http://orcid.org/0000-0003-2579-4655
Peer Review History
| Original SubmissionFebruary 28, 2020 |
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Dear Dr. Killingley, Thank you very much for submitting your manuscript "Minimal transmission in an influenza A (H3N2) human challenge-transmission model within a controlled exposure environment" for consideration at PLOS Pathogens. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments. We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation. When you are ready to resubmit, please upload the following: [1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. [2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file). Important additional instructions are given below your reviewer comments. Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts. Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments. Sincerely, Peter Palese Associate Editor PLOS Pathogens Ron Fouchier Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens *********************** Reviewer's Responses to Questions Part I - Summary Please use this section to discuss strengths/weaknesses of study, novelty/significance, general execution and scholarship. Reviewer #1: This manuscript summarizes the findings of three separate human influenza virus transmission studies performed in a highly controlled setting. While the authors found consistent shedding of the H3N2 challenge virus in nasal swab samples in almost all directly challenged individuals up to day 4, only 1 out of 75 recipients (including protected and unprotected individuals) was confirmed to be infected. Interestingly, the study found substantially lower rates of aerosolized particle shedding in directly infected individuals compared to individuals in a previous study in a natural infection setting. The study could be considered largely a "failed" experiment, but is nonetheless important since it raises important questions on how controlled human challenge studies may substantially differ from natural infection. The viral titers required to successfully infect individuals in challenge studies are generally higher than what is thought to be required in natural infection and based on this study the experimental infection may be even more different from natural infection than previously thought. Reviewer #2: Overall this manuscript describes the result of a human challenge transmission study that did not go as planned. While individuals who were inoculated with virus became infected, there was minimal transmission to contacts. While the study essentially describes negative results, there is great interest in these data with such studies being rarely conducted. Having said this, the authors main conclusion that ventilation was a key factor is not convincingly supported and other alternatives need further exploration. 1. Ln 154. A bit more detail on exactly what constitutes “seronegative (HAI≤10) volunteers” would be informative. Were they seronegative to just the challenge antigen, a range of viruses of the same subtype, a range of viruses of different subtypes etc. 2. Ln 158. EE should be defined here (first mention in text). 3. Ln 173. The authors describe that infection produced an infection rate of 81% 174 (42/52) among inoculated volunteers. Is this typical of H3N2 experimental infections? Data form other studies in presented in ln 285, but a larger comparison to the literature would be of interest. 4. Ln 181. I am a bit confused by the discussion of the ten Donors that had greater than anticipated immunity on admission. What exactly does this mean? Does it mean that they were infected naturally between having admission blood drawn and actually entering quarantine? What viruses were they confirmed positive with? 5. Ln 216. What were the Ct valus of the two contacts that had transient PCR positivity? 6. A quarter of the CR recipients showed signs of ILI? What was the reason for this? Was testing done for any other organism? Could this possibly explain the very low rates of virus transmission, i.e., non-specific antiviral responses due to infection with other respiratory pathogens? 7. The authors state a number of variable that could have impacted the lower than expected transmission rates in the study but tend to favor ventilation as the likely factor. I am a little less than convinced by their arguments and am more inclined to question the high levels of ILI and symptoms in recipients. This finding must be further discussed in the context of the overall findings. ********** Part II – Major Issues: Key Experiments Required for Acceptance Please use this section to detail the key new experiments or modifications of existing experiments that should be absolutely required to validate study conclusions. Generally, there should be no more than 3 such required experiments or major modifications for a "Major Revision" recommendation. If more than 3 experiments are necessary to validate the study conclusions, then you are encouraged to recommend "Reject". Reviewer #1: - A major concern is that serology was only assessed based on HAI and neutralization. However, recent publications have shown that antibodies measured by ELISA can not only be predictive of protection, but may also be a more sensitive tool to assess seroconversion in the absence of HAI titer increase (PMID 31160818). It would substantially improve the manuscript if the authors could measure antibody responses against HA and NA in pre- and post-challenge samples to identify potential pre-existing titers or seroconversion that could not be detected in the traditional assays. - It would be helpful if the authors could comment in more detail on the aerosol shedding in naturally infected individuals. Is it possible that some selection bias might result in more severe cases to be enrolled, who might spread more aerosolized virus due to lower respiratory tract infection? Reviewer #2: (No Response) ********** Part III – Minor Issues: Editorial and Data Presentation Modifications Please use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. Reviewer #1: The title could be changed to more explicitly state intranasal droplet delivery as the route of administration, which may be an important factor in the limited viral spread via droplets. Reviewer #2: (No Response) ********** PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No Figure Files: While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Data Requirements: Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here on PLOS Biology: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5. Reproducibility: To enhance the reproducibility of your results, PLOS recommends that you deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plospathogens/s/submission-guidelines#loc-materials-and-methods |
| Revision 1 |
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Dear Dr. Killingley, We are pleased to inform you that your manuscript 'Minimal transmission in an influenza A (H3N2) human challenge-transmission model within a controlled exposure environment' has been provisionally accepted for publication in PLOS Pathogens. Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests. Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated. IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript. Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS. Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Pathogens. Best regards, Peter Palese Associate Editor PLOS Pathogens Ron Fouchier Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens *********************************************************** Reviewer Comments (if any, and for reference): |
| Formally Accepted |
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Dear Dr. Killingley, We are delighted to inform you that your manuscript, "Minimal transmission in an influenza A (H3N2) human challenge-transmission model within a controlled exposure environment," has been formally accepted for publication in PLOS Pathogens. We have now passed your article onto the PLOS Production Department who will complete the rest of the pre-publication process. All authors will receive a confirmation email upon publication. The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Pearls, Reviews, Opinions, etc...) are generated on a different schedule and may not be made available as quickly. Soon after your final files are uploaded, the early version of your manuscript, if you opted to have an early version of your article, will be published online. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers. Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Pathogens. Best regards, Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens |
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