Reviewer ’s repo rt 
 
Title: HPV Vaccine in the Treatment of Usual type Vul val and Vaginal Intraepithelial 
Neoplasia: A Systematic Review  
 
Version: 0 Date: 22 Sep 2018  
 
Reviewer: Bo Hansen  
 
Reviewer's report:  
 
The manuscript is a systematic review of the literat ure regarding HPV vaccine use for the 
treatment of VIN and VaIN. The review does not include meta -analyses of the data from the 
selected studies. Below, I give comments in chronological order.  
 
 
 
Introduction:  
 
The paper addresses VIN and VaIN, but the introd uction focuses almost exclusively on VIN. 
Consider giving some more attention to VaIN.  
 
 
P. 4, Line 8: The HPV -attributable fraction varies between studies, thus the numbers given here 
may not be as representative as they appear (see e.g. Serrano et al. Eur  J Cancer 2015 and 
Alemany et al. Eur J Cancer 2014 for some alternative numbers). Please rephrase slightly to 
reflect this variation (or be more specific if you want to limit it to some particular 
population/study).  
 
 
P. 4, Line 47: Why mention only one of  the commercially available vaccines?  
 
 
P. 4, Line 57: I believe an upper age limit of 26 for licensing of HPV vaccines does not generally 
apply? In my country, the vaccine can be given from age 9, with no upper age limit  
 
 
P. 5, Line 20: "We hypothesize ... " It is not clear to me why you need to hypothesize anything 
regarding the effect of the HPV vaccine for this literature review  
 
 
 
Methods:  
 
I suggest to include a Prisma statement as an appendix to the paper.  
 
Was the review registered in a database of pros pectively registered systematic reviews, like 
Prospero? Consider adding this information to the manuscript text.  
 
 
P. 6, Line 13: "Patient involvement" is perhaps a little misleading, since there are no patients 
involved in the review itself.  
 
 
Results:  
 
Table 1: Consider adding 1 column per outcome, to improve readability.  
 
 
Although acknowledged already, I think the great variation between studies in terms of 
participant age and type of intervention (vaccine type, schedules, delivery, adjuvants etc) can be 
emphasized even more in the results text.  
 
 
Discussion:  
 
I think the discussion needs to be rewritten to have a stronger focus on what can be deduced from 
this systematic review. Especially the first part (clinical responses to vaccine) lacks this focus.  
 
 
Moreover, I think the discussion should be more critical of the existing evidence, and its 
potential usefulness for therapy. The authors acknowledge that the evidence is weak (turn of p. 
10/11), but the focus on e.g. the ineffectiveness of traditional trea tment (p. 9 and 10) and 
prophylactic/safety effects of the vaccine (p. 11, lines 40 -50) detracts from the a ctual evidence 
produced by this review, and indeed the objective of this study.  
 
 
P. 9, Line 44 -55: Reporting numerical results from a different (and unpublished?) study seems 
out of place. And what does this add to your systematic review?  
 
 
P. 10, strengths and limitations: Please also include some discussion of the strengths and 
limitations of your own review  
 
 
P. 11, Line 5: "...study criteria had to b e widened ..." I cannot see that this is accounted for in the 
methods/results? If you widened your criteria, this should be mentioned  
 
P. 11, line 8: I think this point, about the vaccines investigated being experimental, deserves 
some more attention. E.g.  Why may the reasons for this? What does this mean in terms of the 
relevance of the evidence produced, and hence what does it mean for the clinician?  
 
Conclusions (in the main text and in the abstract):  
 
The objective here is to assess the literature on th is subject, and the conclusions should hence 
explicitly relate to this objective. The safety of the vaccines is not one of the outcomes assessed, 
and should not be part of the conclusion. I also think the conclusions put too much emphasis on 
the suggested effect on treatment. The main finding of the review is that there is little evidence 
regarding HPV vaccines in the treatment of VIN/VaIN, and that the evidence is of very low 
quality and on experimental vaccines.  
 
P.11, line 50: You conclude: "This review  suggests effects on lesion size and symptom relief" - 
however, this is not discussed previously? At some earlier point in the discussion, consider 
summing up the evidence regarding effect on each of the outcome measures you set out to 
address  
 
 
P.11, line 55: You say: "Many of these vaccines were experimental ...." As far as I understand, 
all were experimental.  
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the autho rs. 
 
Yes 
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the edito rs. 
 
Not relevant to this manuscript  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable   
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following quest ions:  
 
1. Have you in the past five years received reimbursements, f ees, funding, or salary from an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents  relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial com peting interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have  no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
  
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to the editor s, which will not be published.  
 
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