Schistosomiasis and hookworm infection in humans: Disease burden, pathobiology and anthelmintic vaccines

Parasitology International 75 (2020) 102051

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Review

Schistosomiasis and hookworm infection in humans: Disease burden, pathobiology and anthelmintic vaccines ⁎

Anisuzzamana,b, , Naotoshi Tsujic,

T

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a

Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Trogerstr. 30, Munich, Germany Department of Parasitology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh c Department of Parasitology and Tropical Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami, Sagamihara, Kanagawa 252-0374, Japan b

A R T I C LE I N FO

A B S T R A C T

Keywords: Schistosomiasis Hookworm infection Pathobiology Anthelmintic vaccine

Helminth diseases are the ancient scourges of humans and their damages are ‘silent and insidious’. Of the helminth infections, schistosomiasis and hookworm infection have a great impact. This review covers information regarding vaccine candidates against schistosomiasis and hookworms that reached at least up to the phase-1 trial and literatures regarding other vaccine candidates have been excluded. For clinical manifestations, all available literatures were included, and for epidemiology and global burden of the diseases (GBD), literatures only within 2000–2019 were included. Literatures were searched surfing various databases including PubMED, Google Scholar, and Science Direct and overall over 150 literatures were identified. Globally ~250 million people are suffering from schistosomiasis, resulting 1430 thousand DALY (disability adjusted life year) per year. On the other hand, about 1.3 billion people are infected with hookworm (HW), and according to WHO, ~878 million school-age children (SAC) are at risk. HW is estimated to cause 65,000 deaths annually, accounts for 845 thousand DALYs as well as to cause 6–35.3% loss in productivity. Despite tremendous efforts, very few anthelmintic vaccine candidates such as Na-GST-1, Na-APR-1 and Na-ASP-2 against HW, and Sm28GST/Sh28GST, Sm-p80, Sm14 and Sm-TSP-1/SmTSP-2 against schistosomiasis reached up to the clinical trials. More efforts are needed to achieve the WHO targets taken against the maladies.

1. Introduction

the resource-deprived low income countries (LiCs). Furthermore, reinfection and anthelmintic resistance are the additional threats to helminth control [7–9]. Despite implementation of decade-long MDA programs in endemic areas, the burden of many helminth diseases is unchanged or even increased [6,10]; this circumstance calls for alternative approaches, one of them being prophylactic anthelmintic vaccines. Unfortunately, despite much effort, an effective commercial vaccine against helminths is not available yet today. Helminth parasites are multi-cellular organisms and their lifecycle is very complex. Moreover, they are shield with many bio-molecular weapons to paralyze the highly orchestrate defense mechanism of the mammalian hosts such as coagulations cascades, inflammatory insults and immune responses [1,11–14]. To evade the protective mechanisms of hosts, the parasites synthesize and secret a lot of bio-active molecules (BAMs) such as enzymes and inhibitors [11,15,16]. Besides, their survival and reproduction are dependent on many BAMs. Neutralization of those molecules hampers the essential biological processes. Therefore, scientists target those molecules as interesting tools to develop

Helminth diseases are the ancient scourges of humans and some are known to infect humans from pre-biblical times and their damages are huge but ‘silent and insidious’ [1]. Unlike bacterial and viral diseases, they usually do not produce acute illnesses but rather chronic diseases that gradually ruin health and result in high morbidity and mortality, and eventually causing great economic impact [2]. Nearly, five billion people are suffering worldwide from one or more species of helminths, of them, schistosomiasis and hookworm (HW) infections are the major threats. Schistosomiasis affects > 250 million people worldwide and about 800 million, mostly children, are at risk [3–5]. On the other hand, about 1.3 billion people are infected with HW, and according to WHO, ~878 million school-age children (SAC) are at risk [2,5,6]. Helminths affect, usually not exclusively, the poorest and the largest segment of the world population. Yet today, control mainly depends on hygienic measures and mass drug administration (MDA) in endemic areas. However, practice of strict hygienic rules is not possible, especially in

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Corresponding author at: Department of Parasitology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh. Corresponding author. E-mail addresses: [email protected] (Anisuzzaman), [email protected] (N. Tsuji).

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https://doi.org/10.1016/j.parint.2020.102051 Received 28 April 2019; Received in revised form 1 November 2019; Accepted 1 January 2020 Available online 03 January 2020 1383-5769/ © 2020 Elsevier B.V. All rights reserved.

