis viverrini research.
2.1 Genomics and transcriptomics
Before exploring the O. viverrini genome and transcriptome, molecular-based studies identified, characterised, and proposed potential drug targets and pathways for exploration. The groundbreaking work of Young et al. (2014) in elucidating the draft genome of O. viverrini provided an advanced understanding of the genetic makeup of the liver fluke parasite (Young et al., 2014). This study provided the first global understanding of the biology of O. viverrini during its establishment and adaptation to life within the bile duct, helping researchers know how the parasite persists in this unique ecological niche.
Genomic findings provided insights into the developmental stages of O. viverrini, revealing that juvenile and immature forms exhibit increased molecular activity and cellular growth. These processes are crucial for their maturation into reproductively competent adults. The expression of distinct genes helps the O. viverrini parasite facilitate tissue differentiation, development, and immune evasion, which are functions that become less active in adulthood. The genomic study utilised existing O. viverrini transcriptomic data at both the assembly and annotation stages. It continued to map RNA-seq to infer relative expression levels of predicted genes and explore developmental expression changes (Jex et al., 2012). This mapping of transcripts to genes allowed researchers to annotate the predicted functional pathways of these genes based on sequence homology to characterised genes in other species, thereby tentatively linking genes to relevant biological processes such as metabolism, growth, and reproduction, even in the absence of complete ortholog characterisation in O. viverrini.
Hence, comparing transcript expression profiles across developmental stages of O. viverrini may help identify genes involved in immune evasion and tissue-specific functions, offering potential intervention targets to block the establishment during early parasite infections. Moreover, the transcriptome analysis of adult and juvenile O. viverrini worms revealed that immature worms exhibited upregulation in the transcription of peptides associated with energy metabolism. This included oxidative phosphorylation, fatty acid metabolism, and amino acid degradation. In contrast, adult parasites showed increased levels of transcripts involved in nucleotide metabolic processes and processing, oocyte meiosis, and egg-specific antigens. The elevated metabolic activity-related genes observed in the juvenile and immature stages may indicate an anabolic state aimed at acquiring sufficient nutrients from the host to support rapid growth and development. Growth hormones likely play a crucial role in driving tissue proliferation, elongation, and differentiation in juvenile and immature parasites. However, the expression of growth hormones may be downregulated once the adult form is attained. In contrast, mature adults may shift towards a relatively catabolic state focused on survival and reproduction (Jex et al., 2012; Young et al., 2014). Thus, genomic and transcriptomic data availability can help us compare gene expression across developmental stages, reveal the stage-specific biological processes, indicate potential therapeutic vulnerabilities, and offer a more holistic view of the molecular adaptions that enable the parasite’s complex life cycle.
2.2 Proteomics
In 2009, Boonmee et al. employed two-dimensional gel electrophoresis to analyse the protein secretion of O. viverrini at various maturation stages (Boonmee et al., 2003). These distinctions were identified in the 4-week adult fluke compared to the first-week juveniles, indicating an age-dependent augmentation in protein secretion during the liver fluke maturation. This study provides insights into the protein expression patterns of O. viverrini during development, which can significantly contribute to our understanding of the pathogenesis of opisthorchiasis.
In 2010, Mulvenna et al. conducted the first detailed proteomic analysis of O. viverrini, using sequential solubilisation of isolated teguments, and a subset of these was localised to the surface membrane of the tegument by labelling O. viverrini flukes with biotin and confirming surface localisation with fluorescence microscopy (Mulvenna et al., 2010). This fractionation approach identified five differentially expressed proteins between juvenile and immature stages, of which two were uncharacterised proteins, Experimental autoimmune prostatitis antigen 2 (EAP-2) involved in calcium homeostasis, the cysteine protease legumain, and two granulins that function as growth factors. The study unveiled two granulins, OvGRN-1 and OvGRN-2, as growth factors expressed in both juvenile and adult parasite stages. Alongside identifying various other peptidases and potential markers and targets, their involvement in crucial processes is implied, with certain protein expressions persisting throughout immature and adult life stages (Table 2). This underscores the potential of omics, advanced informatics technologies, and the increasing accessibility of annotated helminth genomes to substantially expedite progress in computational and practical inquiries within NTDs-based studies.
Table 2. Identifying potential therapeutic targets from -omics data.
