Efficacy of COVID-19 Booster Vaccines in Patients with Hematologic Malignancies: Experiences in a Real-World Scenario

Round 1

Reviewer 1 Report

Tha manuscript "Efficacy of COVID-19 booster vaccines in patients with hematologic malignancies: Experiences in a real-world scenario" reports an interesting study on the effectiveness of COVID-19 booster vaccination in patients with hematologic malignancies.

I think that in general it is a good manuscript, but would recommend some minor changes before acceptance.

1. I would suggest to highlight that most of the patients in the study had lymphoid malignancies vs myeloid - in the simple summary, abstract and discussion (not just at the end of the discussion). Also, mention the small sample size (n=...) and the variable 1st and 2nd doses of vaccine types in the patients, as these are not clear unless you read the whole article, but are important.

2. Also, consider to either remove the results of the patients with myeloid malignancies, or present and discuss those separately (including the abstract, results, and discussion etc), as the treatments and risk factors etc are very different.

3. And as mentioned in the limitations of the study at the end of the discussion, mention in the abstract too that the results may not apply to larger patient population.

4. Please also include in the abstract what antibody level (spike protein) and when it was measured for the study.

5. When referencing other works, and ie vaccination outcomes as regards of effectiveness, pls add what type of vaccines the references were about (ie in the introduction).

6. Pls double-check English/ language editing, ie. in the introduction: "“high risk of severe COVID-19…” seems to be missing "developing" before severe COVID-19...

7. Münster and Göttingen are messed up at most of the affiliations

8. Pls check Nr 1 reference formatting - as it seems that it is not aligned

Overall I suggest to accept the article after the suggested changes.

Author Response

Reviewer 1:

The manuscript "Efficacy of COVID-19 booster vaccines in patients with hematologic malignancies: Experiences in a real-world scenario" reports an interesting study on the effectiveness of COVID-19 booster vaccination in patients with hematologic malignancies.

I think that in general it is a good manuscript, but would recommend some minor changes before acceptance.

1. I would suggest to highlight that most of the patients in the study had lymphoid malignancies vs myeloid - in the simple summary, abstract and discussion (not just at the end of the discussion). Also, mention the small sample size (n=...) and the variable 1st and 2nd doses of vaccine types in the patients, as these are not clear unless you read the whole article, but are important.

Authors: We would like to thank the reviewer for this important point. Indeed, myeloid malignancies are underrepresented in our study. This might hamper the application of our results to a larger cohort of patients with hematologic malignancies, especially with a higher frequency of myeloid malignancies. Thus, we commented as the reviewer suggested on the predominancy of lymphoid malignancies in the Simple Summary (line 30). Further, we added in the Abstract that patients with myeloid neoplasms had higher seroconversion rates (n=7/9, 78%) compared to those with lymphoid malignancies, while similar incidence rates of COVID-19 breakthrough infections were observed ((2/9 (22%) vs. 27/191 (14%) patients, respectively) (lines 63-68). We also commented in the Discussion, that the patients with myeloid neoplasms were underrepresented in our study, mainly attributable to the seldom treatment of the latter in an outpatient setting in our center and again marked the diminished sufficiency of our data regarding generalization on a larger cohort (lines 477-480). At the end, we discussed in lines 485-492 the different seroconversion and antibody titer rates of patients with lymphoid and myeloid malignancies being observed also by other authors which may be attributable to the difference of the respective systemic treatment and risk factors (especially the lower frequency of sustained lymphodepletion).

As the reviewer mentioned, first and second dose of COVID-19 vaccines (basic immunization) were variable in our patient collective: prior to prime-boost vaccination, basic immunization was performed according to the local recommendations with mRNA- and/or vector-based vaccines. We addressed the distinct vaccination regimen in the Supplemental Table 1. Nevertheless, the distinct vaccination regimen (i.e. mRNA- and vector-based double vaccination or heterologous one) did not influence the odds for later seroconversion. We added this information in lines 549-551. To further underline the differences in vaccination schemes we included the information that previous basic immunization was applied according to the local recommendations with mRNA- and vector-based vaccines in the Abstract (lines 48-49).

 

2. Also, consider to either remove the results of the patients with myeloid malignancies, or present and discuss those separately (including the abstract, results, and discussion etc), as the treatments and risk factors etc are very different.

