The efficacy and safety of monoclonal antibody treatments against COVID-19: A systematic review and meta-analysis of randomized clinical trials

TL;DR: In this article, the authors evaluated the efficacy and safety profile of monoclonal antibodies in COVID-19 patients and found that tocilizumab improved hospital discharge and reduced mortality as well as the need for mechanical ventilation.

Abstract: Objectives The use of monoclonal antibody for COVID-19 showed conflicting results in prior studies and its efficacy remains unclear. We aimed to comprehensively determine the efficacy and safety profile of monoclonal antibodies in COVID-19 patients. Methods Sixteen RCTs were analyzed using RevMan 5.4 to measure the pooled estimates of risk ratios (RRs) and standardized mean differences (SMDs) with 95% CIs. Results The pooled effect of monoclonal antibodies demonstrated mortality risk reduction (RR=0.89 (95%CI 0.82-0.96), I2=13%, fixed-effect). Individually, tocilizumab reduced mortality risk in severe to critical disease (RR=0.90 (95%CI 0.83-0.97), I2=12%, fixed-effect)) and lowered mechanical ventilation requirements (RR=0.76 (95%CI 0.62-0.94), I2=42%, random-effects). Moreover, it facilitated hospital discharge (RR=1.07 (95%CI 1.00-1.14), I2=60%, random-effects). Meanwhile, bamlanivimab-etesevimab and REGN-COV2 decrease viral load ((SMD=-0.33 (95%CI -0.59 to -0.08); (SMD=-3.39 (95%CI -3.82 to -2.97)). Interestingly, monoclonal antibodies did not improve hospital discharge at day 28-30 (RR=1.05 (95%CI 0.99–1.12), I2=71%, random-effects) and they displayed similar safety profile with placebo/standard therapy (RR=1.04 (95%CI 0.76-1.43), I2=54%, random-effects). Conclusion Tocilizumab improved hospital discharge and reduced mortality as well as the need for mechanical ventilation, while bamlanivimab-etesevimab and REGN-COV2 reduced viral load in mild to moderate outpatients. In general, monoclonal antibodies are safe and should be considered in severe to critical COVID-19 patients. Registration PROSPERO (CRD42021235112)

Summary

INTRODUCTION

• A previous study reported that the SARS-CoV-2 S2 protein was important for viral entry and thought to be a potential target for neutralizing antibody (Walls et al., 2020) .
• Moreover, at present, the application of monoclonal antibody as a therapeutic agent in COVID-19 shows conflicting results in prior studies, demanding further investigations.

Search Strategy

• The PubMed , ScienceDirect, Cochrane Library, Proquest and Springer databases were systematically searched from January 25 until February 5, 2021, without any limitation of publication year.
• The authors also performed manual searches, extended from February 5 to March 5, 2021, through MedRxiv and citation searching to get evidence from unpublished data and retrieve potential articles without missing any additional eligible studies.

Data Collection

• The title and abstract of the articles were screened by IAW and NRP.
• Duplications were removed using the Mendeley reference manager.

Data Extraction and Quality Assessment

• IAW, NRP, and DSB independently extracted relevant data using the standardized form.
• The following information was extracted: first author's name and publication year, study design, country, sample size, age, disease severity, dosage and administration of monoclonal antibodies, types of comparison, and outcomes (all-cause mortality, need for mechanical ventilation, hospital discharge at day 28-30, change of viral load, and serious adverse events).
• The studies were classified into "low risk of bias," "some concerns," or "high risk of bias" according to the Cochrane risk of bias tool for randomized trial (RoB ver.
• Any discrepancies were consulted with an expert and resolved by discussion until reaching consensus.
• The Grading of Recommendation Assessment, Development, and Evaluation system was used to evaluate the quality of evidence of the findings (Brignardello-Petersen et al., 2018; Puhan et al., 2014) .

Statistical Analysis

• Primary analyses were carried out using the Review Manager version 5.4 (The Cochrane Collaboration).
• Pooled risk ratios (RRs) for dichotomous outcomes were evaluated using Mantel-Haenszel method.
• If the value of I² statistics was <50% or the p-value was >0.1, the fixed-effects model could be applied; otherwise, the random-effects model would be used.
• Subgroup analyses were done on monoclonal antibody types and disease severity for mortality risk, and monoclonal antibody types for the other outcomes.
• Leave-one-out sensitivity analysis was conducted to find the source of statistical heterogeneity and demonstrate how each study affected the overall result.

