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Beneficial and harmful effects of monoclonal antibodies for the treatment and prophylaxis of COVID-19: a systematic review and meta-analysis of randomized controlled trials

      Abstract

      Background

      : We systematically assessed beneficial and harmful effects of monoclonal antibodies for COVID-19 treatment, and prophylaxis in exposed to SARS-CoV-2.

      Methods

      : We searched five engines and three registries until November 3, 2021 for randomized controlled trials evaluating monoclonal antibodies vs. control in hospitalized or non-hospitalized adults with COVID-19, or as prophylaxis. Primary outcomes were all-cause mortality, COVID-19 related death, and serious adverse events; hospitalization for non-hospitalized; and development of symptomatic COVID-19 for prophylaxis. Inverse variance random effects models were used for meta-analyses. GRADE methodology was used to assess certainty of evidence.

      Results

      : Twenty-seven randomized controlled trials were included: 20 in hospitalized (n=8253), five in non-hospitalized (n=2922), and two in prophylaxis (n=2680). In hospitalized patients, monoclonal antibodies slightly reduced mechanical ventilation (relative risk [RR] 0.74, 95%CI 0.60-0.9, I2=20%, low certainty of evidence) and bacteremia (RR 0.77, 95%CI 0.64-0.92, I2=7%, low certainty of evidence); evidence was very uncertain about the effect on adverse events (RR 1.31, 95%CI 1.02-1.67, I2=77%, very low certainty of evidence). In non-hospitalized patients, monoclonal antibodies reduced hospitalizations (RR 0.30, 95%CI 0.17-0.53, I2=0%, high certainty of evidence) and may slightly reduce serious adverse events (RR 0.47, 95%CI 0.22-1.01, I2=33%, low certainty of evidence). In prophylaxis studies, monoclonal antibodies probably reduced viral load slightly (Mean difference [MD] -0.8 log10, 95%CI -1.21 to -0.39, moderate certainty of evidence). There were no effects on other outcomes.

      Conclusions

      : Monoclonal antibodies had limited effects on most of the outcomes in COVID-19 patients, and when used as prophylaxis. Additional data is needed to determine their efficacy and safety.

      Keywords

      Introduction

      By March 28, 2022, approximately 1 million and 6.2 million deaths had been reported due to COVID-19 in the United States and the world, respectively

      Worldometers. COVID-19 Statistics. Available at: https://www.worldometers.info/coronavirus/. Accessed 28 March 2022.

      . Several therapies have received emergency use authorization to prevent hospitalizations or death in COVID-19 patients or to prevent high risk people from becoming infected by SARS-CoV-2. Convalescent plasma, a therapy based on neutralizing SARS-CoV-2 virus with a previously infected person's antibodies, was given emergency authorization; however, it did not demonstrate significant clinical benefits in systematic reviews
      • Jorda A
      • Kussmann M
      • Kolenchery N
      • et al.
      Convalescent Plasma Treatment in Patients with Covid-19: A Systematic Review and Meta-Analysis.
      ,
      • Piscoya A
      • Ng-Sueng LF
      • Parra Del Riego A
      • et al.
      Efficacy and harms of convalescent plasma for treatment of hospitalized COVID-19 patients: a systematic review and meta-analysis.
      .
      Monoclonal antibodies against the SARS-CoV-2 virus have a theoretical advantage over convalescent plasma in that selective antibodies against the SARS-CoV-2 virus can be created and administered to patients

      Infectious Diseases Society of America. Anti-SARS-CoV-2 Monoclonal Antibodies. Available at: https://www.idsociety.org/covid-19-real-time-learning-network/therapeutics-and-interventions/monoclonal-antibodies/ Accessed 28 March 2022.

      . While the anti-SARS-CoV-2 monoclonal antibody products containing casirivimab + imdevimab, bamlanivimab + etesevimab, and sotrovimab have emergency authorizations for treating mild to moderate COVID-19 infections, current use is not recommended against the omicron subvariant of SARS-CoV-2

      Food and Drug Administration. Emergency Use Authorization of drugs and non-vaccine biological products. Available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs Accessed 28 March 2022.

