Dr. Albert Hofman,

Editor in Chief

European Journal of Epidemiology

Subject: Manuscript EJEP1456 "Comparison of the dynamics and correlates of transmission of Herpes Simplex Virus -1 (HSV-1) and Varicella Zoster Virus (VZV) in a sample of the Israeli population"

Dear Dr. Hofman,

Enclosed is a revised version of the manuscript entitled: "Comparison of the dynamics and correlates of transmission of Herpes Simplex Virus -1 (HSV-1) and Varicella Zoster Virus (VZV) in a sample of the Israeli population" by Batya Davidovici et. al

We have revised the manuscript in accordance with the comments and suggestions raised by the reviewer:

Reviewer:

  1. Comment: Calculating the force of infection by age group is interesting especially for modellers and is of importance e.g. to measure the potential impact of vaccination. However it is unclear why the authors decided to compare the risk factors of these viruseswith each other as the route of transmission of HSV-1 and VZV are completely different: HSV-1 is transmitted by close contact among children and VZV is airborne. What is the reason to do this study? The meaning of epidemiological correlation between HSV-1and VZV is also unclear to me and the authors do not given any biologically plausible explanation.

Reply: In view of the reviewer's comment we have better clarified the reason and aims of the study which include the comparison of the age-specific forces of infection of VZV and HSV 1 and the evaluation of the relative importance of the various correlates of infection with the two viruses in view of the assumption that the transmission of VZV could be less dependent on environmental and socioeconomic factors than that of HSV-1 (see please page: 3 line 17 to page 4 line 6). We have also added references 12, 13 and 26 related to this point.

We are not aware of a biological mechanism, which could explain the independent association between infections with the two viruses. We wrote in "Discussion" that this association could indicate a mutual transmission route. Alternatively it can insinuate on another risk factor that was not measured directly, i.e. number of siblings (page 11 lines 17-19).

  1. Comment: For HSV-1 the authors used the ELISA of Focus but it is not clear what the cut-off points were (while this is given for VZV). Alsoi the algorithm for HSV-1 is strange: why retesting of equivocal sera with the same test? Usually equivocal sera should retested with another method to confirm.

2. Reply: The cut-off points for HSV-1 were added to the text of the revised manuscript as requested by the reviewer (page 5 lines 18-21) and reference 16 was added. We agree with the reviewer’s comment regarding the confirmatory assay. There was no commercially available confirmatory assay for HSV 1 when we performed the study. As stated in "Methods" section we retested the "equivocals" with the same assay. We have deleted the words "for confirmation" in the revised version of the manuscript (page 5 lines: 21-22).

We believe that the revised manuscript incorporates the comments and suggestions raised by the reviewer and hope that it is now suitable for publication. Thank you for considering our manuscript.

Sincerely,

Dani Cohen, PhD

Corresponding Author