http://orcid.org/0000-0002-5540-2459
Peer Review History
| Original SubmissionMay 23, 2020 |
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Dear Dr. Friedman, Thank you very much for submitting your manuscript "An HSV-2 nucleoside-modified mRNA genital herpes vaccine containing glycoproteins C, D, and E protects mice against HSV-1 genital lesions and latent infection" 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. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations. Even so both reviewers felt that the mechanistic basis of the superiority of the RNA vaccination approach remains unclear, both value the reported data and just require some clarification of the methods. Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. When you are ready to resubmit, please upload the following: [1] A letter containing a detailed list of your responses to all 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. Thank you again for your submission to our journal. 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, Christian Munz Associate Editor PLOS Pathogens Erik Flemington Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens *********************** Even so both reviewers felt that the mechanistic basis of the superiority of the RNA vaccination approach remains unclear, both value the reported data and just require some clarification of the methods. Reviewer Comments (if any, and for reference): 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: The authors report a study regarding the use of two HSV-2 specific vaccination strategies, either RNA or protein based, using the HSV-2 glycoproteins C, D and E, as antigens. In addition to HSV-2 specific immune responses, also effects on HSV-1 infections were analysed in vivo. This is a very interesting study and the authors provide evidence that a HSV-2 specific vaccination strategy protects from genital disease and furthermore, that also HSV-1 challenged animals are protected. In addition, they found the RNA vaccination approach to be even better, when compared with pure protein vaccination. Reviewer #2: In this clearly written paper Egan et al describe the efficacy of a trivalent Herpes simplex viral vaccine containing glycoproteins C, D and E from HSV-2, expressed either as recombinant baculovirus proteins or as RNA, on genital HSV1 infection of mice and in comparison to effects on HSV2 infection. This extends previously published studies demonstrating greater protection of the RNA vaccine than the protein vaccine against HSV2 genital infection in mice, using similar study protocols. The studies are well conducted and results clear cut, although they do not necessarily explain previously published human trial results with HSV1 and 2 using a gD2-MPL vaccine. Both RNA and protein vaccines protected mice from HSV1 disease and death and infection of the DRG, although the RNA vaccine was more potent against vaginal virus titres two days after infection (but not at day 4). Somewhat surprisingly the RNA vaccine was less potent against HSV1 than HSV2 challenge in this parameter. The paper is short and it seems there would more opportunity to study mechanisms than is provided. Specific Questions: In Figure 2D how were the foci counted. Were multiple sections taken at different parts of the vagina? Was manual or computer aided counting per section done? Was there any variability throughout the vagina? Was there any T cell or other immune cell infiltrate in the vaccine treated mice? In figure 3C: vaginal HSV1 titres at day 2 are on average >1 log higher than in Figure 1E despite using the same inoculum size. Is there a reason for this variability? Figure 4B: Are they surprised there is no inoculum dose effect on vaginal viral titres? Discussion: Are they surprised that the vaginal HSV1 replication out to day 4 in Figure 1E does not result in DRG infection? Do they have an explanation? Presumably this is all local vaginal replication without any axonal-DRG circuit? Some omissions: Given the results in Figures 3C and 4C why not use gD2 alone as an immunogen in an extra arm to see if it mimics the Herpevac results regarding protection against HSV1 versus HSV2? There is no evaluation of T cell responses, even follicular T helper cell responses, in blood or tissue. This might be expected, given the use of adjuvants. ********** 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: The authors found the RNA vaccination approach to be even better, when compared with pure protein vaccination. The reason for this are not completely clear. Could it be that the RNA backbone induces a stronger immune response via a TLR activation of antigen presenting cells? The authors should look at this in more detail. In addition and very interestingly the authors report, that this HSV-2 specific vaccination strategy also generates cross-reactive antibodies, neutralizing HSV-1. It would be interesting to analyse if these neutralizing antibodies protect HSV-1/2 infected animals also in a therapeutic setting, not only in a prophylactic vaccination strategy. Reviewer #2: Given the results in Figures 3C and 4C why not use gD2 alone as an immunogen in an extra arm to see if it mimics the Herpevac results regarding protection against HSV1 versus HSV2? ********** 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: Minor: lane 260 (Fig 4F should be Fig 4C) Reviewer #2: Minor: Does poly C induce interferon? ********** 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: Yes: Alexander Steinkasserer 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: 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. Friedman, We are pleased to inform you that your manuscript 'An HSV-2 nucleoside-modified mRNA genital herpes vaccine containing glycoproteins gC, gD, and gE protects mice against HSV-1 genital lesions and latent infection' 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, Christian Munz Associate Editor PLOS Pathogens Erik Flemington 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. Friedman, We are delighted to inform you that your manuscript, "An HSV-2 nucleoside-modified mRNA genital herpes vaccine containing glycoproteins gC, gD, and gE protects mice against HSV-1 genital lesions and latent infection," 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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