      . However, the anti-SARS-CoV-2 monoclonal antibody bebtelovimab can be used to treat patients with mild to moderate COVID-19 disease and tixagevimab + cilgavimab can be used to prevent COVID-19 infection in high-risk patients, even in regions with high omicron subvariant prevalence

      Food and Drug Administration. Emergency Use Authorization of drugs and non-vaccine biological products. Available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs Accessed 28 March 2022.

      .
      There are also monoclonal antibodies used to impede the inflammatory response to COVID-19, such as interleukin, complement, surface glycoprotein, and granulocyte-monocyte colony stimulating factor inhibitors. Many of these anti-inflammatory monoclonal antibodies have studies assessing their efficacy or safety in COVID-19 patients but the only one with emergency authorization is tocilizumab

      Food and Drug Administration. Emergency Use Authorization of drugs and non-vaccine biological products. Available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs Accessed 28 March 2022.

      .
      Monoclonal antibodies have not been systematically evaluated for their efficacy and safety for the treatment of, or prophylaxis against, COVID-19. We conducted a systematic review with meta-analyses of randomized controlled trials assessing the efficacy and safety of monoclonal antibodies for the treatment or prevention of COVID-19.

      Materials and Methods

      Searches

      We conducted a comprehensive literature search in PubMed, Web of Science, Scopus, Embase and Cochrane Library on November 3, 2021. Also, we searched for ongoing randomized controlled trials at www.clinicaltrials.gov, www.who.int/clinical-trials-registry-platform, and www.clinicaltrialsregister.eu/ctr-search/search. There was no time or language limitation. The PubMed strategy is available in the Supplement.

      Study selection

      Three reviewers (AP, VP, AVH) searched engines and websites and collected records in myendnoteweb.com. Three independent reviewers (AP, COC-T, AAE) assessed titles and abstracts for eligibility; discrepancies were resolved by discussion. We included randomized controlled trials evaluating one or more monoclonal antibody vs. control, conducted in adults who were either hospitalized or non-hospitalized with PCR-confirmed COVID-19 (active treatment) or in adults at high-risk of developing COVID-19 due to close contact to people with PCR-confirmed COVID-19 (prophylaxis). Monoclonal antibodies of interest included anti-inflammatory (tocilizumab, sarilumab, meplazumab, canakinumab, mavrilimumab, itolizumab) and anti-spike protein of SARS-CoV-2 (bamlanivimab, bamlanivimab plus etesevimab, sotrovimab, and casirivimab plus imdevimab). Controls of interest were placebo, standard of care or an active treatment. Studies were excluded if conducted in individuals <18 years-old, did not report of at least one outcome, or include individuals with hepatitis B or HIV infection.

      Outcomes

      Primary outcomes were all-cause mortality, COVID-19 related death, and serious adverse events for all populations; hospitalization for non-hospitalized individuals, and development of symptomatic COVID-19 for prophylaxis studies. Secondary outcomes included hospital stay, invasive mechanical ventilation, viral load, adverse events, and bacteremia. We used definitions provided by authors.

      Data extraction

      Data extraction was completed by two independent reviewers (SY, PK) in a pre-defined Excel format. Disagreements were resolved with a third reviewer (AVH). Extracted data included: 1) first author and year of publication, 2) number of participants, 3) countries involved, 4) population (hospitalized, non-hospitalized, prophylaxis) 5) monoclonal antibody type, dose and duration, 6) control type, dose and duration, 7) follow-up time, 8) median age, 9) male proportion, 10) comorbidities prevalence (i.e. diabetes, hypertension, obesity, coronary artery disease, chronic obstructive pulmonary disease, asthma, chronic kidney disease), 11) concomitant treatments for both monoclonal antibody and control arms, 12) primary outcomes per arm, and 13) secondary outcomes per arm.

      Risk of bias assessment

      Two reviewers (SJ, PK) independently evaluated risk of bias (RoB) of randomized controlled trials using the Cochrane risk of bias tool RoB2.0
      • Sterne JAC
      • Savović J
      • Page MJ
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      . A third reviewer (AVH) resolved discrepancies. The RoB2.0 tool assesses five domains of bias: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. Judgements of bias per domain can be 'low' or 'high', or can express 'some concerns’. The presence of high RoB in at least one domain means the study is at high RoB; the presence of some concerns in at least one domain without a single domain at high RoB means the study has some concerns of bias.

