The Impact of Smoking on Long-Term Protection Following Hepatitis B Vaccination: A 24-Year Cohort Study
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
Dear Editor-in-Chief,
I have now read the manuscript entitled: “The impact of smoking on long-term protection following hepatitis B vaccination. A 24-year cohort study” by Fonzo M. et al. (manuscript Viruses-3090807. The aims of the study are of considerable interest since long-term HBV-vaccine induced immunity is valuable to monitor and identify. Also, it is valuable to understand how well protective antibody levels remain as health-biomarkers in smokers and non-smokers and possibly any gender differences would be of interest and value.
Comments and Questions.
Q1. Line 154. In Table 1, It should be clarified if each separate BMI group: Overweight and Obese were significantly different between smokers and non-smokers?
Q2. Line 171. In Table 2 it would be valuable if the actual geometric mean (GMT) or median +/- 95% C.I of the anti-HBsAg concentration was shown among smokers and non-smokers.
Q3. Preferably, in a Table 3 also show the GMT/Median anti-HBsAG values in males and female participants since the males were significantly more frequent participants among the smokers (perhaps female anti-HBsAG antibody-concentrations are just slightly below the threshold, while males have much more severly reduced antibody-concentrations ?) (such as in Ref.3. Gender impact as in McMahon BJ et al. Ann Int.Med 2005)
Q4. Was there only one, single timepoint of the last analysis (at 18-24 years follow-up) that was tested for anti-HBsAg concentration ?
There could be a temporary period of immunosuppression (due to short-term medical treatment, illness or possibly a technical accidental poor sample handling) that could explain a temporal period of below 10 IU/ml cut-off antibody concentration ?
Q5. Since the Engerix-B and Recombivax HB vaccines seem to have been used as one of the main rHBVsAg vaccines in the current study populations it would be interesting for the readers to see the median anti-HBsAg antibody concentrations in the later follow-up samples. Could this information be added for the different study groups ?
Author Response
Dear Editor-in-Chief,
I have now read the manuscript entitled: “The impact of smoking on long-term protection following hepatitis B vaccination. A 24-year cohort study” by Fonzo M. et al. (manuscript Viruses-3090807. The aims of the study are of considerable interest since long-term HBV-vaccine induced immunity is valuable to monitor and identify. Also, it is valuable to understand how well protective antibody levels remain as health-biomarkers in smokers and non-smokers and possibly any gender differences would be of interest and value.
- Line 154. In Table 1, It should be clarified if each separate BMI group: Overweight and Obese were significantly different between smokers and non-smokers?
- Yes, the distribution was found to be significantly different, in accordance with the test specified in the method section and the relative p-value as reported in the table in question.
- Line 171. In Table 2 it would be valuable if the actual geometric mean (GMT) or median +/- 95% C.I of the anti-HBsAg concentration was shown among smokers and non-smokers.
- As further specified in the subsequent comment, we believe that including this information in the manuscript would not be beneficial, given the number of variables involved as potential confounders and their distribution as highlighted in Table 1.
- Preferably, in a Table 3 also show the GMT/Median anti-HBsAG values in males and female participants since the males were significantly more frequent participants among the smokers (perhaps female anti-HBsAG antibody-concentrations are just slightly below the threshold, while males have much more severly reduced antibody-concentrations ?) (such as in Ref.3. Gender impact as in McMahon BJ et al. Ann Int.Med 2005)
- We recognise that this topic is of interest, however the effect of sex was not among the aims of the present study and we preferred to keep the focus on the association with tobacco smoking. For this purpose, the variable sex was used, but for adjustment only.
- Was there only one, single timepoint of the last analysis (at 18-24 years follow-up) that was tested for anti-HBsAg concentration ?
- Yes, the present study focused on a single endpoint as a means of measuring the outcome of interest.
- There could be a temporary period of immunosuppression (due to short-term medical treatment, illness or possibly a technical accidental poor sample handling) that could explain a temporal period of below 10 IU/ml cut-off antibody concentration ?
- According to the medical history collected during the health assessment, there were no periods of immunosuppressive therapy (even cortisone treatment) or immune-related pathologies.