Study characteristics

• The authors identified 6032 and 7310 studies through primary database and manual searching, respectively.
• After duplication removal, the authors screened potentially relevant studies and obtained 228 studies to be checked for eligibility.
• Some studies were excluded due to the reasons documented in PRISMA diagram .
• Among 16 RCTs, the REMAP-CAP trial (Gordon et al., 2021) was split into two separate intervention groups: the tocilizumab and sarilumab groups.
• The characteristics and outcomes summary for each study, RoB ver.2 assessment, and the certainty of evidence of findings reported using GRADE system are presented in Supplementary Tables.

MORTALITY All-cause mortality

• All-cause mortality was examined from 16 RCTs with a total of 8857 patients.
• Subsequently, subgroup analyses on the disease severity and monoclonal antibody types were conducted, however only tocilizumab and sarilumab therapies for severe-critical COVID-19 patients were pooled, due to limited studies available .

Tocilizumab in severe-critical COVID-19

• Meanwhile, TOCIBRAS trial mainly contributed to the statistical heterogeneity.
• At last, Funnel plot and Egger's test did not show any publication bias.

Sarilumab in severe-critical COVID-19

• Numerically, the RR was lower than that of tocilizumab, but it did not reach statistical significance.
• Egger's test cannot be performed because there were only two studies included in the analysis.

THE NEED FOR MECHANICAL VENTILATION

• Ten RCTs consisted of 6061 patients were examined .
• Only studies involving anti-IL-6R antibodies reported mechanical ventilation outcome.
• All participants were in severecritical disease, except for the participants from COVINTOC trial who were in moderatesevere state.
• The authors also found that EMPACTA trial was the source of heterogeneity in the tocilizumab subgroup.

HOSPITAL DISCHARGE AT DAY 28-30

• Eleven RCTs consisted of 7490 patients were examined .
• Patients in tocilizumab and sarilumab subgroups had severe-critical disease, while patients receiving spike-protein antibodies were in moderate-severe COVID-19.
• The p-value in 4 significant figures was 0.0498, therefore it reached statistical significance.
• The funnel plot and Egger's test did not indicate any publication bias.

SERIOUS ADVERSE EVENTS

• Interestingly, the CORIMUNO-TOCI 1 trial reported that tocilizumab was significantly safer than placebo/standard therapy.
• These two studies were the main sources of heterogeneity in their analysis, although removing those studies from the tocilizumab subgroup did not change the direction of effect and statistical significance (RR=1.00 (95%CI 0.80-1.24), I 2 =0%, fixed-effects).
• Publication bias was indicated in the anti-spike-protein subgroup.

DISCUSSION

• The authors analyses showed that monoclonal antibodies provided benefits on mortality rate reduction, mostly because of the weight of tocilizumab studies.
• Subgroup analysis demonstrated that tocilizumab had a significantly higher hospital discharge rate, but sarilumab and bamlanivimab did not.
• Meanwhile, bamlanivimab-etesevimab and REGN-COV2 reported significant viral load reduction, but each was evaluated only from one RCT, therefore the authors cannot evaluate the pooled effect.
• The authors analyses showed that monoclonal antibodies did not show significant harm or benefit as compared to placebo/standard care.
• Not all studies included in this meta-analysis specified the number of treatment-related severe adverse events.

ANTI-IL-6R

• The efficacy of tocilizumab was mostly reported in studies where the participants received corticosteroids, for example in RECOVERY and REMAP-CAP trials.
• This highlights the potential benefit of the combination of tocilizumab and corticosteroids in mortality risk reduction.
• It might have diminished the differences between the investigational drug and the control group.
• In general, healthcare providers need to consider patients with severe COVID-19 to attain the maximum benefit from the inhibition of IL-6.

ANTI-SPIKE-PROTEIN

• Gottlieb et al. (2021) reported that only bamlanivimab 2800mg showed a higher viral load reduction although it was statistically insignificant, while Chen et al. (2020) reported that bamlanivimab 2800mg significantly reduced viral load.
• Besides, the natural course of the disease also plays a role in viral load reduction.
• This may mask the clinical significance of neutralizing antibody administration.
• It is important to mention that missing data from Gottlieb et al. (2020) was replaced using an approach detailed in Supplementary Materials.

ANTI-C5a

• At present, there was only one study investigating anti-C5a with two outcomes included in this meta-analysis: the all-cause mortality and safety profile of the monoclonal antibody therapy.
• The mortality rate in anti-C5a antibody IFX-1 group vs. placebo was numerically lower, 13.3% vs 26.7%, respectively.
• This finding did not reach statistical significance, probably owing to the small number of participants.
• Additionally, compared to placebo/standard care, neither benefit nor harm was observed.