2.3 Glycomics and metabolomics
These omics fields are in their early stages of research, and ample exploration is yet to be undertaken in this domain. O. viverrini helminth can express distinctive and highly immunogenic glycans; these glycan antigens share structural features with those present in the intermediate and vertebrate hosts, thus resembling host-like glycans (van Die and Cummings, 2009). The immunogenicity of glycans present on the surface proteins of parasites, especially on the O. viverrini tegument, is a critical factor in the parasite’s ability to establish infection and modulate the host immune response (Talabnin et al., 2013). Thus, identifying tegument glycoproteins and their glycan structures in developmental stages can help discover targets that elicit a protective immune response during the early stages of infection (Garcia-Campos et al., 2016).
Metabolomics is another crucial facet of omics research. Studying changes in the parasite’s metabolome during different life stages and in response to the host environment can provide clues about metabolic pathways vital to the parasite’s survival. In the case of Opisthorchis felinues, a plasma metabolomics study of the temporal response to opisthorchiasis in an animal model revealed an altered metabolic response in the host, characterised by amino acid depletion and alterations in lipoprotein and cholesterol levels (Kokova et al., 2020). These alterations likely represent a host defence mechanism against the infection, offering perspectives/understanding that could guide therapeutic approaches.
Therefore, integrating various “omics” techniques, including genomics, transcriptomics, proteomics, glycomics, and metabolomics, can lead to a more profound understanding of the dynamic interaction between O. viverrini and its host. In-depth Omics analyses literature discussed above indicate juvenile parasites’ role in upregulating energy metabolism to support anabolic processes during development, synthesising complex molecules from simpler precursors. Conversely, adult parasites transition to lower metabolic activity and growth hormone expression, prioritising survival and reproduction over continued somatic growth (Figure 2). Hence, immunoproteomic approaches, integrating host serology, capture real-time dynamics in the interplay between fluke antigens and the immune response across infection stages, providing a system-level understanding of liver fluke parasite-regulated immune modulation and complementing proteomics in action.
Figure 2. Schematic representation of hypothesised developmental (stage-specific) metabolic profiles and functions of Opisthorchis viverrini based on omics analyses.
3 Exploring host-parasite interactions: Integrating omics discovery with immunoproteomics
As -omics techniques enable the broad discovery of temporally-resolved molecular alterations underlying host-parasite interactions, disease progression, and therapeutic targets during different stages of parasite infection (Hasin et al., 2017; Mitreva, 2022). Considerable progress in parasitology has been made through generating and interrogating omics data (Gardinassi et al., 2018; Liu et al., 2021; Athieniti and Spyrou, 2023). The term “immunoproteomics” is becoming a mature field with potential impact on developing immunoproteomics-based assays and vaccines (Fulton and Walker, 2013). Immunoproteomics explicitly profiles the host immune recognition of protein antigens, aiding the isolation of immunoreactive proteins and leveraging such data to predict and prioritise optimal vaccine candidates efficiently (Dennehy and McClean, 2012).
Immunocapture of antigenic proteins followed by mass spectrometry has proven an effective strategy for learning vaccine targets from trematode parasites (Bennett and Robinson, 2021). The assays have played a crucial role in identifying antigenic proteins from parasitic organisms, including parasitic trematodes (Reamtong, 2013). They leverage an expanding array of technologies to identify and quantify antigenic peptides and proteins that induce immunity (Hayes et al., 2018).
The immunoproteomics techniques include a wide range of gel-based, array-based, mass spectrometry, DNA-based, and in silico methodologies to gain unprecedented insights into disease aetiology and progression and facilitate the identification of novel vaccine candidates and biomarker discovery (Table 3). By comprehensively profiling the host immune response at the protein (antigen) level, immunoproteomics enhances our understanding of pathogenic mechanisms and enables accelerated selection of optimal antigens for rational vaccine design against complex infectious diseases. Therefore, integrating immunoproteomics strategies with omics-related discoveries provides a powerful approach for unravelling the functions of upregulated proteins during the infection and a successful vaccine design.
Table 3. This table compares the principles, advantages, and limitations and provides an immunoproteomics workflow technique to identify antigens from the liver fluke Opisthorchis viverrini.
3.1 Tegument of O. viverrini as potential vaccine target and biomarker discovery
Immunoproteomics, while crucial for vaccine development, also plays a pivotal role in biomarker discovery and diagnostics by identifying antigens that elicit immune responses (Costa et al., 2023; Germanó et al., 2022; Shi et al., 2018; Zawistowska-Deniziak et al., 2021). The tegument of O. viverrini, a multinuclear syncytium, presents an enticing prospect for vaccine development due to its direct contact with the host bile duct and immune system. Vaccination can effectively stimulate the production of both mucosal and systemic antibodies. Moreover, the anatomical arrangement of O. viverrini allows for an immediate response of the tegument muscles to external stimuli such as mechanical pressure, ion gradients, nutrient gradients, and damage by deviating immune response that favours parasite survival in the host or avoiding damage through the release of ES products and EVs from the tegument (Chaiyadet et al., 2017; Sripa et al., 2012; Thompson and Geary, 2003).
