Humoral Immune Response after COVID-19 mRNA Vaccination in Patients with Liver Cirrhosis: A Prospective Real-Life Single Center Study

Round 1

Reviewer 1 Report

This study by Biliotti et al., provides key insights in to the generation of a serological response to the mRNA COVID-19 vaccination in liver cirrhosis patients. The study presents a clear narrative regarding the serological response and notes the limitations of the study, that require attention in future studies. As such I have only a minor comment that requires addressing.

1.       Please specify what the shaded area and red dotted line represent in the legend for figure 1 and figure 2.

Author Response

1. Please specify what the shaded area and red dotted line represent in the legend for figure 1 and figure 2.

We thank the referee for the comment.

We agree that the meaning of those elements was not clear in the original draft and have revised the manuscript accordingly. The red dotted line represents the cut-off of anti-S antibodies (7.1 BAU/mL) used to define the presence of a humoral response to mRNA COVID19 vaccine. The shaded area under the red dotted line highlights subjects who didn’t develop a humoral response to mRNA COVID19 vaccine. This is now explained in the captions of both figure 1 and 2. We also added a label “cut-off” next to the red dotted line to make the figure more immediately intelligible.

Reviewer 2 Report

The manuscript is describing patients with liver disease that were vaccinated with an mRNA-based vaccine against SARS-CoV-2. The control group was healthcare workers. The healthcare workers were vaccinated earlier and with a shorter period between the first and second doses of vaccine, which makes them not ideal control. Moreover, the control group got different vaccine (Pfizer vs Moderna). Although both vaccines are mRNA-based, it makes the "control" group closer to another experimental group. However, this limitation is discussed in the manuscript. 

The study describes a unique group of liver disease patients and a group of healthcare workers with very minimal follow-up and limited details. Besides this, the study is not novel. It has a rather descriptive and confirmatory nature. 

One major issue is that the "control" group is not a control. It should be reevaluated and potentially rephrased. The so-called "control" group differs in two key parameters (at least): 1) different vaccine was used; 2) different liver disease status (likely healthy health workers). Thus, this group may not be used as a control. It might be used as a reference group with many limitations.

It would be more beneficial to have a broad literature check and compare Moderna-vaccinated patients with Moderna-vaccinated healthy groups in the same country, or following very similar procedures. It would be more beneficial to compare Moderna-vaccinated liver patients to Moderna-vaccinated patients of other groups (although a healthy group would be preferred, or both healthy and patient groups vaccinated with Moderna could be used as reference groups to compare particular parameters, when possible).

Minor points.

1. Line 50, line 245, line 249, line 252, line 257, line 261, line 263, line 274, line 276, line 285, line 319, line 327, line 328,  etc. "m-RNA" should be "mRNA".

2. Line 316. Kindly check the reference " [? ]"

Author Response

1. The manuscript is describing patients with liver disease that were vaccinated with an mRNA-based vaccine against SARS-CoV-2. The control group was healthcare workers. The healthcare workers were vaccinated earlier and with a shorter period between the first and second doses of vaccine, which makes them not ideal control. Moreover, the control group got different vaccine (Pfizer vs Moderna). Although both vaccines are mRNA-based, it makes the "control" group closer to another experimental group. However, this limitation is discussed in the manuscript. 

The study describes a unique group of liver disease patients and a group of healthcare workers with very minimal follow-up and limited details. Besides this, the study is not novel. It has a rather descriptive and confirmatory nature. 

We thank the referee for the careful and insightful review of our manuscript. We believe that the novelty of the present study lies on the identification of male sex and previous HCV infection as predictive factors of a lower serological response to mRNA COVID19 vaccine in subjects with liver cirrhosis. Furthermore, data on the humoral response to mRNA COVID19 vaccine in cirrhotic subjects up to this point has been scarce and sometimes discordant. That being said, we agree with the reviewer’s comment that the short follow-up (fifteen days after two doses of mRNA COVID19 vaccine) renders the study less innovative from this point of view.

2. One major issue is that the "control" group is not a control. It should be reevaluated and potentially rephrased. The so-called "control" group differs in two key parameters (at least): 1) different vaccine was used; 2) different liver disease status (likely healthy health workers). Thus, this group may not be used as a control. It might be used as a reference group with many limitations. It would be more beneficial to have a broad literature check and compare Moderna-vaccinated patients with Moderna-vaccinated healthy groups in the same country, or following very similar procedures. It would be more beneficial to compare Moderna-vaccinated liver patients to Moderna-vaccinated patients of other groups (although a healthy group would be preferred, or both healthy and patient groups vaccinated with Moderna could be used as reference groups to compare particular parameters, when possible).

In our study we have discussed and acknowledged the limitations of our “control group”, including the fact that HCWs and patients had been administered different vaccines, specifically Moderna in the study group and Pfizer in the “control group”. In our hospital, HCWs were vaccinated immediately after COVID-19 vaccine availability (December 2020), at a time when Pfizer was the only approved vaccine. While it is true that HCWs have been vaccinated earlier, the vaccine doses were in both cases administered according to the manufacturers’ schedule and the timepoints of anti-S antibodies assessment, as well as the laboratory techniques used, were the same. In addition, regarding the comparison with the group of HCWs, we believe that the most interesting result of our study consists in the fact that subjects with cirrhosis did not develop a lower humoral response to mRNA COVID-19 vaccination after the second dose, in terms of seroconversion rate (100% in both cases), thus confirming that vaccination in this group of patients is effective.

We agree with the reviewer’s comment that the different type of vaccine administered make the term “control group” not suitable for our study, so we replaced the term with “reference group”. We also further discussed this limitation in the revised version of the manuscript (lines 331-333) and we added two more references showing that the Moderna vaccine induces higher anti-S titres compared to Pfizer, even in immunocompromised subjects (line 259, references 31, 32).

3. Minor points.

Line 50, line 245, line 249, line 252, line 257, line 261, line 263, line 274, line 276, line 285, line 319, line 327, line 328  etc. "m-RNA" should be "mRNA".

These changes have been made in the revised manuscript.

4. Line 316. Kindly check the reference " [? ]"

The correct reference has been added in the revised manuscript.

Round 2

Reviewer 2 Report

The authors had a chance to review the manuscript according to the Reviewers' and Editors' suggestions. The authors responded to the questions raised during the first round of review, and the presentation of the manuscript was improved.