Authors: Again, we thank the reviewer for outlining this important aspect. We decided on adding several remarks on patients with myeloid malignancies as indicated above to savor this patient collective in a study. We are also aware that myeloid malignancies are underrepresented in our cohort and highlighted that in the text (lines 66-68; 477-480) In patients with myeloid malignancies seroconversion the rate was higher [78% (7/9) compared to 54% (103/191) in patients with lymphoid malignancies] (lines 308-309). Following that, we addressed this information in lines 309-313: “Among patients with myeloid neoplasms, the median titer level was 7,556 AU/ml (mean 11,633, SD 14,996 AU/ml) compared to 177 AU/ml (6,763, SD 12,106 AU/ml) in patients with lymphoid malignancies. Eight of nine patients (89%) with myeloid neoplasms underwent systemic treatment at the timepoint of vaccination.”

3. And as mentioned in the limitations of the study at the end of the discussion, mention in the abstract too that the results may not apply to larger patient population.

Authors: We share the reviewer`s opinion on a hampered generalization of our study data to a larger patient cohort. We commented on that in the Abstract (lines 66-68) as following “Following the low frequency of myeloid neoplasms in this study, the results may not be automatically applied to a larger cohort”.

4. Please also include in the abstract what antibody level (spike protein) and when it was measured for the study.

Authors: As suggested by the reviewer, we added this information in the Abstract (lines 52-53) and thank the reviewer for an important suggestion.

5. When referencing other works, and ie vaccination outcomes as regards of effectiveness, please add what type of vaccines the references were about (ie in the introduction).

Authors: Indeed, the references in regard to effectiveness of COVID-19 vaccines depend on different types of the latter. The chosen references include studies on both mRNA- and vector-based vaccines. Further information on the vaccine type was included in the draft as proposed by the reviewer (e.g. lines 87-88 or 484).

6. Please double-check English/ language editing, ie. in the introduction: "“high risk of severe COVID-19…” seems to be missing "developing" before severe COVID-19...

Authors: We thank the reviewer for his/her kind suggestion and double-checked the editing in the draft.

7. Münster and Göttingen are messed up at most of the affiliations

Authors: We corrected these affiliations and thank for the remark.

8. Please check Nr 1 reference formatting - as it seems that it is not aligned

Authors: We adjusted the references in our manuscript and hope that the formatting is now suitable for the publication.

Overall I suggest to accept the article after the suggested changes.

Authors: We very appreciate the positive feedback from the reviewer and would like to thank him/her for diligent work on our manuscript.

Author Response File: Author Response.pdf

Reviewer 2 Report

This is a well referenced paper which is extremely well written. The statistics section is robust in explanation and the tables and figures are excellent. 

particularly, this paper is of interest to those of us caring for these HM patients, and it is encouraging to see that although 45% did not seroconvert, none of the 29 patients who had breakthrough infections died. Additionally, it is of interest that the anti-CD20 B-cell depletion was a negative predictor for seroconversion rates independent of the time between last treatment and booster vaccine.

I recommend for publication with a few minor changes as follows:

Line 119: can you please add the predominant Omicron dates in Germany. So the reader can see the degree of overlap between  Omicron and the inclusion into the study. 

Line 148-158 / section 2.2. Can you please explain a little more how/why the cutoff of 100 AU/mL was used to indicated seroconversion.  Was this based on Abbott manufacturer cutoff? For example the Roche brand cutoff is 0.8 U/mL. If this is based on Abbott cutoff it should be stated.

 

Section 2.3 Definitions: Were there any exclusion criteria? if so list them.  The n=200 is a nice round number, but was this based on a power calculation or simply there were 200 patients boosted during the inclusion criteria?

Please lease include the definition/time cut offs you used for “active treatment”. I am assuming this was ongoing systemic cancer treatment at timepoint of prime-boost vaccination but were patients who had very recently completed their treatment within the last 30 days also considered as “active treatment”?

 

Author Response

This is a well referenced paper which is extremely well written. The statistics section is robust in explanation and the tables and figures are excellent. Particularly, this paper is of interest to those of us caring for these HM patients, and it is encouraging to see that although 45% did not seroconvert, none of the 29 patients who had breakthrough infections died. Additionally, it is of interest that the anti-CD20 B-cell depletion was a negative predictor for seroconversion rates independent of the time between last treatment and booster vaccine.

