Transmission Modelling for Human Non-Zoonotic Schistosomiasis Incorporating Vaccination: Guiding Decision- and Policymaking

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Ursula Panzner reviewed the transmission dynamics established for human schistosomiasis in this manuscript, with a focus on the effects of vaccinations. It is organized in a proper structure, and offers valuable insights into the control and prevention strategies of the disease for the scientific and clinical communities. However, there are a few issues associated with this manuscript, which should be addressed by the author.

First of all, the author overlooked some relevant studies on the transmission of Schistosoma japonicum in this manuscript. These studies include but not limited to, https://doi.org/10.1016/S0001-706X(02)00017-7 and https://doi.org/10.3389/fimmu.2019.00645.

Secondly, the essential references listed in Table 1 were not cited in a proper way. These literatures were numbered totally differently in the table versus in the text.

The biggest issue of this manuscript comes from its English expression. Honestly, it makes me feel miserable to review this manuscript because of its English quality. I will specify this issue in the next section. 

Comments on the Quality of English Language

The author constructed this review paper with too many wordy sentences. Most of them should be broken down to simple and clearer expressions. I have to frequently stop and paraphrase a sentence in my mind, in order to figure out what the author was trying to express. The author also used too many semicolons (;) throughout this manuscript to separate sentences, which is quite unusual in an English literature. Here is an example below:

Lines 154-158, there is an extremely long sentence, quote “Once administered, IgA, IgE, IgM and IgG1-3 subclass immunoglobulins are detectable inducing approximately 12-months protection against re-infection enhanceable for in stance by eosinophils, and IgG4 promoting susceptibility to re-infection due to IgE blocking while modulating anaphylactic responses; regular repeated chemotherapy reduces IgG4 titers.”

I guess this is what the author would actually like to express. “Upon administration of PZQ, immunoglobulins such as IgA, IgE, IgM, and IgG1-3 subclasses become detectable, offering around 12 months of protection against schistosomes re-infection. This protection can be further boosted, for example, by the generation of eosinophils. By contrast, IgG4 can increase the risk of re-infection by blocking IgE and altering anaphylactic reactions. Repeated chemotherapy has been found to lower IgG4 levels.”

This manuscript is full of wordy sentences like the example above. I don’t think any researcher would have enough patience to finish reading it, if it is drafted in such a way. I advise the author to seek help from native English users or AI-based tools. 

Author Response

Manuscript: Transmission modelling for human schistosomiasis incorporating vaccination: guiding decision- and policymaking (ID: parasitologia-2912495)

Point-by-point response to reviewer 1

Thank you very much for your feedback on the manuscript and the opportunity to address your comments. Please find enclosed the point-by-point response to the points raised.

Comments and Suggestions for Authors

Ursula Panzner reviewed the transmission dynamics established for human schistosomiasis in this manuscript, with a focus on the effects of vaccinations. It is organized in a proper structure, and offers valuable insights into the control and prevention strategies of the disease for the scientific and clinical communities. However, there are a few issues associated with this manuscript, which should be addressed by the author.

First of all, the author overlooked some relevant studies on the transmission of Schistosoma japonicum in this manuscript. These studies include but not limited to, https://doi.org/10.1016/S0001-706X(02)00017-7 and https://doi.org/10.3389/fimmu.2019.00645.

Response: Thank you for pointing this out. Both articles mentioned in addition to other articles on S. japonicum were included in the original manuscript submitted. However, they were not enclosed for the purpose of looking into model details, but for highlighting primarily the positive effects of multi-component approaches targeting humans and animals. Given the wide host range of this species and the amount of literature available also on the vaccine site may be material for another manuscript. I hope this addresses your comment sufficiently.

Secondly, the essential references listed in Table 1 were not cited in a proper way. These literatures were numbered totally differently in the table versus in the text.

Response: Thank you for highlighting this. References in Table 1 were checked, updated and are again in line with the main manuscript.

The biggest issue of this manuscript comes from its English expression. Honestly, it makes me feel miserable to review this manuscript because of its English quality. I will specify this issue in the next section.

Response: Thank you for raising this. The entire manuscript underwent extensive English editing and I hope the revised version reads better.

