Estimation of Reduction in Influenza Vaccine Effectiveness Due to Egg-Adaptation Changes—Systematic Literature Review and Expert Consensus

Round 1

Reviewer 1 Report

SPECIFIC POINTS:

L34: …antigenic drift were significant…

L70-72. This sentence may be a bit confusing, I would recommend not mixing concepts such egg-adaptation (driven by egg-based production) and antigenic mismatch (driven by viral genetic drift).

Tables 1 and 2. It would be very informative to show the granular data by season, because egg-adaptation in H3N2 viruses had different impact depending on the season.

L213. Missing reference

L230. As above, specify for which virus subtype and in what season were egg-adaptation and/or drift more relevant.

L248. Here In the discussion (and/or in the conclusions), it may be relevant for the reader to raise the need for multicentric European-wide studies on IVE including genetic characterization of viral strains.

L275-276. H1N1pdm09?

L289. …the other strain… which one?

L296 … while the German experts….

L297 …. Antigenic distance (AD)

L344. Please indicate whether Sequirus did or did not participated in the analysis and drawing conclusions.

Author Response

Reviewer 1:

Responses

L34: ...antigenic drift were significant

Answer: We have updated the text to reflect the reviewer’s suggestion. It now reads: “…egg-adaptation and antigenic drift were significant enough to impact IVE…”

L70-72. This sentence may be a bit confusing, I would recommend not mixing concepts such egg-adaptation (driven by egg-based production) and antigenic mismatch (driven by viral genetic drift).

Answer: We have reworded the statement to read: “…may play a significant role in contributing to the antigenic mismatch with circulating flu viruses.” It is hoped that altering the text in this manner would help resolve any confusion.

Tables 1 and 2. It would be very informative to show the granular data by season, because egg-adaptation in H3N2 viruses had different impact depending on the season.

Answer: We thank the reviewer for this suggestion and agree it indeed would be interesting information. Whereas we acknowledge that the phenomena affect the H3N2 subtype to the greatest extent in the discussion section (line 274), there is no quantitative data available per season, nor was it researched in this study.

It is important to note, that seasonal vaccine match and vaccine effectiveness estimates referred to in the manuscript, are not specifically attributed to either antigenic drift or egg-adaptation changes.

L213. Missing reference

Answer: The authors are unsure of the reviewer’s suggestion as there are no references listed in this line. However, we have updated the text to better reflect any reference (citation, table or figure) which may be present.

L230. As above, specify for which virus subtype and in what season were egg-adaptation and/or drift more relevant.

Answer: We acknowledge the reviewer’s suggestion and agree it indeed would be interesting information. However, the per season data was not within the scope of this study.

L248. Here In the discussion (and/or in the conclusions), it may be relevant for the reader to raise the need for multicentric European-wide studies on IVE including genetic characterization of viral strains.

Answer: We have incorporated the reviewer’s suggestion into our manuscript. It now reads: “The impact of mutations, i.e., egg-adaptation changes and antigenic drift, on IVE is difficult to measure with traditional epidemiological studies, chiefly in real-world set-tings. In the absence of multicentric European-wide studies on IVE, which include genetic characterization of viral strains, and supporting studies evaluating this specific research question, the use of consensus expert opinion in addressing this issue was deemed ap-propriate as it falls within a well-established tradition of generating legitimate evidence.”

L275-276. H1N1pdm09?

Answer: We have updated the manuscript to include the sub-strain.

L289. ...the other strain... which one?

Answer: We acknowledge the confusion this statement has caused and have altered it to read: “….the other strains…”

L296 ... while the German experts....

Answer: We have altered the text to reflect the reviewer’s suggestion.

L297 .... Antigenic distance (AD)

Answer: As we had not previously used the abbreviation AD when referring to antigenic drift, we have removed it from the main text and replaced it in full with “antigenic drift”

L344. Please indicate whether Sequirus did or did not participate in the analysis and drawing conclusions.

Answer: Sequirus’ role has been redefined to accurately state their involvement in the project. It now reads: “Seqirus funded this work, however, they did not participate in the analysis or drawing of conclusions, which was conducted independently by Medialis Ltd.” As per the reviewer’s suggestion.

Author Response File: Author Response.docx

Reviewer 2 Report

In this paper, the authors reported the evaluation from European experts about the impact that egg-adaptation changes have on vaccine mismatch and vaccine effectiveness. They observed the influenza vaccine effectiveness (IVE) and estimated reduction in IVE  for the influenza virus A(H3N2) subtype for the under 65 age group.

This paper has several limitation (the authors reported some of them in the discussion):

• The responses of each expert were specific for their country and regarded only influenza seasons between 2014 and 2019.
• The results are based on expert opinion (few partecipants) and there are no clinical trials or observational studies to address this particular research question.
• The questions were dedicated only to traditional (egg-based) TIV and QIV vaccines. Adjuvanted TIV/QIV vaccines, Live Attenuated Influenza Vaccines (LAIV), cell-based or recombinant vaccines were not considered. Of course for other vaccines the egg-adptation is not important but they can at least compare the effectiveness of the different typ of vaccines.
• They concluded that there is a potential for 9% on average and up to a 16% increase in IVE (against the A(H3N2), <65 age group) if egg-adaptations that arise when employing the traditional egg-based manufacturing process are avoided.  It means that other vaccines are high effectiveness?

