Vaccine Immunogenicity versus Gastrointestinal Microbiome Status: Implications for Poultry Production

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article entitled “Vaccine immunogenicity versus gastrointestinal microbiome status: Implications for poultry production” is very well written and the review is very well done. It presents 86 bibliographical references. However, the article can be improved in two ways. On the one hand, the conclusions are presented qualitatively, so I recommend that the values ​​of the indicators used and their p-values be added. For example, in the phrase that is between lines 236 and 241, but also when appropriate. And on the other hand, I would add more recent articles, especially related to information on poultry, as at the end of 2023 several articles have been published in this regard. This is against the statement that you have made in lines 324-326: Unfortunately, investigations regarding the effects of vaccine responses on gut microbiome status in commercial poultry is nearly non-existent…

Just adding poultry and vaccine and microbiome as keywords in pubmed I have got the following papers mong others that could be relevant:

*Zhao B, Guo Y, Sun R, Zhang L, Yang L, Mei X, Zhang L, Huang J. Quadrivalent hemagglutinin and adhesion expressed on Saccharomyces cerevisiae induce protective immunity against Mycoplasma gallisepticum infection and improve gut microbiota. Microb Pathog. 2023 Dec 31;187:106511. doi: 10.1016/j.micpath.2023.106511.

* Gloanec N, Guyard-Nicodème M, Brunetti R, Quesne S, Keita A, Chemaly M, Dory D. Evaluation of Two Recombinant Protein-Based Vaccine Regimens against Campylobacter jejuni: Impact on Protection, Humoral Immune Responses and Gut Microbiota in Broilers. Animals (Basel). 2023 Dec 7;13(24):3779. doi: 10.3390/ani13243779.

* Heidarpanah S, Thibodeau A, Parreira VR, Quessy S, Segura M, Gottschalk M, Gaudreau A, Juette T, Gaucher ML. Evaluation of the Immunoprotective Capacity of Five Vaccine Candidate Proteins against Avian Necrotic Enteritis and Impact on the Caecal Microbiota of Vaccinated Birds. Animals (Basel). 2023 Oct 26;13(21):3323. doi: 10.3390/ani13213323.

* Fries-Craft K, Schmitz-Esser S, Bobeck EA. Dietary peptide-specific antibodies against interleukin-4 differentially alter systemic immune cell responses during Eimeria challenge with minimal impacts on the cecal microbiota. Poult Sci. 2023 Dec;102(12):103134. doi: 10.1016/j.psj.2023.103134.

* Sayed Y, Hassan M, Salem HM, Al-Amry K, Eid GE. Prophylactic influences of prebiotics on gut microbiome and immune response of heat-stressed broiler chickens. Sci Rep. 2023 Aug 26;13(1):13991. doi: 10.1038/s41598-023-40997-7.

Author Response

Thank you for your helpful and insightful comments and suggestions.

You advised to add p-values to some of the quantitative work that was cited in the review. Examples of these revisions are highlighted on lines 239 (regarding correlation analysis) as well as in Tables 1 and 2.  However, additional p-values were not added in the text due to concerns that the reference to p-values may cause confusion to the reader and because review articles do not usually include p-values in text.

Regarding inclusion of additional recent publications in the review, we incorporated additional recent references at line 313 and 322, and lines 392 through 423. These publications were described along with explanations on how they differ from previously discussed publications (i.e., commercially applied vaccines versus experimental vaccine programs). The articles cited include:

[88]      S. Heidarpanah et al., “Evaluation of the Immunoprotective Capacity of Five Vaccine Candidate Proteins against Avian Necrotic Enteritis and Impact on the Caecal Microbiota of Vaccinated Birds,” Animals, vol. 13, no. 21, p. 3323, Oct. 2023, doi: 10.3390/ani13213323.

[89]      N. Gloanec et al., “Evaluation of Two Recombinant Protein-Based Vaccine Regimens against Campylobacter jejuni: Impact on Protection, Humoral Immune Responses and Gut Microbiota in Broilers,” Animals, vol. 13, no. 24, p. 3779, Dec. 2023, doi: 10.3390/ani13243779.

Reviewer 2 Report

Comments and Suggestions for Authors

1. Please replace the expression of "gut microbes" or "commensal microbes" with "gut microbiota" or "commensal microbiota" throughout the paper;

2. Please include one Figure to summarize the antigen sampling, tolerance, and immune function of commensal bacteria as well as future directions;

3. Please include one table to compare and summarize the interactions between vaccine administration and gut microbiome status.