      Statistical analyses

      This systematic review was reported according to 2020 PRISMA guidelines
      • Page MJ
      • Moher D
      • Bossuyt PM
      • et al.
      PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews.
      . We primarily stratified our analyses by type of population: hospitalized and non-hospitalized COVID-19 patients, and high risk of COVID-19 infection (prophylaxis). We performed random effects meta-analyses using the inverse variance method, the Paule-Mandel method to calculate the between study variance tau
      • Jorda A
      • Kussmann M
      • Kolenchery N
      • et al.
      Convalescent Plasma Treatment in Patients with Covid-19: A Systematic Review and Meta-Analysis.
      , and the Hartnung-Knapp method to adjust 95% confidence intervals (CIs)
      • Veroniki AA
      • Jackson D
      • Viechtbauer W
      • et al.
      Methods to estimate the between-study variance and its uncertainty in meta-analysis.
      ,
      • Knapp G
      • Hartung J.
      Improved tests for a random effects meta-regression with a single covariate.
      . Effects were reported as relative risks (RR) with their 95%CIs for dichotomous outcomes and mean differences (MD) with their 95%CIs for continuous outcomes. Heterogeneity of effects was quantified with the I2 statistic, with an I2>60 defined high heterogeneity
      • Higgins JP
      • Thompson SG.
      Quantifying heterogeneity in a meta-analysis.
      . Three sets of subgroup analyses were pre-specified: by type of drug (tocilizumab vs. other) in hospitalized patients; by type of control (placebo, standard of care, active) in hospitalized patients; and by type of control in hospitalized patients of tocilizumab studies. A p for interaction <0.1 was considered statistically significant for a given subgroup. We only evaluated small study effects with the Egger's test when there were ten or more studies. All analyses were performed in R 4.1.2 (www.r-project.org).
      The certainty of evidence was evaluated using the GRADE methodology (www.gradeworkinggroup.org). The certainty of evidence per outcome was based on the evaluation of five aspects: RoB, inconsistency, imprecision, indirectness and publication bias. Description of certainty of evidence was presented in summary of findings tables using GRADEpro software (McMaster University and Evidence Prime, 2021; www.gradepro.org/).