Comments on the Quality of English Language

The author constructed this review paper with too many wordy sentences. Most of them should be broken down to simple and clearer expressions. I have to frequently stop and paraphrase a sentence in my mind, in order to figure out what the author was trying to express. The author also used too many semicolons (;) throughout this manuscript to separate sentences, which is quite unusual in an English literature. Here is an example below:

Lines 154-158, there is an extremely long sentence, quote “Once administered, IgA, IgE, IgM and IgG1-3 subclass immunoglobulins are detectable inducing approximately 12-months protection against re-infection enhanceable for in stance by eosinophils, and IgG4 promoting susceptibility to re-infection due to IgE blocking while modulating anaphylactic responses; regular repeated chemotherapy reduces IgG4 titers.”

I guess this is what the author would actually like to express. “Upon administration of PZQ, immunoglobulins such as IgA, IgE, IgM, and IgG1-3 subclasses become detectable, offering around 12 months of protection against schistosomes re-infection. This protection can be further boosted, for example, by the generation of eosinophils. By contrast, IgG4 can increase the risk of re-infection by blocking IgE and altering anaphylactic reactions. Repeated chemotherapy has been found to lower IgG4 levels.”

This manuscript is full of wordy sentences like the example above. I don’t think any researcher would have enough patience to finish reading it, if it is drafted in such a way. I advise the author to seek help from native English users or AI-based tools.

Response: Thank you again for pointing out the issues of too wordy, lengthy sentences and too frequent use of semicolons (;). The entire manuscript underwent extensive English editing and I hope the revised version reads better.

Reviewer 2 Report

Comments and Suggestions for Authors

Lines 161-168: Could be removed without affecting the overall idea of the section and improving the readability of the manuscript.

Lines 184-188: The phrase is uncomfortably long, could you please split it.

Lines 184-219: Even though it is highly desirable, at the moment there are no vaccines available that can be included as part of a prevention scheme. Therefore, for clarity, I think this paragraph should be in a new section. Additionally, it could worth mentioning the possibility of identifying new vaccine targets, perhaps with even better protective effect than the ones currently in trials, thanks to the research that is being done in genomics, bioinformatics, bulk- and/or single-cell transcriptomics, etc.

Line 198: 10.3390/vaccines10101724 could also be cited here.

Table 1: Please check and update the references.

Section “Transmission models”: The section has a good summary description of the results obtained in each study but fails in pointing out the strength and weaknesses of each model. It would be useful to have a complementary table comparing the variables considered or not considered in each study. For example, in which studies MDA was considered as a variable in the model, etc.

Figure 1: I do not consider the figure very useful in its current state. In my opinion the figure could be removed entirely, only minorly affecting the clarity of the manuscript. The figure could be improved by adding the risk settings and the expected morbidity control and transmission elimination times. I do not understand the table of variables in the figure. I imagine is the variables considered in the model by Kura et. al, however, as the model is not being shown here, neither described in the manuscript it should be removed.

Section “Model considerations”: It would be useful to clearly state which clinical phase and the levels of protection each of the vaccine candidates have reached (perhaps measured by the levels of cytokines and antibodies), when protection started dropping or for how long it has been measured and, if available, the results between treated and control groups. For example, Riveau et al. (ref. 208) clearly state that “While Bilhvax was immunogenic and well tolerated by infected children, a sufficient efficacy was not reached”, this conclusion is not reflected in the manuscript. I think that these kinds of considerations are relevant to reflect the current state of art.

Section “Conclusions”: I think the section is missing a final consideration regarding which variables should be considered (or not) for accurately modeling schistosomiasis in a context where a protective vaccine is available, for example: targeted population, vaccination plan (initial inoculation and boosters), vaccine coverage, vaccine protection, MDA administration, schistosomiasis prevalence, elimination of molluscs, population re-education policies, etc.

Missing bibliography that should be included in the manuscript:

Santini-Oliveira M, Machado Pinto P, Santos TD, Vilar MM, Grinsztejn B, Veloso V, Paes-de-Almeida EC, Amaral MAZ, Ramos CR, Marroquin-Quelopana M, Coler R, Reed S, Ciol MA, Savino W, Parra JC, Almeida MSDS, Tendler M. Development of the Sm14/GLA-SE Schistosomiasis Vaccine Candidate: An Open, Non-Placebo-Controlled, Standardized-Dose Immunization Phase Ib Clinical Trial Targeting Healthy Young Women. Vaccines (Basel). 2022 Oct 15;10(10):1724. doi: 10.3390/vaccines10101724. PMID: 36298589; PMCID: PMC9607179.