Author Response

Thank you for your helpful comments and suggestions.

You advised that “gut microbes” or “commensal microbes” should be replaced with “gut microbiota” or “commensal microbiota”. These changes were made and are highlighted in the manuscript.

To address your recommendation that a table should be added to compare and summarize interactions between vaccine administration and gut microbiome status, we added two tables to the manuscript.

Table 1 (page 7) details published papers that investigated vaccine-associated immune responses under conditions of dysbiosis.

Table 2 (page 10) details published papers that describe changes in cecal pouch microbiome that are associated with a vaccination program.

With the addition of two tables that categorize and further explain the research being cited, the co-authors believe that these recommendations may now be sufficiently addressed.

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript is interesting and up-to-date.

1. Line 278. "Similar immunological responses...". The previous passage (lines 269-277) states that a decrease in Firmicutes and Bacteroidetes phyla was associated with a better immune response. And in the next fragment (278-281) it is said that Lactobacillus probiotic cocktail led to a better immune response. That is, it is not "Similar immunological responses...", but rather the opposite. Please check it out.

2. Line 304. I think it is worth explaining what the Simpson index is here.

3. My proposal is to make a graphic abstract, or at least 1-2 figures, which would more easily visually demonstrate the connection between microbiota and vaccines. That is, try to present the information from chapter 4 graphically for easier perception.

Author Response

Thank you for your helpful and insightful comments and suggestions.

Thank you for pointing out the discrepancies in statements from lines 268 through 281. These discrepancies were corrected accordingly so all the statements correctly align with the results of the articles being described. Additionally, the Simpson index was briefly described at line 310 and the results from the referenced paper were described in more detail.

You recommended creating a graphical abstract and/or figure(s) to visually describe sections 3 and 4. To address this, we have added two tables that categorize and further explain the research being cited. We believe that the addition of the tables may sufficiently address your recommendation.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors has improved the paper. However I think that it could be much better adding more references, nit just two of them.

Author Response

Dear Reviewer 1,

Your efforts to continuously improve this review article are greatly appreciated.

We have added 17 published research articles that detail microbiota composition following the administration of established and experimental vaccination programs. Within the resubmitted article, these cited publications and additional written sections are highlighted in blue.

The articles added to this literature review include:

86. Zhang, H.; Xie, R.; Zhang, H.; Sun, R.; Li, S.; Xia, C.; Li, Z.; Zhang, L.; Guo, Y.; Huang, J. Recombinant hemagglutinin protein and DNA-RNA-combined nucleic acid vaccines harbored by yeast elicit protective immunity against H9N2 avian influenza infection. Poult Sci 2023, 102, 102662, doi: 10.1016/j.psj.2023.102662.
87. Lyimu, W. M.; Leta, S.; Everaert, N.; Paeshuyse, J. Influence of live attenuated Salmonella vaccines on cecal microbiome composition and microbiota abundances in young broiler chickens. Vaccines (Basel) 2023, 11, 1116, doi: 10.3390/vaccines11061116.
88. Jan, T. R.; Lin, C. S.; Wang, S. Y.; Yang, W. Y. Cytokines and cecal microbiome modulations conferred by a dual vaccine in Salmonella-infected layers. Poult Sci 2023, 102, 102373, doi: 10.1016/j.psj.2022.102373.
89. Videnska, P.; Sedlar, K.; Lukac, M.; Faldynova, M.; Gerzova, L.; Cejkova, D.; Sisak, F.; Rychlik, I. Succession and re-placement of bacterial populations in the caecum of egg laying hens over their whole life. PLoS One 2014, 9, e115142, doi: 10.1371/journal.pone.0115142.
90. Qi, Z.; Shi, S.; Tu, J.; Li, S. Comparative metagenomic sequencing analysis of cecum microbiotal diversity and function in broilers and layers. 3 Biotech 2019, 9, 316, doi: 10.1007/s13205-019-1834-1.
91. Lund, M.; Bjerrum, L.; Pedersen, K. Quantification of Faecalibacterium prausnitzii- and Subdoligranulum variabile-like bacte-ria in the cecum of chickens by real-time PCR. Poult Sci 2010, 89, 1217–1224, doi: 10.3382/ps.2010-00653.
92. Van Hul, M.; Le Roy, T.; Prifti, E.; Dao, M. C.; Paquot, A.; Zucker, J. D.; Delzenne, N. M.; Muccioli, G.; Clément, K.; Cani, P. D. From correlation to causality: the case of Subdoligranulum. Gut Microbes 2020, 12, 1849998, doi: 10.1080/19490976.2020.1849998.
93. Miquel, S.; Martín, R.; Bridonneau, C.; Robert, V.; Sokol, H.; Bermúdez-Humarán, L. G.; Thomas, M.; Langella, P. Ecolo-gy and metabolism of the beneficial intestinal commensal bacterium Faecalibacterium prausnitzii. Gut Microbes 2014, 5, 146–151, doi: 10.4161/gmic.27651.
94. Liu, J.; Robinson, K.; Lyu, W.; Yang, Q.; Wang, J.; Christensen, K. D.; Zhang, G. Anaerobutyricum and Subdoligranulum are differentially enriched in broilers with disparate weight gains. Animals 2023, 13, 1834, doi: 10.3390/ani13111834.
95. Amen, O.; El Hendy, A. H.; Elfeil, W. K.; Hussein, A. G. Evaluating the efficacy of commercial Escherichia coli killed vac-cine in broiler chickens. J Adv Vet Res 2023, 13, 1037-1043. Retrieved from https://www.advetresearch.com/index.php/AVR/article/view/1350
96. Paudel, S.; Hess, C.; Abdelhamid, M. K.; Lyrakis, M.; Wijewardana, V.; Kangethe, R. T.; Cattoli, G.; Hess, M. Aerosol de-livered irradiated Escherichia coli confers serotype-independent protection and prevents colibacillosis in young chickens. Vaccine 2023, 41, 1342–1353, doi: 10.1016/j.vaccine.2022.12.002.
97. Beirão, B. C. B.; Ingberman, M.; Mesa, D.; Salles, G. B. C.; Muniz, E. C.; Caron, L. F. Effects of aroA deleted E. coli vaccine on intestinal microbiota and mucosal immunity. Comp Immunol Microbiol Infect Dis 2021, 75, 101612, doi: 10.1016/j.cimid.2021.101612.
98. Lozica, L.; Gholi, C. S. M.; Kela, A.; Tomić, I. L. D. H.; Gottstein, Ž. Autogenous Escherichia coli vaccine application as an innovative antimicrobial therapy in poultry farming—A case report. Vaccines (Basel) 2022, 10, 1567, doi: 10.3390/vaccines10091567.
99. Chandran, S.; Hewawaduge, C.; Aganja, R. P.; Lee, J. H. Prokaryotic and eukaryotic dual-expression plasmid-mediated delivery of Campylobacter jejuni antigens by live-attenuated Salmonella: A strategy for concurrent Th1 and Th2 immune activation and protection in chickens. Dev Comp Immunol 2024, 153, 105134, doi: 10.1016/j.dci.2024.105134.
100. Haems, K.; Van Rysselberghe N.; Goossens, E.; Strubbe, D.; Rasschaert, G.; Martel, A.; Pasmans, F.; Garmyn, A. Reduc-ing Campylobacter colonization in broilers by active immunization of naive broiler breeders using a bacterin and subunit vaccine. Poult Sci 2023, 102, 103075, doi: 10.1016/j.psj.2023.103075.
101. Huaringa, D.; Zea, O.; Huapaya, S.; Jimenez, L.; Salazar, M.; Molina, D.; Espinoza, S.; Vílchez-Perales, C. Evaluation of three vaccination schemes against Clostridium perfringens alpha toxin and their effects on the performance, level of intestinal lesions, and serum antibody titers in broilers. Avian Dis 2023, 67, 170-176, doi: 10.1637/aviandiseases-D-23-00001.
102. Gautam, H.; Ayalew, L. E.; Shaik, N. A.; Subhasinghe, I.; Popowich, S.; Chow-Lockerbie, B.; Dixon, A.; Ahmed, K. A.; Tikoo, S. K.; Gomis, S. Exploring the predictive power of jejunal microbiome composition in clinical and subclinical ne-crotic enteritis caused by Clostridium perfringens: Insights from a broiler chicken model. J Transl Med 2024, 22, 80, doi: 10.1186/s12967-023-04728-w.