      Results

      Selection of studies

      We identified 1446 citations from databases and 20 from registries (Figure 1). After removing duplicates, and title, abstract and full text reviews, 27 randomized controlled trials met our inclusion criteria. Twenty studies were conducted in hospitalized COVID-19
      • Bian H
      • Zheng ZH
      • Wei D
      • et al.
      Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase 2 trial.
      • Caricchio R
      • Abbate A
      • Gordeev I
      • et al.
      Effect of Canakinumab vs Placebo on Survival Without Invasive Mechanical Ventilation in Patients Hospitalized With Severe COVID-19: A Randomized Clinical Trial.
      • Cremer PC
      • Abbate A
      • Hudock K
      • et al.
      Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial.
      • Gordon AC
      • Mouncey PR
      • et al.
      REMAP-CAP Investigators
      Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.
      • Hamed DM
      • Belhoul KM
      • Al Maazmi NA
      • et al.
      Intravenous methylprednisolone with or without tocilizumab in patients with severe COVID-19 pneumonia requiring oxygen support: A prospective comparison.
      • Hermine O
      • Mariette X
      • Tharaux PL
      • et al.
      Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial [published correction appears in JAMA Intern Med. 2021 Jan 1;181(1):144] [published correction appears in JAMA Intern Med. 2021 Jul 1;181(7):1021].
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      • Kumar S
      • Souza RD
      • Nadkar M
      • et al.
      A two-arm, randomized, controlled, multi-centric, open-label phase-2 study to evaluate the efficacy and safety of Itolizumab in moderate to severe ARDS patients due to COVID-19.
      • Lescure FX
      • Honda H
      • Fowler RA
      • et al.
      Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial.
      • Lundgren JD
      • Grund B
      • et al.
      ACTIV-3/TICO LY-CoV555 Study Group
      A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.
      • Rashad A
      • Mousa S
      • Nafady-Hego H
      • Nafady A
      • Elgendy H.
      Short term survival of critically ill COVID-19 Egyptian patients on assisted ventilation treated by either Dexamethasone or.
      • Rosas IO
      • Bräu N
      • Waters M
      • et al.
      Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia.
      • Salama C
      • Han J
      • Yau L
      • et al.
      Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia.
      • Salvarani C
      • Dolci G
      • Massari M
      • et al.
      Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.
      • Soin AS
      • Kumar K
      • Choudhary NS
      • et al.
      Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial.
      • Stone JH
      • Frigault MJ
      • Serling-Boyd NJ
      • et al.
      Efficacy of Tocilizumab in Patients Hospitalized with Covid-19.
      • Veiga VC
      • Prats JAGG
      • Farias DLC
      • et al.
      Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial.
      • Vlaar APJ
      • de Bruin S
      • Busch M
      • et al.
      Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial.
      • Wang D
      • Fu B
      • Peng Z
      • et al.
      Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial.
      • Zhao H
      • Zhu Q
      • Zhang C
      • et al.
      Tocilizumab combined with favipiravir in the treatment of COVID-19: A multicenter trial in a small sample size.
      , five studies in non-hospitalized COVID-19
      • Chen P
      • Nirula A
      • Heller B
      • et al.
      SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19.
      • Dougan M
      • Nirula A
      • Azizad M
      • et al.
      Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19.
      • Gottlieb RL
      • Nirula A
      • Chen P
      • et al.
      Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial.
      • Gupta A
      • Gonzalez-Rojas Y
      • Juarez E
      • et al.
      Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab.
      • Weinreich DM
      • Sivapalasingam S
      • Norton T
      • et al.
      REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19.
      , and two studies in individuals at high-risk to developing COVID-19
      • Cohen MS
      • Nirula A
      • Mulligan MJ
      • et al.
      Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial.
      ,
      • O'Brien MP
      • Forleo-Neto E
      • Musser BJ
      • et al.
      Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19.
      . Two trials evaluated two different monoclonal antibodies: Gordon et al.
      • Gordon AC
      • Mouncey PR
      • et al.
      REMAP-CAP Investigators
      Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.
      evaluated tocilizumab and sarilumab, and Gottlieb et al.
      • Gottlieb RL
      • Nirula A
      • Chen P
      • et al.
      Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial.
      evaluated bamlanivimab and bamlanivimab plus etesevimab.