Parasitology International 75 (2020) 102051

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65,000 280,000 845 1413

LA, Latin America.

Usually in SI (especially duodenum) mesenteric veins veins of bladder

Spatial distribution

Hookworms (A.duodenale N.americanus) Schistosomes S. mansoni S. japonicum S. haematobium

HW such as Ancylostoma duodenale and Necator americana are are tiny (~0.5 cm) but voracious blood-sucking roundworms. After skin penetration, larvae are carried into the lungs and through tracheal migration, settle in the duodenum and survive up to a decade [1,29]. HW bites deeply into the intestinal submucosa and secrete an arsenal of anticoagulants, which inhibit thrombin, factor Xa, XIa, and VIIa at the

Location in host

3. Disease burden and pathobiology of hookworm infections

Helminths

Table 1 Location, spatial distributions, and global burden of hookworms and schistosome infections.

People affected (Million)

Schistosomiasis is caused by the trematodes of the genus Schistosoma, commonly known as the blood flukes. Only in Sub Saharan Africa (SSA), the annual mortality due to schistosomiasis is 280,000 [3]. In addition, several hundred million people are struggling with post-treatment residual morbidity. In the regions with typical transmission pattern, 60–80% of SAC and 20–40% of adults remain infected [18]. Annually 1430 thousand DALY has recently been estimated (Table 1), and is much more debilitating than leishmaniasis [19,20]. S. haematobium and S. mansoni are prevalent in Africa and the Middle East, whereas only S. mansoni is present in Latin America, and S. japonicum is found in Asia [21]. Following transdermal infection, larvae (cercariae) remain in the skin for three days and transform into the skin-stage schistosomulae (SkS) and reach to lungs where develop into slender lung stage (LuS). During migration LuS transform into gut stage (GuS), characterized by the development of rudimentary gut, and develop into liver stage (LiS)/juvenile worm very rapidly in the liver and pair up. Thereafter, juvenile worms reach to the mesenteric veins (S. mansoni and S. japonicum) or in the veins of bladder (S. haematobium) and mature [15,22–24], and survive up to 40 years (Table 1). Morbidities arise principally due to the granulomatous, CD4+ T cell-mediated host responses to their spiny eggs, characterized by the infiltration of lymphocytes, eosinophils and activated macrophages. Intestinal schistosomiasis is manifested by hepatitis, hepatomegaly, Symmer's clay pipestem fibrosis, splenomegaly and perivascular granulomas [5,25,26]. Clinically, the disease is characterized by pot belly, emaciation and severe loss of vigor. Due to portal hypertension, esophageal varices may develop, which can rupture leading to fatal haematemesis, vomiting of blood. On the other hand, in urogenital schistosomiasis, pelvic pain, itching, dysuria, and haematuria are common. In males, haematospermia and painful ejaculation are frequently encountered and in females, profuse abnormal vaginal discharge, and bleeding are commonly seen. Urinary bladder cancer, usually Squamous cell carcinoma, can be developed in prolonged cases, therefore, International Agency for Research on Cancer (IARC) has classified S. haematobium as a biocarcinogen [5,27]. Worms and eggs can also be found in lungs, kidneys, gonads and even in the central-nervous system [18,28].

1300 250

2. Disease burden and pathobiology of schistosomiasis

Asia, Africa, LA Asia, Africa, LA Africa & Middle East

DALYs (Thousand)

Mortality (annual)

Ref

anthelmintic vaccines. Among hundreds of BAMs identified from economically important helminths, very few reached to the human trials [17]. Rigorous surfing of available literatures on the saga of development of anthelmintic vaccines suggests that very few vaccine candidates only against schistosomiasis and HW have reached up to human trials, and Bilhvac, a schistosome vaccine, has recently completed phase III trials. We searched literatures using various databases including PubMED, Google Scholar, and Science Direct. Information regarding vaccine candidates against schistosomiasis and human hookworms that reached at least up to the phase-1 trial were included and literatures regarding other vaccine candidates were excluded. For clinical manifestations, all available literatures were included and for epidemiology and GBD, literatures only 2000–2019 were included. Overall over 150 literatures were identified. Here, we describe that schistosomiasis and HW still are big challenges for the improvement of human health, especially in the resource deprived and under privileged LiCs, and warrant much more effort and funding for the development of vaccine to achieve WHO roadmap.