- Since the Engerix-B and Recombivax HB vaccines seem to have been used as one of the main rHBVsAg vaccines in the current study populations it would be interesting for the readers to see the median anti-HBsAg antibody concentrations in the later follow-up samples. Could this information be added for the different study groups ?
- We would like to thank you for your comment. As previously stated, the limitations of our study preclude the availability of such information for our purposes.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe aim of this study was to assess the impact of smoking on long-term antibody persistence following primary hepatitis B vaccination.
Specific comment:
Keywords: replace “HbsAb” with “HBsAb”
Line 37: replace “smoking” with “tabacco smoking”
Line 43: In the review, no evidence is reported regarding “exercise” and hepatitis B vaccination
Line 95: replace “smoking” with “tabacco smoking”
Lines 96-97 and lines 179-180: authors should more emphasize studies reporting the effect of tobacco smoking on the long-term persistence of immunity after hepatitis B vaccination
Line 108: from the description, the study would appear to be a cross-sectional study (already defined as retrospective study in the Ref 23); no evidence is reported that the cohort was followed over time.
Line 111: please add “italian guidelines…”
Line 112: please add which PNPV you are referring to (2023-25?)
Line 114: the reference N 23, does not lead back to the PNPV
Since this is a young population, the authors investigated the type of smoking habit (tobacco smoking or e-cigarettes?).
Table 1: of the feature "Age" should be reported that it was measured in "years"; of the feature "Age at 1st dose" should be reported that it was measured in "months"
Table 1: it is not well understood why the feature of BMI is reported: this feature was not part of the objective of the study as well as its results were not analyzed and discussed. After all, the potential role of BMI on response to hepatitis B vaccination is well known but not its role on long-term immunity.
Line 160 e Abstract: shouldn't the proportion of smokers be 302/2133 = 14.2%?
Line 162: replace with 53.3%, as reported in Table 1
Line 167: as suggested from guidelines, did individuals with antibody concentration <10 IU/L receive a booster dose of vaccine? Was a different anamnestic response observed between smokers and nonsmokers?
Line 178, Discussion: some parts of the discussion appear not in line with the objectives of the study (see lines 198-211 and 212-221)
Line 180: please add “tabacco smoking”
Lines 186-187: the authors should better justify why this study confirms the negative influence of smoking on the short-term response to hepatitis B vaccine, since all individuals were enrolled in the study about 20 years after the first dose of vaccine.
Lines 286-287: considering the age of the subjects enrolled, the authors should assume that all were mandatorily vaccinated by law with recombinant, mostly monovalent vaccine.
Line 292-293: regarding the “….absence of information concerning the length of time the person smoked…), the authors could have considered that according to some data from the ISS, about 70% of the Italian population began smoking at mean age of 17.6 years; therefore, given the mean age of the population of this study, a smoking period of about 3 years could be assumed.
Line 304: Perhaps as an additional limitation, the authors should report that smoking use with electronic cigarettes has not been investigated.
Line 305-306: considered that the mean age at 1st dose is 2.94 months, it is very likely that the prevalence of obesity at that time was zero.
Line 312: authors should report which studies support the effect of comorbidity on the long-term-persistence of antibodies.
Line 321-324: authors should revise these conclusions.
References: authors should revise journal names given in some references (i.e. n. 4, 25, 34, 35, 37, 47).
Author Response
- Keywords: replace “HbsAb” with “HBsAb”
- Done
- Line 37: replace “smoking” with “tabacco smoking”
- Done
- Line 43: In the review, no evidence is reported regarding “exercise” and hepatitis B vaccination
- Thank you. The error in question was a typographical one. The variable "exercise" has been removed from the sentence.
- Line 95: replace “smoking” with “tabacco smoking”
- Done
- Lines 96-97 and lines 179-180: authors should more emphasize studies reporting the effect of tobacco smoking on the long-term persistence of immunity after hepatitis B vaccination
- I am grateful for your feedback. I have updated the description of the topic in question to include more comprehensive references.
- Line 108: from the description, the study would appear to be a cross-sectional study (already defined as retrospective study in the Ref 23); no evidence is reported that the cohort was followed over time.
- Consistently, the sentence was consistently modified, and the study was described as "retrospective”.
- Line 111: please add “italian guidelines…”
- Done
- Line 112: please add which PNPV you are referring to (2023-25?)