      Characteristics of included randomized controlled trials

      Table 1 displays features of the 20 trials in hospitalized COVID-19 patients
      • Bian H
      • Zheng ZH
      • Wei D
      • et al.
      Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase 2 trial.
      • Caricchio R
      • Abbate A
      • Gordeev I
      • et al.
      Effect of Canakinumab vs Placebo on Survival Without Invasive Mechanical Ventilation in Patients Hospitalized With Severe COVID-19: A Randomized Clinical Trial.
      • Cremer PC
      • Abbate A
      • Hudock K
      • et al.
      Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial.
      • Gordon AC
      • Mouncey PR
      • et al.
      REMAP-CAP Investigators
      Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.
      • Hamed DM
      • Belhoul KM
      • Al Maazmi NA
      • et al.
      Intravenous methylprednisolone with or without tocilizumab in patients with severe COVID-19 pneumonia requiring oxygen support: A prospective comparison.
      • Hermine O
      • Mariette X
      • Tharaux PL
      • et al.
      Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial [published correction appears in JAMA Intern Med. 2021 Jan 1;181(1):144] [published correction appears in JAMA Intern Med. 2021 Jul 1;181(7):1021].
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      • Kumar S
      • Souza RD
      • Nadkar M
      • et al.
      A two-arm, randomized, controlled, multi-centric, open-label phase-2 study to evaluate the efficacy and safety of Itolizumab in moderate to severe ARDS patients due to COVID-19.
      • Lescure FX
      • Honda H
      • Fowler RA
      • et al.
      Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial.
      • Lundgren JD
      • Grund B
      • et al.
      ACTIV-3/TICO LY-CoV555 Study Group
      A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.
      • Rashad A
      • Mousa S
      • Nafady-Hego H
      • Nafady A
      • Elgendy H.
      Short term survival of critically ill COVID-19 Egyptian patients on assisted ventilation treated by either Dexamethasone or.
      • Rosas IO
      • Bräu N
      • Waters M
      • et al.
      Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia.
      • Salama C
      • Han J
      • Yau L
      • et al.
      Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia.
      • Salvarani C
      • Dolci G
      • Massari M
      • et al.
      Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.
      • Soin AS
      • Kumar K
      • Choudhary NS
      • et al.
      Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial.
      • Stone JH
      • Frigault MJ
      • Serling-Boyd NJ
      • et al.
      Efficacy of Tocilizumab in Patients Hospitalized with Covid-19.
      • Veiga VC
      • Prats JAGG
      • Farias DLC
      • et al.
      Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial.
      • Vlaar APJ
      • de Bruin S
      • Busch M
      • et al.
      Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial.
      • Wang D
      • Fu B
      • Peng Z
      • et al.
      Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial.
      • Zhao H
      • Zhu Q
      • Zhang C
      • et al.
      Tocilizumab combined with favipiravir in the treatment of COVID-19: A multicenter trial in a small sample size.
      . Nine, eight, and three of the studies had monoclonal antibodies compared to standard of care, placebo, and active control, respectively. Nineteen of the 20 studies assessed anti-inflammatory monoclonal antibodies (13 tocilizumab, two sarilumab, and one each meplazumab, canakinumab, mavrilimumab, itolizumab, vilobelimab) while one assessed an anti-SARS-CoV-2 virus monoclonal antibody (bamlanivimab). Nineteen trials were two group comparisons (monoclonal antibody vs. control) while one trial
      • Gordon AC
      • Mouncey PR
      • et al.
      REMAP-CAP Investigators
      Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.
      had three arms (tocilizumab or sarilumab vs. standard of care). The follow-up ranged from 14 to 90 days with four trials at 14 days, one at 21 days, 13 at 28-30 days, and two at >30 days.
      Table 1Characteristics of 27 included randomized controlled trials
      Author, yearreference, acronymCountry(ies)Population, % VaccinationSample sizeMonoclonal antibody, duration and total doseControlMean age (SD)Male (%)Hypertension (%)Diabetes (%)Heart Disease (%)Reported outcomesFollow up days
      Bian, 202111ChinaHospitalized, vaccination NA28Meplazumab, 5 days, 30 mgStandard of care56.5 (15.1)57.132.110.710.7Time to viral clearance, Elevated aspartate aminotransferase or alanine transaminase28
      Caricchio, 202112USA, EuropeHospitalized, vaccination NA454Canakinumab, 1 day, 660 mgPlacebo58.5 (14.1)58.855.736.120.3All-cause mortality, serious adverse events, adverse events, COVID-19 related death, bacteremia28
      Cremer, 202113USAHospitalized, vaccination NA40Mavrilimumab, 1 day, 420 mgPlacebo56.2 (15.7)65.055.042.5NAAll-cause mortality, serious adverse events, mechanical ventilation, length of stay28
      Gordon, 202114 REMAP-CAPAustralia, New Zealand, UK, Belgium, Thailand, Sri Lanka, USA, Canada, Northern Ireland, NetherlandsHospitalized, vaccination NA895Tocilizumab, 1 to 2 days, 560 to 1120mg Sarilumab, 1 day, 400 mgStandard of care61.3 (12.7)72.1NA36.410.8All-cause mortality,serious adverse events, mechanical ventilation, bacteremia21
      Hamed, 202115United Arab EmiratesHospitalized, vaccination NA49Tocilizumab, 1 day, 400 mgActive48.5 (11.3)81.622.442.9NAAll-cause mortality, COVID-19 related death, mechanical ventilation, length of stay45
      Hermine, 202116FranceHospitalized, vaccination NA131Tocilizumab, 1 to 3 days, 560 to 960 mgStandard of care64.4 (12.0)67.7NA33.631.3All-cause mortality,serious adverse events, adverse events, mechanical ventilation, bacteremia28
      Horby, 202117