LIMITATION

• This meta-analysis has several limitations: (1) some studies were open-labelled; thus, the risk of bias regarding allocation concealment in those studies could not be ruled out; (2) We mainly discussed IL-6R inhibitors (e.g., tocilizumab) because most published RCTs are tocilizumab-associated studies and existing studies on other antibodies are scarce.the authors.the authors.
• (3) The small number of participants in some studies may increase the likelihood of type II statistical error.
• Larger scale RCTs are required to confirm the findings; (4) many other trials are ongoing; therefore, this study needs to be updated as soon as more trials become available.
• Nevertheless, this meta-analysis provides a solid evidence by incorporating only RCTs.
• To the best of their knowledge, this is the first meta-analysis that investigated the efficacy and safety of various monoclonal antibodies on clinical and laboratory outcomes, as well as their safety profile in patients with COVID-19.

CONCLUSION

• In conclusion, monoclonal antibody is beneficial in reducing mortality risk and the need for mechanical ventilation, but not hospital discharge in COVID-19 patients.
• In contrast to sarilumab, tocilizumab reduces mortality risk in severe to critical patients, reduces the need for mechanical ventilation, and increases hospital discharge at day 28-30.
• Bamlanivimab monotherapy does not reduce mortality, increase hospital discharge, nor reduce viral load; while bamlanivimab-etesevimab and REGN-COV2 significantly decrease viral load.
• IFX-1 shows no benefit in mortality risk reduction.
• No major safety concern was documented for all the monoclonal antibodies.

Figures

Figure 4 Subgroup analysis between types of monoclonal antibody and the number of COVID-19 patients discharged from hospital at day 28-30

Figure 3 Subgroup analysis between types of monoclonal antibody and the need for mechanical ventilation among COVID-19 patients

Figure 2 Subgroup analysis between types of monoclonal antibody and mortality among COVID-19 patients

Figure 1 PRISMA diagram of the literature search

Figure 5 Forest plot for the correlation between monoclonal antibody and viral load change from baseline

Figure 6 Subgroup analysis between types of monoclonal antibody and the number of serious adverse events in COVID-19

Full text

1
The efficacy and safety of monoclonal antibody treatments against COVID-19: A
1
systematic review and meta-analysis of randomized clinical trials
2
3
Ifan Ali Wafa
a
, Nando Reza Pratama
a
, David Setyo Budi
a
, Henry Sutanto
b,c
, Alfian Nur
4
Rosyid
d
, Citrawati Dyah Kencono Wungu
e,f,
*
5
6
7
8
a
Faculty of Medicine, Universitas Airlangga, Indonesia
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b
Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht
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University, The Netherlands
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c
Department of Physiology and Biophysics, State University of New York (SUNY)
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Downstate Health Sciences University, New York, USA
13
d
Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas
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Airlangga, Indonesia
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e
Department of Physiology and Medical Biochemistry, Faculty of Medicine, Universitas
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Airlangga, Indonesia
17
f
Institute of Tropical Disease, Universitas Airlangga, Indonesia
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19
20
21
22
23
Word Count: 3480 words (excluding abstract and references)
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25
26
27
28
Correspondence:
29
Citrawati Dyah Kencono Wungu, MD., PhD.
30
Department of Physiology and Medical Biochemistry, Airlangga University
31
Jalan Mayjen Prof. Dr. Moestopo No.47, Surabaya, Indonesia
32
Email:
citrawati.dyah@fk.unair.ac.id
33
34
. CC-BY-NC 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.04.21258343doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

2
Abstract
35
Objectives: The use of monoclonal antibody for COVID-19 showed conflicting results in
36
prior studies and its efficacy remains unclear. We aimed to comprehensively
37
determine the efficacy and safety profile of monoclonal antibodies in COVID-
38
19 patients.
39
Methods: Sixteen RCTs were analyzed using RevMan 5.4 to measure the pooled
40
estimates of risk ratios (RRs) and standardized mean differences (SMDs) with
41
95% CIs.
42
Results: The pooled effect of monoclonal antibodies demonstrated mortality risk
43
reduction (RR=0.89 (95%CI 0.82-0.96), I
2
=13%, fixed-effect). Individually,
44
tocilizumab reduced mortality risk in severe to critical disease (RR=0.90
45
(95%CI 0.83-0.97), I
2
=12%, fixed-effect)) and lowered mechanical ventilation
46
requirements (RR=0.76 (95%CI 0.62-0.94), I
2
=42%, random-effects).
47
Moreover, it facilitated hospital discharge (RR=1.07 (95%CI 1.00-1.14),
48
I
2
=60%, random-effects). Meanwhile, bamlanivimab-etesevimab and REGN-
49
COV2 decrease viral load ((SMD=-0.33 (95%CI -0.59 to
50
-0.08); (SMD=-3.39 (95%CI -3.82 to -2.97)). Interestingly, monoclonal
51
antibodies did not improve hospital discharge at day 28-30 (RR=1.05 (95%CI
52
0.99–1.12), I
2
=71%, random-effects) and they displayed similar safety profile
53
with placebo/standard therapy (RR=1.04 (95%CI 0.76-1.43), I
2
=54%, random-
54
effects).
55
Conclusion: Tocilizumab improved hospital discharge and reduced mortality as well as the
56
need for mechanical ventilation, while bamlanivimab-etesevimab and REGN-
57
COV2 reduced viral load in mild to moderate outpatients. In general,
58
monoclonal antibodies are safe and should be considered in severe to critical
59
COVID-19 patients.
60
Keywords: COVID-19; Monoclonal Antibody; Mortality; Viral load; Meta-analysis
61
Registration: PROSPERO (CRD42021235112)
62
. CC-BY-NC 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.04.21258343doi: medRxiv preprint