The tegument analysis of the array of proteins in O. viverrini is crucial for unravelling the intricate host-parasite relationship, enhancing opisthorchiasis diagnosis, and advancing the development of marker based studies, therapeutic target based studies to manage O. viverrini infection effectively (Liau et al., 2023; Kafle and Suttiprapa, 2024). Studies using serum from O. viverrini-infected animals and humans have shown seroreactivity with antigens of the tegument, eggs, reproductive organs, and secretory products (Wilkins et al., 1999; Kafle and Suttiprapa, 2024). These proteins have the potential to be considered vaccine candidates and are more likely to come into contact with the host and may play roles in the parasite’s survival (Young et al., 2014; Molehin et al., 2022). The scanning electron microscopy of the tegument membrane demonstrated stage-specific morphological alterations on the surface of the O. viverrini parasite (Apinhasmit et la., 1993). Moreover, several studies have shown differences in tegument proteins based on the gender of worms (Pérez-Sánchez et al., 2008; Zhang et al., 2013; Winkelmann et al., 2022). Thus providing robust evidence for the pivotal role of tegument proteins in parasite reproduction, signal transduction, nutrition, pathogenesis, and host immune modulation (Dalton et al., 2004; Loukas et al., 2007). These interactions are postulated to occur through the parasites’ outer tegument layer and the release of soluble metabolites (Suttiprapa et al., 2018), and this intricate crosstalk fosters tumorigenesis through complex intercellular communication (Elinav et al., 2013).
Moreover, the surface proteins are often considered promising biomarkers due to their heightened specificity for pathogens, particularly in host-parasite interactions. This specificity reduces the likelihood of cross-reactivity with host proteins, making them valuable targets for diagnostic and therapeutic purposes (Retra et al., 2015; Zhang et al., 2015; de Jong and Kocer, 2023).
3.2 Early interaction of O. viverrini with the host immune system
The survival and pathogenesis of O. viverrini depend on the successful evasion of the host immune response by the juvenile and immature fluke stages, which mature into hermaphrodite adults, eventually causing opisthorchiasis. It has been observed that O. viverrini metacercaria possesses several antigens similar to those found in adult worms and their metabolic products (Wongratanacheewin et al., 1988).
Comparing protein profiles of O. viverrini metacercariae, NEJs to developing immature and mature worms helps reveal stage-specific protein expression. This analysis using LC-MS and bioinformatics may offer insights into the roles of these proteins in the parasite’s development, survival, and reproduction. Several studies have demonstrated the early detection of antibodies in serum as early as 15 days post-infection, with notable inflammatory cell infiltration and the onset of hepatic pathology observed from the third day following infection (Bhamarapravati et al., 1978; Chawengkirttikul and Sirisinha, 1988). This suggests that NEJs and immature O. viverrini flukes interact and activate the host immune system during the initial invasion and establishment phases. Furthermore, the suggestion that O. viverrini induces immune-suppressive responses early on may facilitate parasite persistence, thereby contributing to developing hepatobiliary diseases associated with chronic O. viverrini infection (Sripa et al., 2018). Such investigations identify host-upregulated proteins and signalling pathways detrimental to the parasite, which is crucial for uncovering potential survival strategies in susceptible hosts.
4 Integrating immunoproteomics with immunoinformatics for discovering vaccine candidate
With the plethora of knowledge in the Omics domain, immunoinformatics, combining immunology and bioinformatics, offers innovative solutions in drug design and identifying vaccine candidates (María et al., 2017; Tomar, 2020). Variations in proteins released in the form of EVs (Trelis et al., 2022) and ES proteins (Wang et al., 2013; Yeshi et al., 2022), and tegument surface proteins may help O. viverrini maintain stability, survival, and immune evasion strategies. This can be explored in the systematic vaccine design (Figure 3). Hence, whole proteome analysis in trematode parasitism is beneficial for identifying crucial parasite proteins associated with virulence, exploring essential protein interactions, and uncovering distinctive immuno-modulatory mechanisms contributing to prolonged infection (van der Ree and Mutapi, 2015). Moreover, longitudinal profiling of antibody responses through immunoproteomic tools reveals antigenic proteins expressed in specific parasite developmental stages, from NEJ to immature and adult developmental phases.