[2,6,20] [5,20,24]

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site of biting to keep the blood in a fluid state [30]. Blood oozes out continuously from the biting wound for a considerable period of time resulting in a huge blood-loss. A single adult parasite can cause a loss of 0.2 ml of blood/day, and a burden of 40–160 worms is sufficient to cause microcytic, hypochromic iron deficiency anemia (IDA) [31,32]. HW infection is found worldwide but mostly in Asia, Africa and Latin America. About 1.3 billion people are infected, and according to WHO, ~878 million SAC are at risk (Table 1) of which only 77 million (8.78%) are treated by MDA [6]. HW along with other soil-transmitted helminthes (STHs) have been reported to cause over 80% morbidity in LiCs [33]. HW-induced chronic anemia severely affects growth and intellectual development of children and adds an additional threat to pregnant women and their fetuses. Clinically, especially in children, is characterized by the mild to moderate ascites, pale mucous membrane, emaciation and weakness. In LiCs, one-third of expecting mothers are infected, 56% of which suffer from anemia and 20% of maternal deaths are attributed to anemia [34]. HW is estimated to cause 65,000 deaths annually, account for 845 thousands DALYs as well as to cause 6–35.3% loss in productivity [20,35]. In addition, A. caninum, a dog-HW, has recently been reported to infect humans in Africa [36,37], indicating an extra threat to zoonotic HW infection from companion animals. Excretory/secretory (ES) products of HW reduce CD4+ T cells and IL-4 but increases IL-12 and IFNᵧ; thus, impair B cell activations and eventually suppress hosts' immunity [38,39]. In fact, generalized immunosuppression by HW infection is now well documented, which is characterized by the accelerated secretion of IL-10, expansion of Foxp3lymphocytes, programed cell death protein 1 (PD-1), lymphocyte activation gene 3 (LAG-3) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) [40]. Ultimately, HW smartly manages inflammatory and immune responses of hosts from port of entry (skin) to the site of predilection (intestine) via lungs to establish prolonged infections, and survive.

binding protein and detoxifies free heme, which is vital for the survival of the worm [44,45]. Recombinant Na-GST-1 (rNa-GST-1) has been expressed in Pichia pastoris and rNa-GST-1/Alhydrogel immunization induced strong and persistent IgG responses [46]. Approximately, 40% protection was achieved in immunized hamsters challenged with N. americana [44] and immunization with rAc-GST-1, a homologue of NaGST-1, led to a 53.7% protection rate in the same model [12]. People living in endemic countries tend to develop high IgG1 levels against NaGST-1 and show a significantly reduced HW infection [47]. A pilot scale manufacture of Na-GST-1 has been conducted according to current Good Manufacturing Practice (cGMP) and currently an alum formulation is under phase I trial among healthy adult volunteersin the USA and Brazil [48]. Na-APR-1 is a 407-aa long (45 kDa) aspartic protease of N. americanus with hemoglobinase activity, and is essential for hemoglobin digestion [49]. The rNa-APR-1 has been expressed in baculovirus, E. coli, P. pastoris and tobacco plants (Nicotiana benthamiana) but the highest yield and stability were achieved in the latter [13,49,50]. Considering the safety and stability, the recombinant protein has been modified by site-directed mutagenesis to demolish proteolytic activity keeping immunogenicity intact [13]. A vaccine has been formulated using Alhydrogel [13,51] and currently an aqueous formulation with a Toll-like receptor-4 (TLR4) agonist, glucopyranosyl lipid A (GLA), is under evaluation to robust its immunogenicity [45]. Immunization of dogs conferred partial protection against heterogeneous challenge infections (66.6% and 29.5% reduction of EPG and worm burden, respectively). In endemic areas in Brazil, specific-IgG responses were detected in 62% of the population (42% had IgG1, 0.6% IgG2, 15% IgG3, 53% IgG4) and only 0.6% had IgE antibodies [13].In addition, bivalent vaccine containing rNa-GST-1 and rNa-APR-1 has been formulated using Alhydrogel, which induces neutralizing antibodies. The combined vaccine interferes with the establishment of adult HW infection in the gut mucosal layer and thwarts blood feeding; resulting in reduced worm burden and HW-induced blood loss [45,48]. However, none of the vaccine candidates induced sterilizing immunity. Co-administration (30 μg of a N-GST-1 and 30 μg of Na-APR-1 with Alhydrogel plus GLA) trials are underway among healthy volunteers in Gabon, Africa [45]. Na-ASP-2 is a 21 kDa secreted, pathogenesis related-1 protein isolated from infective stage of N. americana and the crystal structure has been solved [43]. Immunization of dogs and hamsters with rNa-ASP-2 significantly reduced worm burden (30–46%) and fecundity [52]. rNaASP-2/Alhydrogel induced persistent, high level of IgG1, IgG2a and IgM in rats with Th2 cytokine responses [53,54]. Anti-Na-ASP-2 antibodies inhibited larval migration through skin [55]. A phase 1 study was conducted using rNa-ASP-2/Alhydrogelin healthy, hookwormnaïve adult volunteers in the USA that proved to be well-tolerable and immunogenic [56]. Unfortunately, a phase 1 trial in the endemic areas of Brazil induced generalized urticarial reactions in several volunteers after immunization with a single dose (10 μg) [57]. The reaction was

