Clinical Efficacy of the Neutralizing Antibody Therapy Sotrovimab in Patients with SARS-CoV-2 Omicron BA.1 and BA.2 Subvariant Infections

Round 1

Reviewer 1 Report

Manuscript viruses-2424786 by Miyashita et al. describes efficacy experiments of Sotrovimab activity in patients infected with Omicron variants. Authors evaluate the efficacy of sotrovimab in patients with COVID Omicron BA.1 and BA.2 subvariants compared to placebo group, and prove that the sotrovimab decreased the chances of BA.1 and BA.2 infected patients with requirement of oxygen therapy among high-risk patients with mild to moderate COVID-19 symptoms and high risk. This would suggest the efficacy of the sotrovimab treatment in high risk patients infected with Omicron.  

This is a well written paper and I only have minor comments:

Introduction: it is recommended that authors make a brief conclusion of the study by the end of the introduction to elaborate the significance of the study. 

Discussion, line 211-213: reference should be 17 by Zaqout not 16.

Discussion: there seems to be conflicting results among efficacy studies of sotrovimab used in patients infected with Omicron variants. A brief discussion of causes for such discrepancies would help audience better understand the difficulty of evaluating such monoclonal antibody treatment. Also, the conclusion of the study is based on the No. of patients who received oxygen therapy among different treatment groups compared to placebo group. However, those numbers of patients qualified for oxygen therapy is very small (e.g. 8 and 20 for treatment and control group). A discussion of the cons of this is recommended to help audience understand the limit of the study. Any other parameters (such as RR or OR) can be used to support the conclusion are  also encouraged to discuss.

Author Response

Thank you very much for your excellent comments and suggestions concerning our manuscript. In accordance with your advice, we have included additional information and re-written the manuscript.

 

1. Thank you very much for your important suggestion. Following your advice, we included a brief conclusion of the study in the Introduction section (page 6, line 18 to page 7, line 3).
2. We apologize for our mistake. Following your advice, we have rephrased the reference number “16” to “Zaquot A. et al.” in the Discussion section.
3. As noted in your comments, the limitation of our study is small sample size. A small sample size may have influenced the divergence results between Qatar’s study and our study. Following your advice, we have included the information about discrepancy and limitation evaluating the monoclonal antibody treatment (page 16, lines 9 to 13).

 

Author Response File: Author Response.docx

Reviewer 2 Report

This paper described a propensity score matched cohort study of Sotrovimab on mild to moderate COVID-19 patients infected with BA.1 and BA.2. The authors concluded that sotrovimab treatment may be associated with a reduced requirement of oxygen therapy.  The manuscript is orgnized logically, read smoothly and easy to follow. However, as the clinial study of Sotrovimab has been studied by several other groups, it is less innovative. Moreover, only oxygen therapy requirement was used as parameter, the other important indicators of disease progression and the viral nucleic acid conversion time or symptom disappearance time are not mentioned. The article can be further improved in the following aspects:

 

1. As neutralization ability is supposed to be the main function of mAbs therapy. The in vitro result of Sotrovimab, such as how many fold did the neutralization potency decreased against BA.1 and BA.2 should be clearlly described in the introduction or disccusion part.  

2. In addition to oxygen therapyn requirment and death, the other parameters, such as the recovery time should be also be discussed in the discussion part. Is there no difference? 

 

3. The limitation of this study should also be added in the discussion part. Since the ciculating strain has been changed to XBB, how about its effect on XBB?This antibody is supposed to bind R346, most of the recent variants contain this mutation. When the neutralization activiy is completely lost, is the Fc function or the ADCC function still effective?

 

Author Response

Thank you very much for your excellent comments and suggestions concerning our manuscript. In accordance with your advice, we have included additional information and re-written the manuscript.

 

1. We agree with your comments that neutralization ability is supposed to be the main function of monoclonal antibody therapy. Following your advice, we have included the information about in vitro results of sotrovimab against BA.1 and BA.2 subvariant in the Introduction and Discussion section (page 6, lines 1 to 3; page 16, lines 14 to 16). 　
2. Following your advice, we have included the information about recovery time in the Discussion section (page 16, lines 4 to 9).
3. Following your advice, we have included the limitation of our study in the Discussion section (page 18, lines 1 to 6). We also stated the information about neutralization activity and ADCC function of XBB subvariant (page 17, lines 5 to 11).

Reviewer 3 Report

This manuscript reports on the therapy efficacy of sotrovimab in patients with SARS-CoV-2 Omicron BA.1 and BA.2 subvariant infection. However, it is hard to find any sound discussion on the efficacy of monoclonal antibody in the manuscript. Is sotrovimab effective in BA.2 infection due to weak neutralization? Or ADCC? The mere description of the clinical results hardly indicates the scientific significance of the article. Many reports suggest that sotrovimab offers little protection in the BA.2 pandemic. In addition, the manuscript was not carefully written, and there was a lot of italics where it should not have been. Moreover, the English style in the manuscript should be improved with help of native skilled English speaker for vantage look.

Major comments:
1. Sotrovimab is no longer authorized to treat COVID-19 in any U.S. region due to increases in the proportion of COVID-19 cases caused by the Omicron BA.2 sub-variant in April 2022. The Centers for Disease Control and Prevention (CDC) Nowcast data from April 5, 2022, estimates that the proportion of COVID-19 cases caused by the Omicron BA.2 variant is above 50% in all Health and Human Services (HHS) U.S. regions. Data included in the health care provider fact sheet show the authorized dose of sotrovimab is unlikely to be effective against the BA.2 sub-variant. Due to these data, sotrovimab is not authorized in any U.S. state or territory at this time. Health care providers should use other approved or authorized products as they choose appropriate treatment options for patients.

Meanwhile, both in vitro and in vivo experiments have confirmed that sotrovimab can escape BA.2 and its branches to a certain extent. Therefore, the clinical effect analysis of sotrovimab is not significant.

 

2. The data in the manuscript were analyzed using a simple grouping description. The efficacy of sotrovimab was evaluated by oxygen therapy. There are many factors related to the course of the disease, and the present factors in the manuscript do not show that sotrvimab actually worked for patients. Virological tests such as viral load comparisons should be added.

 

3. In both treatment cohorts, a higher proportion of the population was vaccinated than the control group. It is hard to distinguish between the vaccine and Sotrovimab, which boosts immunity after infection.

The English style in the manuscript should be improved with help of native skilled English speaker for vantage look.

Author Response

Thank you very much for your excellent comments and suggestions concerning our manuscript. In accordance with your advice, we have included additional information and re-written the manuscript.

 

1. We agree with your comments. We stated the facts that sotrovimab is no longer authorized to treat COVID-19 in any U.S. region due to increases in the proportion of COVID-19 cases caused by the Omicron BA.2 subvariant. In addition, we also stated the facts that health care providers should use other approved or authorized products as they choose appropriate treatment options for patients (page 17, line 12 to page 14, line 2).
2. We agree with your comments. Unfortunately, we did not evaluate the viral load in this study. We stated facts in the limitation section (page 18, lines 1 to 2).
3. We agree with your comments. In both treatment cohorts, a higher proportion of the population was vaccinated than the control group. Thus, it may be hard to distinguish between the vaccine and sotrovimab, which boosts immunity after infection (page 18, lines 2 to 5).