Figure 3. Step-by-step thematic guide for vaccine construction against Opisthorchis viverrini.
The strategy for developing a vaccine against cancer-inducing O. viverrini parasites involves using epitopes from antigens to elicit an immune response. However, the primary challenge in creating a cancer vaccine lies in understanding the immunology of infection and identifying inflammation-inducing antigens that can potentially help parasites in vital functions. These challenges can be addressed by blending omics and immunoproteomics results with immunoinformatics (Figure 4).
Figure 4. Integrated approaches in vaccine development against Opisthorchis viverrini.
The in silico screening and experimental validation process streamlines identifying and evaluating potential antigens from a liver fluke parasite, offering a faster and more efficient alternative to traditional methods. Candidate antigens can be evaluated in silico for population coverage (Bui et al., 2006), antigenicity (Doytchinova and Flower, 2007), physicochemical properties (Wilkins et al., 1999), and ability to induce B- and T-cell epitopes (Bui et al., 2006; Khan et al., 2022). Particularly intriguing are fluke-specific antigens predicted to stimulate both humoral and cellular immune responses in infected hosts, reflecting scientific inclination and necessity. Structural modelling and prediction of immunogenic epitopes using servers like AlphaFold2 (Jumper et al., 2021; Yang, et al., 2023) allows rigorous in vitro testing through molecular docking and dynamics to generate hypotheses regarding immune receptors, proteins and designed vaccine interaction (Soleymani et al., 2022). Recombinant protein expression techniques such as cloning predicted multi-epitope subsequences into prokaryotic vectors like pET28b (+) provide a robust means of antigen production and evaluation in immunogenicity studies. (Martinelli, 2022). Various computational and bioinformatics tools and techniques are available in immunoinformatics, particularly in the context of vaccine development (Table 4), which can be utilized for parasitic and infectious diseases.
Table 4. Comprehensive methodological workflow for vaccine design.
The synergistic application of experimental vaccine design using omics and computational immunoinformatics represents a promising approach to develop safe, efficacious multi-antigen helminth vaccines rationally. This integrated framework may help overcome decades of challenges by accelerating the selection of optimized antigens that induce robust, broad, and long-lasting immunity against diverse helminth strains. Such vaccines targeting multiple parasite stages and species could significantly reduce the health burden of soil-transmitted helminthiases and other NTDs that predominantly impact low-resource populations worldwide.
5 Implication of immunoinformatics in helminth vaccine design
Vaccination has played a pivotal role in mitigating the spread of numerous pathogens and is a cornerstone in disease eradication efforts (Rauch et al., 2018). However, despite its proven efficacy, a notable absence of licensed anti-helminth vaccines for human use remains. Furthermore, helminths, being eukaryotic organisms, present many challenges for vaccination strategies due to their distinct biological characteristics. Hence, immunoinformatics and reverse vaccinology offer transformative avenues in vaccine development. These methodologies leverage computational tools and genomic insights to streamline the identification of potential vaccine candidates from the pool of identified proteins.
Researchers use helminth genomes and proteomes to identify antigenic proteins that initiate immune responses, aiding in the development of customized vaccines. Immunoinformatics methods then prioritize vaccine candidates based on their capacity to elicit protective immune responses, reducing the risk of vaccine failure during advanced clinical trials. Immunoinformatic analysis has been conducted across diverse parasite species. For the focus of our review, we present a curated selection of studies employing the vaccine development pipeline specifically within the domain of helminth parasites, as illustrated in (Table 5). This implies ongoing progress in helminth vaccine research through continual discovery and prioritization of novel candidates.
Table 5. Immunoinformatics-based identification of helminth vaccine targets.