I recommend for publication with a few minor changes as follows:

1. Line 119: can you please add the predominant Omicron dates in Germany. So the reader can see the degree of overlap between Omicron and the inclusion into the study. 

Authors: The omicron variant was predominant in Germany since the second calendar week 2022 according to the government’s central scientific institution in the field of biomedicine “Robert-Koch-Institute”. We added this information in lines 124-126 and are thankful for this kind advice.

2. Line 148-158 / section 2.2. Can you please explain a little more how/why the cutoff of 100 AU/mL was used to indicated seroconversion.  Was this based on Abbott manufacturer cutoff? For example the Roche brand cutoff is 0.8 U/mL. If this is based on Abbott cutoff it should be stated.

Authors: According to the manufacturer`s guidance the detection limit of the SARS-CoV-2 IgG II Quant assay is 50 AU/ml. However, we decided to define seroconversion by the presence of anti-SARS-CoV-2 (anti-Spike) antibodies ≥ 100 AU/ml (≥14.2 BAU/ml) which corresponds to the double detection limit of the assay used (manufacturer`s definition). To clarify our strategy in this regard, we added this explanation in lines 175-178: “Seroconversion was defined by the presence of anti-SARS-CoV-2 (anti-Spike) antibodies ≥ 100 AU/ml (≥14.2 BAU/ml) which corresponds to the double detection limit of the SARS-CoV-2 IgG II Quant assay (manufacturer`s definition).”

3. Section 2.3 Definitions: Were there any exclusion criteria? if so list them.  The n=200 is a nice round number, but was this based on a power calculation or simply there were 200 patients boosted during the inclusion criteria?

Authors: We thank the reviewer for this important point. Besides the necessity of an application of two vaccines prior to prime-booster vaccination there were no exclusion criteria. To highlight this, we added this information in lines 137-138: “Besides the necessity of double vaccination prior to prime-booster vaccination, there were no other exclusion criteria in this study.”

The number of 200 patients resulted from all patients with hematologic malignancies who met the inclusion criteria and consented in a blood draw to assess the anti-spike antibody levels. We did not base the number of patients on a power calculation. 

4. Please include the definition/time cut offs you used for “active treatment”. I am assuming this was ongoing systemic cancer treatment at timepoint of prime-boost vaccination but were patients who had very recently completed their treatment within the last 30 days also considered as “active treatment”?

Authors: We totally agree with the reviewer on the importance of this information in the manuscript and would like to thank him/her for this remark. We defined ongoing or active treatment as a cancer treatment either accompanying or being completed up to 2 months prior to prime-boost vaccination. We addressed this point in lines 184-185  as following: “Active cancer treatment was defined as a treatment either accompanying or being completed up to 2 months prior to prime-boost vaccination.”

 

Authors: Once again, thank you very much to the reviewer for the suggested improvements.

Author Response File: Author Response.pdf

Reviewer 3 Report

In this manuscript authors describe a single centre experience of serology measurement regarding immune response to anti-SARS-CoV-2 vaccine in patients with baseline hematological malignancy. Data are clearly presented and the text is easy to follow. Although there are certain aspects that would need to be solved, I do not reckon these are major.

 

INTRODUCTION

- I would suggest to marge the sentences in a way that you provide 3 paragraphs: What do we know?, What do we not know?, What did we do?

- "To date, there are no comprehensive analyses", please, include "To the best of our knowledge".

 

METHODS

- "all patients needed to have received two vaccine doses with either a mRNA-based (i.e." Does this mean that there were patients excluded from analysis due to their vaccination scheme? If this is not the case, maybe it would be better to state that patients were vaccinated according to local rules, and provide details on such.

- Please, check whether your continuous variables are non-/parametric and use the statistics accordingly: non-parametric (median and interquartile ranges, and Mann-Whitney U or Kruskal-Wallis H for the comparisons), if normally distributed, as it is currently, but with mean and standard deviation.

- Please, use the terms "univariaBLE" and "multivariaBLE".

 

RESULTS

- When referring to biological characteristics, please use the term "sex" over "gender".

 

FIGURES

- I would suggest to use a colour coding colour-blinded friendly (red and green together -> no)

 

REFERENCES

1-4: I would suggest to rearrange the selected references as they are limited to either single institution or country experiences. There are already several initiatives and publications with multicentric and international analyses. I find this relevant as the protocols for the management of such patients might be quite different at local level and international publications support in a better way your arguments/comments.