4. Anthelmintic vaccine candidates on trial or development Presently, albendazole and mebendazole are used especially against STHs, including HW. Praziquantel (PZQ) and to a much lesser extent triclabendazole, bithionol and tribendimidine are used against trematodes, including schistosomes. In addition to re-infection, anthelmintic resistance is another limiting factor in the success of deworming programs [41,42], urging anthelmintic vaccines for a sustainable control. Up to now, much effort has been put into vaccine development and a large numbers of helminth-proteins/peptides have been identified and characterized as potential candidates, and some of which have already been approved for field studies (Table 2). 4.1. Vaccine candidates for human hookworms Na-GST-1 is a 24 kDa glutathione-s-transferase identified from N. americanus consisting of 205 amino acids (aa) and a glycosylation site, and the crystal structure has been solved [43]. Na-GST-1 is a heme Table 2 Advances in vaccine developments against hookworms and schistosomes. Helminths

Hookworms

Schistosomes

Vaccine candidates

Na-GST-1 Na-APR-1 Na-Asp-2 Sm28GST/ Sh28GST (Bilvax) Sm p80 Sm 14 Sm-TSP-1 & Sm-TSP-2

Prof of protection from pre-clinical trials

Ref

Adjuvant

Immune responses

Protection (%)

Present status

Alhydrogel Alhydrogel; Alhydrogel+GLA Alhydrogel Alhydrogel GLA-SE FCA FCA/FIA

IgG1 IgG1 IgG1, IgG2a, IgM & IgE IgG1, IgG2, IgG3 & Th2 cytokines IgG High: IgG1, IgG2, Low: IgM, IgA, IgE IgG1, IgG2a

40–53.7 66.6 (EPG); 29 (WB) 30–46 30–60 30–70 50–68 65–69 (EPG)

Phase Phase Phase Phase Phase Phase Phase

I, U I, U I, C* III, U I, PCT I, C I, U

[12,46,47] [13,48,50,51] [53–56] [58–64] [69–78] [83–87] [89,90]

U, under way; C, completed; PCT, prepared for clinical trial; GLA-SE, glucopyranosyl lipid adjuvant-stable emulsion; FCA, Freund's Complete Adjuvant; FIA, Freund's Incomplete Adjuvant; *, halted. 3