      RECOVERY
      UKHospitalized, vaccination NA4116Tocilizumab; 1 to 2 days; 600 to 1200 mgStandard of care63.6 (13.7)67.3NA28.422.6All-cause mortality, serious adverse events, adverse events, mechanical ventilation, bacteremia28
      Kumar, 202118IndiaHospitalized, vaccination NA30Itolizumab, 7 to 30 days, 280 mgStandard of care49.1 (13.0)86.7NANANAAll-cause mortality, serious adverse events, adverse events, mechanical ventilation, bacteremia30
      Lescure, 202119Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and SpainHospitalized, vaccination NA416Sarilumab, 1 day, 400 mgPlacebo58.6 (12.9)62.742.526.49.9All-cause mortality, serious adverse events, adverse events, bacteremia29
      Lundgren, 202120 ACTIV-3/TICO LY-CoV555USA, Denmark SingaporeHospitalized, vaccination NA314Bamlanivimab, 1 day, 7000 mgPlacebo60.7 (16.7)58.049.028.74.1All-cause mortality, adverse events, bacteremia90
      Rashad, 202121EgyptHospitalized, vaccination NA149Tocilizumab, 1 to 2 days, 560 to 1120 mgActive61.8 (12.8)56.947.728.412.8All-cause mortality, mechanical ventilation14
      Rosas, 202122USA, UK, SpainHospitalized, vaccination NA438Tocilizumab, 1 day, 560 mgPlacebo60.8 (14.3)69.962.138.128.1All-cause mortality, serious adverse events, adverse events, mechanical ventilation, bacteremia, length of stay28
      Salama, 202123USA, Mexico, Kenya, South Africa, Peru, BrazilHospitalized, vaccination NA389Tocilizumab, 1 day, 560 mgPlacebo55.9 (14.5)59.2NANANAAll-cause mortality, serious adverse events, adverse events, mechanical ventilation, bacteremia, length of stay.28
      Salvarani, 202124ItalyHospitalized, vaccination NA126Tocilizumab, 1 day, 800 mgStandard of care61.6 (12.0)61.144.415.1NAAll-cause mortality, serious adverse events, adverse events, mechanical ventilation, bacteremia14
      Soin, 202125IndiaHospitalized, vaccination NA180Tocilizumab, 1 to 7 days, 480 to 960 mgStandard of care54.5 (13.4)84.984.984.915.1All-cause mortality, serious adverse events, adverse events, mechanical ventilation, bacteremia28
      Stone, 202026USAHospitalized, vaccination NA243Tocilizumab, 1 day, 560 mgPlacebo58.7 (17.3)58.348.831.018.6All-cause mortality, serious adverse events, mechanical ventilation, bacteriemia28
      Veiga, 202127BrazilHospitalized, vaccination NA129Tocilizumab, 1 day, 560 mgStandard of care57.4 (14.6)68.249.632.610.9All-cause mortality, serious adverse events, adverse events, mechanical ventilation, bacteremia, length of stay28
      Vlaar, 202028NetherlandsHospitalized, vaccination NA30Vilobelimab, 15 to 22 days, 800 mgPlacebo60.5 (8.7)73.330.026.7NAAll-cause mortality, serious adverse events, COVID-19 related death, bacteremia,28
      Wang, 202129ChinaHospitalized, vaccination NA65Tocilizumab, 1 to 2 days, 500 mgStandard of care63.2 (10.3)50.830.815.4NASerious adverse events, adverse events, length of stay14
      Zhao H, 202130ChinaHospitalized, vaccination NA31Tocilizumab, 7 days, 400 mgActive67.0 (33.3)52.442.99.514.3Serious adverse events, adverse events, mechanical ventilation14
      Chen, 202131USANon-hospitalized, vaccination NA452Bamlanivimab, 1 day, 3486 mgPlacebo48 (48.3)44.9NANANAViral load29
      Dougan, 202132USANon-hospitalized, vaccination NA1035Bamlanivimab + etesevimab, 1 day, 5600 mgPlacebo53.8 (16.8)48%NANANAAll-cause mortality, serious adverse events, adverse events, COVID-19 related death, bacteremia, viral load, length of stay, COVID-19 related hospitalization29
      Gottlieb, 202133USANon-hospitalized, vaccination NA577Bamlanivimab, 1 day, 3486 mg; Bamlanivimab + etesevimab, 1 day, 5600 mgPlacebo44.5 (18.5)45.4NANANAAll-cause mortality, serious adverse events, adverse events, COVID-19 related death, mechanical ventilation, viral load, COVID-19 related hospitalization or emergency department visit*.29
      Gupta, 202134USA, Canada, Brazil, SpainNon-hospitalized, vaccination NA275Sotrovimab, 1 day, 500 mgPlacebo53.9 (54.9)45.6NA22.60.7All-cause mortality, serious adverse events, adverse events, mechanical ventilation29
      Weinreich, 202135USANon-hospitalized, vaccination NA583Casirivimab + imdevimab, 1 day, 5169 mgPlacebo43.7 (13.4)48.7NANANAAll-cause mortality, serious adverse events, adverse events, COVID-19 related death, viral load29
      Cohen, 202136USAProphylaxis, vaccination 0%1175Bamlanivimab, 1 day, 4200 mgPlacebo53.5 (47.3)25.3NANANAAll-cause mortality, serious adverse events, adverse events, COVID-19 related death, bacteremia, viral load29
      O'Brien, 202137USA, Romania MoldovaProphylaxis, vaccination 0%1505Casirivimab + imdevimab, 1 day, 1200 mgPlacebo46.9 (57.5)45.9NA6.8NASerious adverse events, adverse events, bacteremia28
      NA: Not available; *12 out 15 (80%) of COVID-19 related hospitalizations or ED visits were hospitalizations.
      Table 1 displays features of the five trials in non-hospitalized COVID-19 patients
      • Chen P
      • Nirula A
      • Heller B
      • et al.
      SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19.
      • Dougan M
      • Nirula A
      • Azizad M
      • et al.
      Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19.
      • Gottlieb RL
      • Nirula A
      • Chen P
      • et al.
      Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial.
      • Gupta A
      • Gonzalez-Rojas Y
      • Juarez E
      • et al.
      Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab.
      • Weinreich DM
      • Sivapalasingam S
      • Norton T
      • et al.
      REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19.
      . All trials assessed anti-SARS-CoV-2 monoclonal antibodies (two bamlanivimab, two bamlanivimab + etesevimab, one sotrovimab, one casirivimab + imdevimab). Four studies had two group comparisons (monoclonal antibody vs. placebo) while one had three arms (bamlanivumab or bamlanivumab + etesevimab vs. placebo). All of the trials had 29 days of follow-up.
      There were only two trials
      • Cohen MS
      • Nirula A
      • Mulligan MJ
      • et al.
      Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial.
      ,
      • O'Brien MP
      • Forleo-Neto E
      • Musser BJ
      • et al.
      Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19.
      assessing the prophylactic impact of anti-SARS-CoV-2 monoclonal antibodies in high-risk patients versus placebo (Table 1). Studies assessed bamlanivimab or casirivimab + imdevimab, and had follow-up times of 29 or 28 days, respectively.
      Figure S1 shows RoB assessments of the 27 randomized trials and 12 were found to have low RoB, nine some concerns of bias, and six high RoB. The selection of the reporting result was the item most likely to receive a high risk of bias in this literature set. There was no evidence of small study effects for all meta-analyses.