Author Response

In this manuscript authors describe a single center experience of serology measurement regarding immune response to anti-SARS-CoV-2 vaccine in patients with baseline hematological malignancy. Data are clearly presented and the text is easy to follow. Although there are certain aspects that would need to be solved, I do not reckon these are major.

 

Authors: We kindly thank the author for his/her kind remarks and the positive feedback to our paper.

 

 

INTRODUCTION

- I would suggest to marge the sentences in a way that you provide 3 paragraphs: What do we know?, What do we not know?, What did we do?

Authors: We thank the reviewer for his/her remark to merge the sentences in the introduction. Following this advice, we reorganized the introduction into 3 paragraphs as proposed.

 

- "To date, there are no comprehensive analyses", please, include "To the best of our knowledge".

Authors: We included this wording as suggested in line 109.

METHODS

- "all patients needed to have received two vaccine doses with either a mRNA-based (i.e." Does this mean that there were patients excluded from analysis due to their vaccination scheme? If this is not the case, maybe it would be better to state that patients were vaccinated according to local rules, and provide details on such.

Authors: We are very thankful to the reviewer for her/his important improvement suggestion. To meet the inclusion criteria, the application of two vaccines doses prior to prime-boost vaccination was necessary. At the same time, no patient was excluded due to the distinct vaccination regime (e.g. vector-, mRNA- or heterologous based double vaccination) prior to booster. We added this information as kindly suggested by the reviewer in lines 131, 134-135 and 137-138: “The choice of the basic (double) vaccination had no influence on the inclusion of patients in this study. Besides the necessity of double vaccination prior to prime-booster vaccination, there were no other exclusion criteria in this study.”

- Please, check whether your continuous variables are non-/parametric and use the statistics accordingly: non-parametric (median and interquartile ranges, and Mann-Whitney U or Kruskal-Wallis H for the comparisons), if normally distributed, as it is currently, but with mean and standard deviation.

Authors: We would like to thank the reviewer for the suggestions regarding statistics in our study. We thoroughly reviewed the continuous variables in our study as proposed. As variables were parametric, we added the standard deviation and mean values in our results. The comparisons were performed according with t-tests or Chi-square tests according to the parametric character.

- Please, use the terms "univariaBLE" and "multivariaBLE".

Authors: We adapted the terms as suggested by the reviewer and would like to apologize for these mistakes.

 

RESULTS

- When referring to biological characteristics, please use the term "sex" over "gender".

Authors: We adapted the terms as kindly proposed by the reviewer. 

FIGURES

- I would suggest to use a colour coding colour-blinded friendly (red and green together -> no)

Authors: We highly appreciate this meaningful suggestion and applied an alternative color-coding (blue/orange instead of red/green) in Figures 2 and 3. With updated figures we hope to provide a more color-blinded friendly visualization.

 

REFERENCES

1-4: I would suggest to rearrange the selected references as they are limited to either single institution or country experiences. There are already several initiatives and publications with multicentric and international analyses. I find this relevant as the protocols for the management of such patients might be quite different at local level and international publications support in a better way your arguments/comments.

 

Authors: We are very thankful to the reviewer for this significant aspect mentioned. We totally agree that multicentric and international analyses have a much higher importance in this context. To acknowledge that, we included two multicentric and international analyses to the selected references [references 5 and 6].: The EPICOVIDEHA survey developed by Pagano et al. reported of COVID-19 mortality and risk factors for severe COVID-19 malignancies in 3,801 patients with hematologic malignancies in Europe and found a high risk for lethal COVID-19 courses in HM patients (40.7% in the first COVID-19 wave vs. 24.8% in the second COVID-19 wave) [reference 5].

The analysis of Vijenthira et al. provides a systematic review and meta-analysis of 39 studies with in total 3,377 patients (35 studies of adult patients, 4 studies including pediatric patients with hematologic malignancies) on outcomes of COVID-19 infections in patients with hematologic malignancies in Europe, Asia and North America. The primary outcome was a pooled mortality estimate which was 34% (and hence higher compared to COVID-19 mortality in non-hematologic malignancy patients) [reference 5].

We hope that the addition of these multicentric and international studies might support our arguments/comments and strategies applied more strongly.

Author Response File: Author Response.pdf