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mansoni and detected in all developmental stages including eggs, and is located in the tegument and gut of the parasite [80]. rSm14 has been expressed in E. coli and its crystal structure has been solved [81]. Sm14 is closely (42%) related to heart FABP and myelin P2 of human and has 27–42% homology with other FABPs. rSm14 binds palmitic and linoleic acid through the N-terminal domain [82]. Schistosomes are unable to de novo synthesize fatty acids and sterol and require hosts' lipids to maintain their membrane and physiological functions. Sm14 plays a vital role in the lipid metabolism and survival of S. mansoni. rSm14 alone or rSm14/Freund's Complete Adjuvant (FCA) provides 50–68% protection in mice, and 89% protection in rabbits [83]. Interestingly, sheep and mice immunized with rSm14 provided cross-protection to Fasciola hepatica and were completely free from hepatic damage [83,84]. However, a DNA vaccine failed to elicit significant levels of protection [85]. rSm14 induced high levels of IgG, and protective immune responses largely depended on IFNγ and TNFα [86]. Anti-rSm14 antibodies, largely IgG1 and IgG2 but also low levels of IgM, IgA and IgE were detected from schistosomiasis patients [87]. cGMP production has been performed [67] and an open, non-placebocontrolled and dose-standardized phase I clinical trial has been conducted in a non-endemic area of Brazil. Three intramuscular immunizations (30-day interval) with rSm14 (50 μg)/GLA-SE (10 μg) induced high levels of specific total IgG, IgG1 and IgG3 30 days after the first immunization, and IgG2 and IgG4 after 60 days, however, IgE was not observed. Thus, the vaccine is strongly immunogenic, well-tolerated and safe [88]. Sm-TSP-1 and Sm-TSP-2 belong to tetraspanins or transmembrane4-superfamily (TM4SF) and consist of 4 transmembrane domains, 2 intracellular C- and N-termini and 2 extracellular domains. Sm-TSP-1 and Sm-TSP-2 have been identified in S. mansoni and are detected in the outer tegument of the worm, as well as in eggs, miracidia, cercaria and schistosomula. Sm-TSP-1 is 247 aa and Sm-TSp-2 is 239 aa long. Tretraspanin knockdown in schistosomula caused vacuolation and thinning of the tegument, suggesting its vital role in the maintenance of tegument integrity and thus, parasite survival [89]. rSm-TSP-2, but not rSm-TSP-1, was strongly recognized by already recovered and naturally resistant individuals from endemic areas in Brazil. EC2 of Sm-TSP-1 and Sm-TSP-2 were expressed in E. coli and an immunization trial with FCA/FIA in mice induced high levels of IgG1 and IgG2a. They reduced worm burden and liver-egg-counts by 57% and 64% (Sm-TSP-2) and 34% and 52% (Sm-TSP-1), as well as fecal-egg-count by 65–69% [90]. Sm-TSP-2 has been expressed in P. pastoris for cGMP production and now is currently under investigation in a phase I trial in Texas, USA [67].

associated with pre-existing Na-ASP-2-specific IgE. Sero-surveillance consequently revealed high levels of IgE against Na-ASP-2 in endemic people. Specific sites of the Na-ASP-2 are uniquely or jointly recognized by IgG and IgE and, therefore, further development was halted [47]. 4.2. Vaccine candidates in advanced studies from human schistosomes Sm28GST/Sh28GST, a glutathione-S-tranferasewith 211 aa, identified from S. mansoni [58] and orthologues have also been identified from S. haematobium, S. japonicum and S. bovis, and the crystal structure has been solved. Sm28GST/Sh28GST is present in the tegument, parenchyma and genital organs, and expressed in schistosomula and adult worms [59]. Recombinant protein has been expressed in E. coli and purified to homogeneity. rSm28GST/BCG induced robust production of IgG1, IgG2a and IgG2b in mice, and antibodies efficiently neutralized the enzymatic activity of Sm28GST. Anti-Sm28GST, in the presence of mouse eosinophils, kills schistosomula through antibody dependent cellular cytotoxicity (ADCC) [58,60,61]. In rats, aSm28GST DNA vaccine induced significant levels of mainly IgG2a and IgG2b, which killed schistosomula in vitro through ADCC [62]. Anti-Sm28GST antibodies also conferred partial protection against S. japonicum, S. haematobiumand S. bovis challenge infection [63,64]. Sh28GST, isolated from S. haematobium, shows the same type of cross reactivity and also leads to protection against other human schistosomes. Therefore, Sh28GST (Bilhvax) was planned to use in human trials. A phase Ia trial among 24 healthy adult males suggests that Sh28GST has neither local nor systemic toxicity, and no cross reactivity with human GST. All subjects, immunized with rSh28GST (100 μg)/alumhydroxide) developed high levels of specific neutralizing antibodies, which was 100-fold higher than observed IC50 after the 3rd booster [65]. A phase Ib trial among children in Senegal gave the same results indicating its safety among children. A phase II trial has also been completed. It induced high levels of IgG1, IgG2, IgG3 and Th2 cytokines (IL-5, IL-10 and IL-13). Presently, the phase 3 trial is in progress [66,67]. Sm-p80, a calcium-dependent non-lysosomal cysteine protease, belonging to the calpain family, that consists of 758 aa. It was identified first from S. mansoni [68] and homologues had been identified in S. Haematobium and S. japonicum. Sm-p80 has been detected in the syncytial epithelium of the tegument and the underlying musculature [69]. It is associated with surface membrane synthesis, renewal and recycling, and linked with immune evasion [41]. Sm-p80 does not show cross reactivity with mammalian homologues and significantly induced protection against S. mansoni, S. japonicum and S. haematobium [70–73]. rSm-p80 has been expressed in large scale and purified to homogeneity and immunization with the rSm-p80 provides 30–70% protection [41]. Anti-rSm-p80 kills schistosomula through ADCC in the presence of lung-lavage cells [74]. A formulation with TLR agonists (TLR4, TLR 7/8 and TLR9) reduces worm burden by 60% in baboons and 70% in mice. In addition, 100% reduction of liver and intestinal egg burden has been observed in both models [41,75]. Additionally, immunization of infected baboons with rSm-p80/GLA-SE reduced > 36% worm burden, ~54% tissue eggs and > 33% excreted fecal eggs, indicating the vaccine can be used in endemic regions, even in infected people following drug treatments [76]. Very recently, a double-blind study suggests that Sm-p80 significantly reduces (93.45%) egg-induced in baboons [77]. Robust Sm-p80-specific IgG, IgG1, IgG2a and IgM have been detected in multiple mammalian models, including non-human primates, and lasts up to 5–8 years in baboons [21]. Interestingly, the vaccine has transmission blocking efficacy since it reduces egg hatchability up to 85% [78]. rSm-p80 + GLA-Alum formulation induces mixed Th (Th1, Th2 and Th17) responses [79]. Importantly, Sm-p80-specific IgE has not been detected in humans in endemic areas; thus, reduces the risk of hypersensitivity after vaccination [21]. The protein is now under cGMP production fora phase I trial. Sm14 is a small fatty acid binding protein (FABP) consisting of 133 aa with molecular weight of 14.8 kDa. Sm 14 has been identified in S.