3
INTRODUCTION
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Since December 2019, a novel coronavirus disease (COVID-19) firstly discovered in
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Wuhan, China has spread globally and profoundly affected various aspects of life (Li et al.,
65
2020). The viral infectious disease is caused by SARS-CoV-2; an enveloped, positive-sense,
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single-stranded genomic ribonucleic acid (+ssRNA) virus from the group of Betacoronavirus
67
in the family of Coronaviridae (Hu et al., 2021). In the lungs, SARS-CoV-2 binds to
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angiotensin converting enzyme type-2 (ACE-2) receptors at the membrane of pulmonary
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alveolar cells type-2 and undergoes endocytosis. Subsequently, the interaction of viral
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antigen with RIG-I-like receptors (RLRs) activates the host immune system as an effort to
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eliminate the virus from the body (Hertanto et al., 2021), predisposing to the clinical
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presentations of COVID-19 patients, ranging from asymptomatic or mild up to severe disease
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state with pneumonia and acute respiratory distress syndrome that can ultimately lead to
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death (Lai et al., 2020).
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The development of optimal and effective therapies for COVID-19 is essential to
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minimize COVID-19 morbidity and mortality (Lu, 2020; Li and De Clercq, 2020). Several
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components of the virus and host immune system have been identified as potential targets in
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COVID-19 management. A previous study reported that the SARS-CoV-2 S2 protein was
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important for viral entry and thought to be a potential target for neutralizing antibody (Walls
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et al., 2020). Moreover, the SARS-CoV-2 infection could trigger a hyperactive immune
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response, leading to cytokine release syndrome (CRS) or cytokine storm (Hertanto et al.,
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2021). Among numerous proinflammatory cytokines involved in CRS, interleukin (IL)-6 is
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one of the most critical and has been associated with a poor prognosis (Zhang et al., 2020a;
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Zhang et al., 2020b; Zhao, 2020). Therefore, the inhibition of IL-6 (e.g., by preventing the
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binding to its receptors) could prevent the occurrence of CRS and lower the severity of the
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disease. Moreover, complement C5a and white blood cells (i.e., neutrophil and monocytes)
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were detected in the bronchoalveolar lavage fluid (BALF) of COVID-19 patients, supporting
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the chemoattraction role of C5a in lungs-derived C5aR1-expressing cells; which is
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responsible for cell damage and ARDS (Carvelli et al., 2020). Of note, C5a is one of the
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major drivers for complement-mediated inflammation that rapidly responds to pathogens and
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cellular injury (Woodruff and Shukla, 2020).
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Monoclonal antibody is one of the proposed therapeutic options for COVID-19. Anti-
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SARS-CoV-2 monoclonal antibodies are among the latest investigational COVID-19
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treatments granted with emergency use authorization (EUA) from the United States Food and
95
. CC-BY-NC 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.04.21258343doi: medRxiv preprint