Comments on the Quality of English Language

English quality should be improved

Author Response

Manuscript: Transmission modelling for human schistosomiasis incorporating vaccination: guiding decision- and policymaking (ID: parasitologia-2912495) 

Point-by-point response to reviewer 2

Thank you very much for your feedback on the manuscript and the opportunity to address your comments. Please find enclosed the point-by-point response.

Lines 161-168: Could be removed without affecting the overall idea of the section and improving the readability of the manuscript.

Response: Thank you for pointing this out. Most of the context of L161-168 was removed and reads as “The latter likely occurs due to genetic variability or maturation of immature not fully eliminated parasite stages that are exposed to remaining sub-lethal drug concentrations. It’s standard dose is efficacious against all species though apparently better against S. japonicum over S. mansoni and S. haematobium, and mixed infections.”. I hope this eases the readability of the manuscript and addresses your comment sufficiently.

Lines 184-188: The phrase is uncomfortably long, could you please split it.

Response: Thank you for raising this. The phrase was revised and reads as “The early S. mansoni radiation-attenuated cercarial vaccine elicited shortly post-immunization long-lasting multi-species CD4+ Th1/Th2 immunoresponses of >70%. Building on this emphasizes the necessity to expand prevention by vaccination alone to induce protection against transmission, infection, and disease recurrence, or combined with PZQ as vaccine-linked therapy.”. I hope the sentence reads better.

Lines 184-219: Even though it is highly desirable, at the moment there are no vaccines available that can be included as part of a prevention scheme. Therefore, for clarity, I think this paragraph should be in a new section. Additionally, it could worth mentioning the possibility of identifying new vaccine targets, perhaps with even better protective effect than the ones currently in trials, thanks to the research that is being done in genomics, bioinformatics, bulk- and/or single-cell transcriptomics, etc.

Response: Thank you for highlighting the issue that there are currently no vaccines on the market for actual preventive use. Taking this into consideration, the aim within the submitted article was to highlight in a purely scientific manner that few candidates advanced at least to clinical testing while acknowledging the numerous promising novel candidates that are still in the experimental stage. Going into much detail about novel schistosomal vaccine candidates in the current pipeline accompanied by their technological platforms may be material for another manuscript and would make this already very wordy manuscript even longer. The following part within L184-219 was revised and reads as “Numerous antigenic moieties of e.g. surface membranes, excretory/secretory proteins, tegument, cytosol, and gastrointestinal tract, detected by platforms ranging from initial Schistosome saline extracts to latest ‘OMICS’, are still at the experimental stage. Only few candidates, though not on the market yet, advanced to clinical phases, i.e., Sm14 or S. mansoni fatty acid-binding protein (FABP) in ongoing phase II, Sm-TSP-2/Sm-TSP-2Al® or S. mansoni tetraspanin in phase I, Smp80/SchistoShield® or S. mansoni large-subunit calpain in ongoing phase I, and Sh28GST/Bilhvax® or S. haematobium glutathione S-transferase in phase III. The latter was discontinued lacking efficacy.”. I hope I could clarify this sufficiently. 

Line 198: 3390/vaccines10101724could also be cited here.

Response: Thank you again. The publication of Santini-Oliveira M. et al. was cited here and is also included in the list of references.  

Table 1: Please check and update the references.

Response: Thank you. References in Table 1 were checked, updated and are again in line with the main manuscript.

Section “Transmission models”: The section has a good summary description of the results obtained in each study but fails in pointing out the strength and weaknesses of each model. It would be useful to have a complementary table comparing the variables considered or not considered in each study. For example, in which studies MDA was considered as a variable in the model, etc.

Response: Thank you for raising this. I have expanded Table 1 by incorporating more/additional model variables where available, including a section about the major strengths and weaknesses, and hope this addresses your comment adequately. Regarding MDA, this was included in the original submission within Table 1 under the category “intervention”. I have separated the information about MDA from data about vaccination and hope this increases the overall clarity about the models detected.   

Figure 1: I do not consider the figure very useful in its current state. In my opinion the figure could be removed entirely, only minorly affecting the clarity of the manuscript. The figure could be improved by adding the risk settings and the expected morbidity control and transmission elimination times. I do not understand the table of variables in the figure. I imagine is the variables considered in the model by Kura et. al, however, as the model is not being shown here, neither described in the manuscript it should be removed.