- The reference is not to the period between 2023 and 2025, but rather to the national plans that were in place at the time of the examinations. This detail has been integrated into the main text accordingly.
- Line 114: the reference N 23, does not lead back to the PNPV
- Please refer to the previous comment.
- Since this is a young population, the authors investigated the type of smoking habit (tobacco smoking or e-cigarettes?).
- Tobacco smoking. This concept was integrated into the manuscript in a consistent manner.
- Table 1: of the feature "Age" should be reported that it was measured in "years"; of the feature "Age at 1st dose" should be reported that it was measured in "months"
- The age at the first dose was converted to months.
- Table 1: it is not well understood why the feature of BMI is reported: this feature was not part of the objective of the study as well as its results were not analyzed and discussed. After all, the potential role of BMI on response to hepatitis B vaccination is well known but not its role on long-term immunity.
- The rationale behind this approach was that BMI, along with other variables presented in the table, were employed for the purpose of adjustment in the subsequent analysis.
- Line 160 e Abstract: shouldn't the proportion of smokers be 302/2133 = 14.2%?
- Yes, the error was a typographical one. The correct value is 14.2%. Both sentences have been edited accordingly.
- Line 162: replace with 53.3%, as reported in Table 1
- Replaced.
- Line 167: as suggested from guidelines, did individuals with antibody concentration <10 IU/L receive a booster dose of vaccine? Was a different anamnestic response observed between smokers and nonsmokers?
- Unfortunately, the requisite information was not available for the purposes of this study.
- Line 178, Discussion: some parts of the discussion appear not in line with the objectives of the study (see lines 198-211 and 212-221)
- The first paragraph is designed to examine the impact of smoking on vaccinations other than hepatitis B, thereby providing further insights and potential points of contact with the primary focus of the current paper. The second paragraph seeks to highlight similarities with mechanisms related to overweight/obesity, which may warrant consideration.
- Line 180: please add “tabacco smoking”
- Done
- Lines 186-187: the authors should better justify why this study confirms the negative influence of smoking on the short-term response to hepatitis B vaccine, since all individuals were enrolled in the study about 20 years after the first dose of vaccine.
- The concept of corroboration has been removed from the challenge, and the two notions were described in terms of their coexistence. The paragraph was therefore rewritten accordingly.
- Lines 286-287: considering the age of the subjects enrolled, the authors should assume that all were mandatorily vaccinated by law with recombinant, mostly monovalent vaccine.
- Edited accordingly.
- Line 292-293: regarding the “….absence of information concerning the length of time the person smoked…), the authors could have considered that according to some data from the ISS, about 70% of the Italian population began smoking at mean age of 17.6 years; therefore, given the mean age of the population of this study, a smoking period of about 3 years could be assumed.
- We would like to express our gratitude for the information provided. We found your assistance to be most generous, and we are grateful for it. However, we believe that this information is not directly relevant to the purpose of our discussion, as our study population may exhibit a number of differences compared with the general population of the same age.
- Line 304: Perhaps as an additional limitation, the authors should report that smoking use with electronic cigarettes has not been investigated. Line 305-306: considered that the mean age at 1st dose is 2.94 months, it is very likely that the prevalence of obesity at that time was zero.
- Thank you for you comment. Your commentary has afforded us the opportunity to reexamine the concept presented in these few lines and to prioritize what we consider to be of greater importance. The paragraph has been rephrased to enhance readability and clarity.
- Line 312: authors should report which studies support the effect of comorbidity on the long-term-persistence of antibodies.
- Past research was briefly described and consistently referenced.
- Line 321-324: authors should revise these conclusions.
- The conclusions were formulated anew in order to enhance clarity and to ensure consistency with the study results.
- References: authors should revise journal names given in some references (i.e. n. 4, 25, 34, 35, 37, 47).
- Done.
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsSpecific comments:
Table 1, Age at first dose (months): are you shure that the value in months is correct? The enrolled population, by law, should have been vaccinated in the first year of age.
Table 1: the SD values are not reported, as instead indicated.
Author Response
Specific comments:
Table 1, Age at first dose (months): are you shure that the value in months is correct? The enrolled population, by law, should have been vaccinated in the first year of age.
Table 1: the SD values are not reported, as instead indicated.