The results are not clearly presented, the figures have a wrong numbers and are not correctly cited in the text.

They should improve results and discussion by comparing their results with data available for other vaccines. The analysis of the importance of the reported work and the application of these results should also be added.

Author Response

Reviewer 2:

In this paper, the authors reported the evaluation from European experts about the impact that egg-adaptation changes have on vaccine mismatch and vaccine effectiveness. They observed the influenza vaccine effectiveness (IVE) and estimated reduction in IVE for the influenza virus A(H3N2) subtype for the under 65 age group.

This paper has several limitations (the authors reported some of them in the discussion):

Responses:

We would like to thank the reviewer very much for their patience and constructive comments.

1. The responses of each expert were specific for their country and regarded only influenza seasons between 2014 and 2019.

Answer: The answers from all experts were processed using summary statistics to produce estimates at both the country-level and European-level (EU5), as described in Line 156.

2. The results are based on expert opinion (few participants) and there are no clinical trials or observational studies to address this particular research question.

Answer: While we appreciate the reviewers concern, our approach was adopted due to the difficulty in employing clinical trials or observational studies to address our particular research question.

3. The questions were dedicated only to traditional (egg-based) TIV and QIV vaccines. Adjuvanted TIV/QIV vaccines, Live Attenuated Influenza Vaccines (LAIV), cell-based or recombinant vaccines were not considered. Of course for other vaccines the egg-adptation is not important but they can at least compare the effectiveness of the different type of vaccines. They concluded that there is a potential for 9% on average and up to a 16% increase in IVE (against the A(H3N2), <65 age group) if egg-adaptations that arise when employing the traditional egg-based manufacturing process are avoided. It means that other vaccines are high effectiveness?

Answer: The authors feel that the request made by the reviewer lies outside of the scope of this study. This study focused on only the vaccine manufacturing aspect and the impact egg-adaption changes have. Therefore, given the multifactorial nature of their development and design, only TIV’s and QIV’s were investigated. It is important to note that the conclusions drawn in this study are based solely on the data obtained for the manufacturing aspect of vaccine efficacy.

5. The results are not clearly presented; the figures have wrong numbers and are not correctly cited in the text.

Answer: While the reviewer’s comment is vague, we have made a number of changes to the presentation of our data in the results section. Table numbers and table in-text citations have been reviewed and improved. It is hoped that the changes made will satisfy the reviewers concerns. 

6.They should improve results and discussion by comparing their results with data available for other vaccines. The analysis of the importance of the reported work and the application of these results should also be added.

Answer: We acknowledge and thank the reviewer for this suggestion. The suggested application of these results will form the basis of future work, in which we will compare our results with available data for other vaccines in a more generalised efficacy study.  

Author Response File: Author Response.docx

Reviewer 3 Report

I read with interest the manuscript submitted to me for review. It has a certain interest for readers and as an evaluation of the egg-adaptations changes on the effectiveness/efficiency of the influenza vaccine it is certainly innovative.

I have some doubts in tables 3, 4, 5 and 6: since otherwise the numbers do not match, probably not> 18 but <18. If you then consider the +65 (I guess, but maybe I'm wrong, over 65) and the previous class is 8-64, where have the 65s gone?

Author Response

Reviewer 3:

I read with interest the manuscript submitted to me for review. It has a certain interest for readers and as an evaluation of the egg-adaptations changes on the effectiveness/efficiency of the influenza vaccine it is certainly innovative.

Responses:

1: I have some doubts in tables 3, 4, 5 and 6: since otherwise the numbers do not match, probably not> 18 but <18. If you then consider the +65 (I guess, but maybe I'm wrong, over 65) and the previous class is 8-64, where have the 65s gone?

Answer: We would like to thank the reviewer very much for their patience and constructive comment. As such, we have revised the manuscript to address the confusion in presenting the age categories in the above-mentioned tables. The age categories have been listed as follows:

• <18 yrs
• 18-64 yrs
• ≥65 yrs

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The authors did not consider my comment on the conclusions which remained a summary of the discussion. The perspectives indicated in their attached reply are not included in the main text.

The authors did not consider my comment on the incorrect citation of the figures: in the text (line 171) they cited figures 6 and 7. Figures 6 and 7 (attached at the end of the manuscript) appear to be a copy of figures 1 and 2 which are not cited in the text. If they read their manuscript carefully, they might find that my comment is not vague ...

Also in the main text they reported the sentence "Figure 6 AND Figure 7 HERE" (line 174) which suggests to me that they did not re-read the manuscript before sending the revised version.

I apologize if my comment was vague or if I misinterpreted the numbering of the figures. 

Author Response

Please see the attachment.

Author Response File: Author Response.docx