5. Conclusions and future directions In most immunization studies, mainly the extent of humoral responses is considered as surrogate markers for the efficacy of a vaccine candidate. But monitoring cellular responses such as the development of central (TCM), effector (TEM) and residence (TRM) memory T cells would be more meaningful to predict the efficacy of a vaccine candidate since in helminth infection cellular responses playa more critical role than the humoral responses. Furthermore, the cellular compartment of immunity generally provides more durable and prompt protection upon entry of an infectious agent. Therefore, seeding of TRM at the port of entry (e.g., skin), along the site of critical tissue passage (e.g., lungs and liver) or at the organ of permanent residence (e.g., gut wall in case of HW) could provide strong, prompt and durable protection. Vaccine candidates should thus induce high level of seeding of TRM both in permissive and non-permissive target organs. Selection of an appropriate adjuvant is a vital issue during formulating a vaccine. An adjuvant significantly increases the immunogenic potential of an antigen. It increases the half-life of an immunogen, improves the delivery to and processing of an antigen by APCs, and induces the production of immunomodulatory cytokines. Strong but balanced and specific Th1 and 4

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Th2 immunity targeting of different stages of lifecycle is expected for a high level durable protection. A combination of adjuvants can be promising e.g., adding CpG or TLR-agonists in order to generate a Th1biased immune response. Attention should be paid during recombinant expression and purification since stability and efficacy of a recombinant also depend on the methods of recombinant production. Additionally, protective response also depends on the animal model used, e.g., BALB/ c and BL/6 mice respond more strongly to irradiated S. mansoni than CBA mice. Conventionally, laboratory mice reared in SPF condition are used in immunization trials but in reality, SPF mice are ‘like newborn, but not adult, humans’. SPF mice lack exposure to verities of pathogens, devoid of TEM, and immune responses are not as high as in real conditions [91]. Collectively, research targeting anthelmintic vaccines needs rigorous effort as well as scholastic plans, and deserves more funding and prioritization in order to sustainably address those neglected tropical diseases that affect millions of people worldwide.

[11]

[12]

[13]

[14] [15]

[16]

Authorship Authors attest they meet the ICMJE criteria for authorship.

[17]

Funding [18]

The works were supported by the postdoctoral research grant from Alexander von Humboldt, Germany to Anisuzzaman.

[19]

Declaration of Competing Interest

[20]

None. [21]

Acknowledgements

[22]

The authors would like to thank Katharina Klohe (Centre for Global Health, Technical University of Munich, Munich, Germany) for helpful comments and suggestions, and Professor Dr. med. Clarissa Prazeres da Costa (Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany) for critical reviewing of the manuscript.

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