Response: Figure 1 was removed from the main manuscript and is accompanying it as supplementary material. I hope this is a suitable solution for potential readers interested in looking at the model of Kura et al. in more detail. The risk settings of Kura’s model are in line with WHO’s classification, i.e., low or <10% prevalence, moderate or 10-50% prevalence and high or ≥50% prevalence, which is why they were not specifically mentioned in Figure 1. The related and revised sentence in the manuscript reads as “Kura’s endpoints are WHO’s 5% morbidity control and 1% transmission elimination in low-, moderate, and high-risk sites as per WHO’s prevalence classification. Endpoints are assessed within 300 simulations over a 15-year period.” In addition, I have revised the related section “setting” in Table 1, which reads as “Low (<10%), medium (10-50%), high (≥50%) endemicity as per WHO’s classification”. Regarding the targeted 5% morbidity control and 1% transmission elimination, this is modeled by Kura et al. within a model duration of 15 years. The time periods needed to achieve the targets by MDA alone, vaccination alone or MDA and vaccination combined is described in the manuscript, thus not explicitly stated in Figure 1. The table accompanying the possibly simplified model structure illustrated in Figure 1 shows its detailed variables and variable assumptions. The paragraph (L356-371, revised manuscript) outlines Kura’s model in line with criteria reported for the other models detected. I hope this clarifies all points raised adequately.

Section “Model considerations”: It would be useful to clearly state which clinical phase and the levels of protection each of the vaccine candidates have reached (perhaps measured by the levels of cytokines and antibodies), when protection started dropping or for how long it has been measured and, if available, the results between treated and control groups. For example, Riveau et al. (ref. 208) clearly state that “While Bilhvax was immunogenic and well tolerated by infected children, a sufficient efficacy was not reached”, this conclusion is not reflected in the manuscript. I think that these kinds of considerations are relevant to reflect the current state of art.

Response: Thank you for pointing this out. The latest status of clinical testing by vaccine candidate was included in section “3. Treatment and prevention” from L217 (revised manuscript) onwards. It reads as “Only few candidates, though not on the market yet, advanced to clinical phases, i.e., Sm14 or S. mansoni fatty acid-binding protein (FABP) in ongoing phase II, Sm-TSP-2/Sm-TSP-2Al® or S. mansoni tetraspanin in phase I, Smp80/SchistoShield® or S. mansoni large-subunit calpain in ongoing phase I, and Sh28GST/Bilhvax® or S. haematobium glutathione S-transferase in phase III. The latter was discontinued lacking efficacy.” I hope this clarifies their latest clinical developmental stage. Please note that despite Sm14 is in phase II, only findings from the phase I trial are publically accessible. These are included in the manuscript commencing from L473 (revised manuscript) and read as “Sm14 GLA-SE-adjuvanted was administered intramuscularly followed by two boosters to healthy, non-exposed Brazilian male and non-pregnant female adults aged 18-49 years during the phase I safety and immunogenicity trial with 4-month follow-up. It lead to augmenting total IgG titers in 88% of subjects commencing from the first booster on day 30 besides IgG1-4 subclasses while lacking IgE expression. Findings from the Sm14/GLA-SE IIa dose-escalation safety and immunogenicity trial with 3-month follow-up among healthy, exposed Senegalese male adults aged 18-45 years receiving a single pre-treatment with PZQ pending publication (trial status: completed). Healthy and S. mansoni and/or S. haematobium infected Senegalese children aged 8-11 years obtained Sm14/GLA-SE in a phase IIb safety and immunogenicity trial with 3-month follow-up subsequent to administering once pre-treatment with PZQ, findings pending publication (trial status: completed).”. Smp80/SchistoShield® in undergoing a challenge study (trial status: not yet recruiting) as well as phase I (trial status: active, not recruiting) and phase Ib (trial status: not yet recruiting) trials, but trials pending to be conducted and findings to be published. Therefore, for Sm14 and Smp80 I am unfortunately unable to address your comment in full by stating the latest status of protection, including when it started and declined, and longevity of protection in cases versus controls. Findings for Sm-TSP-2 were also revised for more clarification starting from L460 (revised manuscript) and reads as “Sm-TSP-2 Alhydrogel-adjuvanted was given to healthy, non-exposed American male and non-pregnant female adults aged 18-50 years in a phase I safety, reactogenicity and immunogenicity trial with 12-month follow-up. 30ug and 100ug over 10ug rSm-TSP-2 induced highest IgG titers at 4.5 months post immunization with waning at 5.5 months among all arms. Sm-TSP-2/Alhydrogel was also administered to healthy, exposed Brazilian male and non-pregnant female adults aged 18-50 years in a phase Ib safety, reactogenicity and immunogenicity trial with 12-month follow-up. IgG and IgG subclass immunoglobulins with IgG1 being preponderant across arms peaked two weeks after administering the third dose. Antibody levels declined across arms at the end of follow-up, except for the 100ug arm. Findings from immunizing healthy, exposed Ugandan male and non-pregnant female adults aged 18-45 years with Sm-TSP-2/Alhydrogel in a phase I/IIb dose-escalation, safety, immunogenicity and efficacy trial with 23-month follow-up pending publication (trial status: active, not recruiting).”. The revised section of Sh28GST/Alhydrogel commences from L485 (revised manuscript) onwards reads as “Sh28GST Alhydrogel-adjuvanted was given subcutaneously to non-exposed Caucasian males aged 18-30 years in a phase I dose-escalation, safety, tolerability and immunity trial with 6-month follow-up. It elicited a preponderant IgG1 response over IgG2-4 subclasses following the first dose up to trial end while IgA over IgE remained low throughout. S. haematobium infested Senegalese male and female children aged 6-9 years received in a phase III2 safety, efficacy, pathology and immunogenicity trial with 38-month follow-up Sh28GST/Alhydrogel sub-cutaneously subsequent to three doses of PZQ pre-treatment. The median follow-up without recurrence was 22.9 and 18.8 months among vaccinees and controls, respectively. At trial end, 86.4% of vaccinated experienced ≥1 recurrence compared to 89.6% of controls. In the vaccine arm, total IgG titers augmented up to month 65 and did not wane up to trail end. IgG1, IgG2 and IgG4 subclass immunoglobulins developed similar to total IgG while IgG3, IgA and IgE remained low throughout.”. I hope this addresses your comment adequately. Lastly, regarding Sh28GST/Bilhvax®, it is stated in L222 (revised manuscript) that the vaccine candidate was discontinued due to lack of efficacy. As this fact is included prior to looking at the models detected, it was not highlighted later on again in this/other sections. I hope this addresses your comment.