6 Future direction and conclusion
The lack of attention, prioritization and funding of helminth infections within health organisations and research spheres can be attributed to the absence of opisthorchiasis vaccines currently available for clinical use. Recent strides in transcriptomics, genomics, and proteomics have shed light on the potential engagement of genes and proteins during the early stages of O. viverrini, influencing aspects such as survival, motility, immune evasion, and pathogenicity. However, to obtain a clear view of antigen targets, it is crucial to integrate data across various “omics” modalities (Vahabi and Michailidis, 2022), and immunoinformatics represents a sensitive high-throughput platform for profiling immunogenic antigens from the parasite. Insilico analysis with high predictive outcomes can limit the use of animal models, leading to more sustainable research (Pappalardo et al., 2019). In the future, there is hope that in silico trials can replace human trials (Ebert et al., 2021). Furthermore, in silico analyses in the O. viverrini vaccine design process can significantly reduce costs and expedition timelines. Computational screening of antigen candidates can yield substantial savings by minimising experimental wet-lab validation and animal trials, thereby mitigating financial barriers for this under-resourced yet high-impact disease (Saldanha et al., 2023). This approach expedites the entry of numerous vaccine candidates into clinical trials, often ahead of schedule (Shawan et al., 2023). However, the vaccine design against carcinogenic parasites like O. viverrini must carefully account for the inflammation associated with its infection and the potential presence of undiagnosed tumours in endemic populations. This consideration is vital due to the intricate interplay between tumours and immune cells, whereby various pathways influence each other, ultimately steering toward distinct outcomes (Gonzalez et al., 2018; Bedognetti et al., 2019). Multistage vaccines have been proposed as an effective strategy in complicated pathogens, as this may show a synergistic effect and would be particularly desirable for biliary tissue-dwelling pathogenic flukes (Maizels, 2021). Furthermore, the choice of proper and safe synthetic immunomodulatory adjuvants should be carefully selected/designed (Zhao et al., 2023) and follow-up in vivo studies. Overall, combining immunoproteomics and immunoinformatics offers a compelling strategy to accelerate the rational design and development of vaccines, holding significant potential for preventing and controlling infectious diseases in forthcoming years.
7 Implications and limitations
The current period marks an exciting phase for research in this field, with significant advancements seen in recent years, particularly in the structure-based design of new antigens, antibodies, and binders. Traditional vaccine development faces significant challenges, including high costs, hesitancy, stringent safety requirements, and societal demands for perfect efficacy. Additionally, issues like immunosenescence, limited adjuvants, and concurrent health problems in the developing world complicate efforts. Therefore, the global availability of in silico technologies in vaccine design and access to tools utilising supercomputers via internet-enabled interfaces maximises their utilization across diverse research communities internationally. In NTDs based research, merging AI and ML with biological, medical, and biochemistry-based approaches holds immense promise for driving breakthroughs. This convergence is poised to accelerate the discovery of novel biologics, offering new avenues for combating such neglected diseases effectively (Rodrigues and Ersching, 2014; Winkler, 2021). This initiative aims to end the neglect and contribute to achieving the Sustainable Development Goals (World Health Organization, 2020).
While converging experimental and computational vaccine design holds promise for rational helminth vaccine development, certain limitations must also be acknowledged. These in silico based tools require high-quality input data to train algorithms and predict outcomes accurately. Further experimental validation is advised to refine helminth vaccine formulations before proceeding to clinical testing. Moreover, ensuring vaccine effectiveness and safety profiles suitable for use in endemic areas where NTDs are prevalent and infrastructure is limited poses difficulties. In summary, while integrating immunoproteomics and immunoinformatics holds promise for optimising vaccine design, transitioning from theoretical constructs to practical, field-ready vaccines for helminth diseases remains a formidable long-term challenge. Overcoming both natural and technical barriers necessitates sustained dedication from all stakeholders involved.
Author contributions
AK: Data curation, Methodology, Conceptualization, Formal analysis, Validation, Investigation, Visualization, Writing–original draft, Writing–review and editing. SO: Data curation, Supervision, Formal analysis, Project administration, Validation, Funding acquisition, Writing–review and editing.
Funding
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The study was funded by the Doctoral Research Fund to the corresponding author, SCO. AK was supported by a Postgraduate Study Support Grant of the Faculty of Medicine, Khon Kaen University for his studies.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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Keywords: opisthorchiasis, liver fluke, host-parasite, proteomics, immunoproteomics, immunoinformatics, vaccinology
Citation: Kafle A and Ojha SC (2024) Advancing vaccine development against Opisthorchis viverrini: A synergistic integration of omics technologies and advanced computational tools. Front. Pharmacol. 15:1410453. doi: 10.3389/fphar.2024.1410453
Received: 01 April 2024; Accepted: 10 June 2024;
Published: 15 July 2024.
Edited by:
Chandra Sekhar Sirka, All India Institute of Medical Sciences Bhubaneswar, IndiaReviewed by:
Arijit Bhattacharya, Adamas University, IndiaFrancesco Branda, Campus Bio-Medico University, Italy
Abdullah Reda, Mayo Clinic, United States
Copyright © 2024 Kafle and Ojha. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Suvash Chandra Ojha, c3V2YXNoX29qaGFAc3dtdS5lZHUuY24=