 

These articles are in addition to four publications that were added for the previous revision (yellow highlighted text in the manuscript):

78. Bi, S.; Zhang, J.; Qu, Y.; Zhou, B.; He, X.; Ni, J. Yeast cell wall product enhanced intestinal IgA response and changed ce-cum microflora species after oral vaccination in chickens. Poult Sci 2020, 99, 6576–6585, doi: 10.1016/j.psj.2020.09.075.
79. Hanchi, H.; Mottawea, W.; Sebei, K.; Hammami, R. The genus Enterococcus: Between probiotic potential and safety con-cerns—An update. Front Microbiol 2018, 9, 1791, doi: 10.3389/fmicb.2018.01791.
80. Heidarpanah, S.; Thibodeau, A.; Parreira, V. R.; Quessy, S.; Segura, M.; Gottschalk, M.; Gaudreau, A.; Juette, T.; Gaucher, M. L. Evaluation of the immunoprotective capacity of five vaccine candidate proteins against avian necrotic enteritis and impact on the caecal microbiota of vaccinated birds. Animals 2023, 13, 3323, doi: 10.3390/ani13213323.
81. Gloanec, N.; Guyard-Nicodème, M.; Brunetti, R.; Quesne, S.; Keita, A.; Chemaly, M.; Dory, D. Evaluation of two recom-binant protein-based vaccine regimens against Campylobacter jejuni: Impact on protection, humoral immune responses and gut microbiota in broilers. Animals 2023, 13, 3779, doi: 10.3390/ani13243779.

 

In the previous review, it was advised that the following papers could be relevant to this review article:

(Not included in revision, but research that used Saccharomyces vector for avian influenza vaccine was cited, Zhang et al. 2023) *Zhao B, Guo Y, Sun R, Zhang L, Yang L, Mei X, Zhang L, Huang J. Quadrivalent hemagglutinin and adhesion expressed on Saccharomyces cerevisiae induce protective immunity against Mycoplasma gallisepticum infection and improve gut microbiota. Microb Pathog. 2023 Dec 31;187:106511. doi: 10.1016/j.micpath.2023.106511.

(Included in revisions) * Gloanec N, Guyard-Nicodème M, Brunetti R, Quesne S, Keita A, Chemaly M, Dory D. Evaluation of Two Recombinant Protein-Based Vaccine Regimens against Campylobacter jejuni: Impact on Protection, Humoral Immune Responses and Gut Microbiota in Broilers. Animals (Basel). 2023 Dec 7;13(24):3779. doi: 10.3390/ani13243779.

(Included in revisions) * Heidarpanah S, Thibodeau A, Parreira VR, Quessy S, Segura M, Gottschalk M, Gaudreau A, Juette T, Gaucher ML. Evaluation of the Immunoprotective Capacity of Five Vaccine Candidate Proteins against Avian Necrotic Enteritis and Impact on the Caecal Microbiota of Vaccinated Birds. Animals (Basel). 2023 Oct 26;13(21):3323. doi: 10.3390/ani13213323.

(Not included in revisions) * Fries-Craft K, Schmitz-Esser S, Bobeck EA. Dietary peptide-specific antibodies against interleukin-4 differentially alter systemic immune cell responses during Eimeria challenge with minimal impacts on the cecal microbiota. Poult Sci. 2023 Dec;102(12):103134. doi: 10.1016/j.psj.2023.103134.

(Not included in revisions) * Sayed Y, Hassan M, Salem HM, Al-Amry K, Eid GE. Prophylactic influences of prebiotics on gut microbiome and immune response of heat-stressed broiler chickens. Sci Rep. 2023 Aug 26;13(1):13991. doi: 10.1038/s41598-023-40997-7.

 

Reason for non-inclusion of articles: Published articles like those by Sayed et al. (2023) were not extensively included in this review since they only concentrate on changes to gut microbiome associated with prebiotic or probiotic application. However, it would be very informative to formulate a review article that concentrates on how environmental stressors (such as heat stress) impact gut microbiota. Additional published papers were screened and selected based on how well the published research fits the scope of poultry pathogens discussed in this review article.

Once again, thank you for your time and energy. We feel that our integration of the additional journal articles as per your suggestions improved the contents of this review article, and hope that we have addressed your suggestions satisfactorily. 

 

Round 3

Reviewer 1 Report

Comments and Suggestions for Authors

The paper is much better now.