Section “Conclusions”: I think the section is missing a final consideration regarding which variables should be considered (or not) for accurately modeling schistosomiasis in a context where a protective vaccine is available, for example: targeted population, vaccination plan (initial inoculation and boosters), vaccine coverage, vaccine protection, MDA administration, schistosomiasis prevalence, elimination of molluscs, population re-education policies, etc.

Response: Thank you. The “conclusions” section was revised and reads as “Model predictions aiming to support decision- and policymaking towards 1% transmission elimination and 5% morbidity control demonstrate that solely a multi-component approach containing vaccination will likely be capable to address the WHO’s goals set. Combining long-term effects of vaccination with short-term effects of chemotherapy as regular repeated vaccine-linked therapy seems most promising. Notably, vaccine effects of simulations are derived solely from experimental animal models rather than human trials. The population targeted for intervening measures needs to be selected in the context of the at-risk level of a setting, and the measures’ parasitic targets, i.e., infection, fecundity, establishment and morbidity, and coverage, i.e., 40-80% for PZA MDA and 60-100% for vaccine, as well as efficacy, i.e., 75-95% for PZQ MDA and 15-100% for vaccine, and longevity of protection, i.e., 1-3yrs for PZQ MDA and 10-50yrs for vaccine. Notably, longevity over magnitude of protection is pivotal. Addressing pre-schoolchildren likely leaves them unprotected later in life while directing measures at schoolchildren probably protects them when they are at highest risk. Administering chemotherapy additionally to around 40% adults may enhance population-based effects. Vaccination as well as antiparasitic therapy needs to be given repeatedly as demonstrated by simulations, including catch-up campaigns, as immunity in addition to herd immunity builds slowly. Notably, non-adherence or non-compliance constituting sources of ongoing transmission, and current and/or previous infections as well as existing acquired immunity must be taken into account to avoid adverse events.”. Model constructs detected did not include the elimination of molluscs and educational policies, thus, no concluding remarks were stated. I hope this addresses your comment adequately.

