Roles for Pathogen Interference in Influenza Vaccination, with Implications to Vaccine Effectiveness (VE) and Attribution of Influenza Deaths
Round 1
Reviewer 1 Report
This is a review trying to prove that influenza vaccination inadvertently increases the risk of infection from other winter non-influenza pathogens. Although the authors try to create a comprehensive review of the literature, it is not clear to me how they draw this conclusions. The literature they present is not convincing that influenza vaccination inadvertently increases the risk of infection from other winter non-influenza pathogens.
Author Response
Thank you for your time and comments.
All changes are in red text.
To address your comments the abstract has been revised and a section has been added at the start of the review to allow the reader to quickly assimilate the outcomes of the previous three papers in this series.
The conclusions have also been modified.
Figure A1 has been added to further illustrate the issues raised in Figure 6. Single year of age analysis is seemingly of considerable importance.
We believe that the role of small RNAs in influenza vaccination gives an adequate explanation as to how influenza vaccination could modify pathogen interference in particular years. Can you be most helpful and point out specific sections or paragraphs in which you feel that the meaning is not clear or needs improvement.
An epilogue has been added at the end to give an overall research context.
Once again many thanks for your input.
Reviewer 2 Report
The manuscript “idr-1829906” entitled "Roles for pathogen interference in influenza vaccination, with implications to vaccine effectiveness (VE) and attribution of influenza deaths" is very interesting and well organized review article. The authors provided insights to Pathogen interference, factors affecting this interference and possible interaction with influenza vaccination. I find this review of high interest especially for those studying pathogen-pathogen and pathogen-host interactions. Figures and Tables are clear and well presented. References are adequate and updated. I consider this manuscript of interest but after minor revision:
1. Excessive use of transition statements (e.g. See Section 2.4., see Section 4, see below, Also see Figure 1, ……….). Kindly use figure citation instead.
2. Figure 1, kindly revise the axis titles.
3. Kindly revise the improper use of punctuations and question marks in whole manuscript (e.g. Pathogen interference and variation in VE?)
Author Response
Thank you very much for your time and encouraging words.
The abstract has been changed to clarify a few points.
Please note that a new section has been added at the start of the review to quickly bring the reader up to speed as to how this series has reached the point where pathogen interference and influenza vaccination need to be discussed in detail.
The following changes have been made and are highlighted in red text.
Data in Figure 3 for 2022 has been updated and this allowed some further comments regarding COVID pathogen interference. COVID-19 looks to be the equivalent to an 'apex predator'.
Figure A1 has been added in the Appendix to further illustrate the issues raised in Figure 6. Single year of age analysis is seemingly of considerable importance.
Point #1 As you will appreciate this review attempts to illustrate to the reader the interlinked complexity behind the multiple issues. Hence, our perceived need to show how the sections interlink by use of see Section X.Y, etc. Over half of these interlinkages have been removed, but feel free to suggest more. The citation to Figure 1 has been added throughout the text.
Point#2 The caption to Figure 1 has been revised and the word 'long-term' has been added to the Y-axis. A description has also been added to the X-axis. A change has also been made to the text to clarify. Please feel free to suggest a better way.
Point #3 has been addressed and question marks removed from section headings.
An epilogue has been added at the end to give an overall research context.
Once more, many thanks for your valued input.
Reviewer 3 Report
First, I would like to appreciate the effort from the authors to write such a concise and descriptive review on a very alarming topic. As a reader, I really enjoyed the review article and felt that it must help the infectious disease research community as a guideline. Now, as a reviewer, I wanted to pass few comments, that might help improve the review article to a more accessible form and more lucid in flow for the readers.
1. If I am not very wrong, Figure 1 and 3, x-axis labels are somewhat wrongly compiled, or messed up. They do not show up how the authors intended, I believe.
2. 'Pathogen interference' should be well defined at line 44.
3. Reading the Introduction several times, I felt it more as a report, not an introduction. I agree that references are required and they are properly cited at places. But the flow of the story is needed somewhat rearrangement. e.g., lines 71-77, this paragraph should not be presented in the Introduction.
4. The authors have mentioned about the variability of vaccination responses in 8.5. I would elaborate that topic and investigate if there is any covariate with coinfections and superinfections driving the variability.
5. There are literature reported on defective interfering virus influenza vaccines. I would recommend to incorporate them in section 8.
Author Response
Thank you very much for your time and encouraging words.
The abstract has been changed to clarify a few points.
Please note that a new section has been added at the start of the review to quickly bring the reader up to speed as to how this series has reached the point where pathogen interference and influenza vaccination need to be discussed in detail.
The following changes have been made and are highlighted in red text.
A few minor grammatical changes have been made.
Data in Figure 3 for 2022 has been updated and this allowed some further comments regarding COVID pathogen interference. COVID-19 looks to be the equivalent to an 'apex predator'.
Figure A1 has been added to further illustrate the issues raised in Figure 6. Single year of age analysis is seemingly of considerable importance.
Point#1 The title to Figure 1 has been revised and the word 'long-term' has been added to the Y-axis. A description has also been added to the X-axis. A change has also been made to the text to clarify. Please feel free to suggest a better way. Figure 3 has likewise been revised.
Point #2 A change has been made in the definition of pathogen interference, please advise if more is needed.
Point#3 Hopefully addressed in the revised abstract, added Background section, and revised Introduction.
Your suggestions regarding points #4 and 5 are very apposite. Additional references have been added. Complexity seemingly abounds at every turn!
Point #4 A new section has been added to discuss this issue.
Point #5 An additional section has been added to address this issue.
An epilogue has been added at the end to give an overall research context.
Once again, many thanks for your valued input.
Round 2
Reviewer 1 Report
In my initial review, I rejected this manuscript as it was not clear to me how they draw this conclusions. The literature they present is not convincing that influenza vaccination inadvertently increases the risk of infection from other winter non-influenza pathogens. After the revision, it is still not obvious how this conclusion was drawn.
Author Response
Dear Reviewer,
We have discussed your concerns and believe that the issues have been adequatly covered. Yes we could go into even greater detail, but this is already a long and complex review with 300 references.
The whole idea of the review was to raise awareness, and stimulate further research. We feel we have achieved our aims.
Given that the other two reviewers are happy with the changes that have been made, and that they have accepted the technical arguments, we feel to leave the review as is.
The other technical arguments are perhaps better covered in a seperate paper.
So please accept our thanks for your comments and be assured that we will continue to develop the field.
Best Regards,
Rod and Andrey