      Effects of monoclonal antibodies in hospitalized patients

      Table 2 shows the certainty of evidence of monoclonal antibody effects in hospitalized patients. There were no differences between monoclonal antibody and controls (standard of care, placebo or active treatment) for all-cause mortality (Figure 2), COVID-19 related death (Figure 3) or serious adverse events (Figure 4), with low certainty of evidence for these outcomes. For the secondary outcomes, length of stay was not different between monoclonal antibodies and controls, with very low certainty of evidence (Figure S2). Monoclonal antibodies slightly reduced mechanical ventilation (RR 0.74, 95%CI 0.60 to 0.90, I2=20%, low certainty of evidence, Figure S3) and bacteremia (RR 0.77, 95%CI 0.64 to 0.92, I2=7%, low certainty of evidence, Figure S6) vs. controls; the evidence was very uncertain about the effect of monoclonal antibodies on adverse events (RR 1.31, 95%CI 1.02 to 1.67, I2=77%, very low certainty of evidence, Figure S5, Table 2). Subgroup analyses in hospitalized COVID-19 patients showed differential effects for mechanical ventilation when comparing tocilizumab vs. non-tocilizumab effects, and for all-cause mortality when comparing monoclonal antibody effects vs. types of controls and tocilizumab effects vs. types of controls (Supplement).
      Table 2Summary of findings table of effects of monoclonal antibodies in hospitalized COVID-19 patients.
      OutcomesAnticipated absolute effects* (95% CI)Relative effect