4
Drug Administration (FDA). Briefly, monoclonal antibodies recognize one epitope of an
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antigen while polyclonal antibodies recognize multiple epitopes (Lipman et al., 2005). The
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variable region can be modified to target specific molecules, including the S2-protein,
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cytokines, and cytokine receptors. Among 5 Antibody isotypes—IgA (subclasses IgA1 and
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IgA2), IgE, IgD, IgM, and IgG (subclasses IgG1, IgG2, IgG3 and IgG4) —IgG is commonly
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selected for therapeutic purposes due to its strong binding affinity to an antigen and its Fc
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receptor, supported by its long serum half-life (Chames et al., 2009; Lu, 2020). As the
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consequence, the administration of neutralizing monoclonal antibody targeting SARS-CoV-2
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spike proteins allows the inhibition of virus attachment to human ACE-2 receptors, thus
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inhibits viral entry (Tian et al., 2020). To prevent complement system activation triggered
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during SARS-CoV-2 infection, a recent study proposed the use of monoclonal antibody
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against C5a (anti-C5a) (Woodruff and Shukla, 2020). Among available monoclonal
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antibodies for COVID-19, anti-IL-6 receptors and anti-SARS-CoV-2 are widely studied in
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clinical trials (Yang et al., 2020; Patel et al., 2021).
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Nonetheless, the efficacy and safety of this pharmacological agent remain
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controversial (FDA, 2020; Patel et al., 2021). Moreover, at present, the application of
111
monoclonal antibody as a therapeutic agent in COVID-19 shows conflicting results in prior
112
studies, demanding further investigations. Thus, this meta-analysis aims to assess the
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previously reported efficacy and safety of monoclonal antibodies on clinical and laboratory
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outcomes and its safety profile in COVID-19 patients.
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MATERIALS AND METHODS
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Search Strategy
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The PubMed (MEDLINE), ScienceDirect, Cochrane Library, Proquest and Springer
119
databases were systematically searched from January 25 until February 5, 2021, without any
120
limitation of publication year. We also performed manual searches, extended from February 5
121
to March 5, 2021, through MedRxiv and citation searching to get evidence from unpublished
122
data and retrieve potential articles without missing any additional eligible studies. The
123
following keywords were used: “(COVID-19) AND ((Monoclonal Antibody) OR
124
(Neutralizing Antibody) OR (Serotherapy)) AND ((Viral Load) OR (Oxygen) OR (Duration)
125
OR (Mortality) OR (Inflammation))”. Additional details about the search strategy are
126
available in Supplementary Materials.
127
. CC-BY-NC 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.04.21258343doi: medRxiv preprint

5
Data Collection
128
The title and abstract of the articles were screened by IAW and NRP. Duplications
129
were removed using the Mendeley reference manager. We independently screened the title
130
and abstract of all retrieved studies based on the following eligibility criteria: (1) participants
131
confirmed at any clinical stage of COVID-19 with/without other comorbidities; (2) adult (
≥
18
132
years) male/female study population; (3) the study involved monoclonal antibody treatments
133
of interest; (4) the study compared the intervention group with control (placebo or/and
134
standard of care or combination therapy); (5) the study evaluated efficacy (i.e. mortality, need
135
for mechanical ventilation, hospital discharge, virologic outcomes) or safety outcomes
136
(serious adverse events); (6) study type was randomized controlled trial (RCT).
137
Data Extraction and Quality Assessment
138
IAW, NRP, and DSB independently extracted relevant data using the standardized
139
form. The following information was extracted: first author’s name and publication year,
140
study design, country, sample size, age, disease severity, dosage and administration of
141
monoclonal antibodies, types of comparison, and outcomes (all-cause mortality, need for
142
mechanical ventilation, hospital discharge at day 28-30, change of viral load, and serious
143
adverse events). Serious adverse events were defined as any untoward medical occurrence
144
that are potentially related to monoclonal antibody treatment.
145
The studies were classified into “low risk of bias,” “some concerns,” or “high risk of
146
bias” according to the Cochrane risk of bias tool for randomized trial (RoB ver.2) (Sterne et
147
al., 2019). Any discrepancies were consulted with an expert and resolved by discussion until
148
reaching consensus. The Grading of Recommendation Assessment, Development, and
149
Evaluation (GRADE) system was used to evaluate the quality of evidence of the findings
150
(Brignardello-Petersen et al., 2018; Puhan et al., 2014).
151
Statistical Analysis
152
Primary analyses were carried out using the Review Manager version 5.4 (The
153
Cochrane Collaboration). Pooled risk ratios (RRs) for dichotomous outcomes were evaluated
154
using Mantel-Haenszel method. Standardized mean differences (SMDs) of continuous
155
outcomes were pooled using inverse variance. I
2
test was used to quantify heterogeneity
156
between studies, with values I
2
>50% represents moderate-to-high heterogeneity. If the value
157
of I² statistics was <50% or the p-value was >0.1, the fixed-effects model could be applied;
158
otherwise, the random-effects model would be used. Begg's funnel plot and Egger’s test were
159
. CC-BY-NC 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.04.21258343doi: medRxiv preprint

Frequently asked questions

Q1. What are the contributions in this paper?

Ifan Ali Wafa, Nando Reza Pratama, David Setyo Budi, Henry Sutanto, Alfian Nur 4 Rosyid, Citrawati Dyah Kencono Wungu * this paper