Missing bibliography that should be included in the manuscript: Santini-Oliveira M, Machado Pinto P, Santos TD, Vilar MM, Grinsztejn B, Veloso V, Paes-de-Almeida EC, Amaral MAZ, Ramos CR, Marroquin-Quelopana M, Coler R, Reed S, Ciol MA, Savino W, Parra JC, Almeida MSDS, Tendler M. Development of the Sm14/GLA-SE Schistosomiasis Vaccine Candidate: An Open, Non-Placebo-Controlled, Standardized-Dose Immunization Phase Ib Clinical Trial Targeting Healthy Young Women. Vaccines (Basel). 2022 Oct 15;10(10):1724. doi: 10.3390/vaccines10101724. PMID: 36298589; PMCID: PMC9607179.

Response: Thank you. The publication of Santini-Oliveira M. et al. was cited and is also included in the list of references.

Reviewer 3 Report

Comments and Suggestions for Authors

The review paper entitled "Current Status of the Sm14/GLA-SE Schistosomiasis Vaccine: Overcoming Barriers and Paradigms towards the First Anti-Parasitic Human(itarian) Vaccine" is very interesting and demonstrates a robust update of the bibliography. The paper's main impact lies in its organization of information, presenting distinct hotspots of Schistosomiasis in a didactic manner, not only focusing on vaccine challenges. I believe that the impact of the paper has been enhanced by the authors' inclusion of the current status of world vaccination projects against Schistosomiasis.

Regarding minor comments:

The abstract provides a comprehensive overview of schistosomiasis, highlighting its global impact and the challenges associated with both acute and chronic forms of the disease. I suggest to emphasizes the importance of vaccination as a critical strategy in overcoming limitations and problems associated with mass drug administration and anthelmintic resistance.

I suggest including the paper "Development of the Brazilian anti-schistosomiasis vaccine based on the recombinant fatty acid binding protein Sm14 plus GLA-SE adjuvant. Front. Immunol. 2015, 6" in this review.

Author Response

Manuscript: Transmission modelling for human schistosomiasis incorporating vaccination: guiding decision- and policymaking (ID: parasitologia-2912495)

Point-by-point response to reviewer 3

Thank you very much for your feedback on the manuscript and the opportunity to address your comments. Please find enclosed the point-by-point response to the issues raised.

The review paper entitled “Current Status of the Sm14/GLA-SE Schistosomiasis Vaccine: Overcoming Barriers and Paradigms towards the First Anti-Parasitic Human(itarian) Vaccine” is very interesting and demonstrates a robust update of the bibliography. The paper’s main impact lies in its organization of information, presenting distinct hotspots of Schistosomiasis in a didactic manner, not only focusing on vaccine challenges. I believe that the impact of the paper has been enhanced by the authors’ inclusion of the current status of world vaccination against Schistosomiasis.

Response: Thank you for pointing out the review paper of Tendler M. et al. that I am well aware of. It is indeed a well-balanced, comprehensive compilation of the developmental path of the Sm14/GLA-SE vaccine candidate besides general information about schistosomiasis. I have read Tendler M.’s paper again, and cited it in the re-submitted review article where appropriate in an attempt to improve it. I hope I have addressed your comment sufficiently.

Regarding minor comments:

The abstract provides a comprehensive overview of schistosomiasis, highlighting its global impact and the challenges associated with both acute and chronic forms of the disease. I suggest to emphasizes the importance of vaccination as a critical strategy in overcoming limitations and problems associated with mass drug administration and anthelmintic resistance.

I suggest including the paper “Development of the Brazilian anti-schistosomiasis vaccine based on the recombinant fatty acid binding protein Sm14 plus GLA-SE adjuvant. Front. Immunol. 2015, 6” in this review.

Response: Thank you again for your scientific input on the manuscript. I have revised the abstract by including the main weaknesses of chemotherapy to highlight in turn the importance of vaccination. The respective revised section reads as “Preventive measures should be complemented by vaccination, inducing long-term protection against transmission, infection, and disease recurrence, given the latest advancements in schistosomal vaccines. Vaccines become pivotal when considering constraints of chemotherapy, i.e., lack of protection against re-infection, and evolving resistance or reduced sensitivity.” Thank you also for highlighting the review article of Tendler M. et al. that I have cited in the submitted manuscript where appropriate for its better rounding off. I hope the revised article reads better and I have addressed your comment sufficiently.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The author addressed most of my concerns with the original manuscript. I am glad to see its improved quality, particularly in English expression.

Reviewer 2 Report

Comments and Suggestions for Authors

I am satisfied with the revised version of the manuscript, I have no further suggestions.