      (95% CI)
      № of participants

      (studies)
      Certainty of the evidence

      (GRADE)
      Risk with standard of care, active therapy or placeboRisk with Monoclonal antibodies
      All-cause mortality follow-up: range 14 days to 90 days26 per 10025 per 100

      (21 to 29)
      RR 0.94

      (0.80 to 1.11)
      7800

      (18 RCTs)
      ⨁⨁◯◯

      Low
      . RoB: Three RCTs were at high risk of bias, and eight RCTs had some concerns of bias.
      COVID-19 related death

      follow-up: range 28 days to 45 days
      8 per 1005 per 100

      (2 to 14)
      RR 0.65

      (0.25 to 1.72)
      524

      (3 RCTs)
      ⨁⨁◯◯

      Low
      . RoB: Vlaar et al. RCT was at high risk of bias in the selection of the reported results.
      ,
      . Imprecision: 95%CI of RR 0.25 to 1.72
      Invasive mechanical ventilation

      follow-up: range 14 days to 45 days
      19 per 10014 per 100

      (11 to 17)
      RR 0.74

      (0.60 to 0.92)
      5807

      (14 RCTs)
      ⨁⨁◯◯

      Low
      . RoB: Three RCTs were at high risk of bias, and seven RCTs had some concerns of bias.
      Length of hospital stay

      assessed with: days

      follow-up: range 14 days to 45 days
      The mean length of hospital stay was 18.1 daysMD 1.86 days lower

      (6.1 lower to 2.38 higher)
      -1098

      (6 RCTs)
      ⨁◯◯◯

      Very low
      . RoB: Two RCTs (Salama et al, Rosas et al) had some concerns of bias, and one RCT (Veiga et al.) was at high risk of bias.
      ,
      . Inconsistency: I2 was 79%
      ,
      . Imprecision: 95%CI of MD from -6.1 to 2.4 days
      Any adverse events

      follow-up: range 14 days to 90 days
      22 per 10029 per 100

      (23 to 37)
      RR 1.31

      (1.02 to 1.67)
      6628

      (13 RCTs)
      ⨁◯◯◯

      Very low
      . RoB: Two RCTs (Zhang et al, and Veiga et al.) were at high of bias, and six RCTs had some concerns of bias.
      ,
      . Inconsistency: I2 was 77%
      Serious adverse events

      follow-up: range 14 days to 45 days
      6 per 1006 per 100

      (5 to 7)
      RR 0.93

      (0.80 to 1.08)
      7831

      (17 RCTs)
      ⨁⨁◯◯

      Low
      . RoB: Three RCTs were at high risk of bias, and seven RCTs had some concerns of bias.
      Bacteremia

      follow-up: range 14 days to 90 days
      5 per 1004 per 100

      (3 to 5)
      RR 0.77

      (0.64 to 0.92)
      7789

      (14 RCTs)
      ⨁⨁◯◯

      Low
      . RoB: Two RCTs (Veiga et al., and Vlaar et al.) were at high risk of bias, and eight RCTs had some concerns of bias.
      Explanations
      a . RoB: Three RCTs were at high risk of bias, and eight RCTs had some concerns of bias.
      b . RoB: Vlaar et al. RCT was at high risk of bias in the selection of the reported results.
      c . Imprecision: 95%CI of RR 0.25 to 1.72
      d . RoB: Three RCTs were at high risk of bias, and seven RCTs had some concerns of bias.
      e . RoB: Two RCTs (Salama et al, Rosas et al) had some concerns of bias, and one RCT (Veiga et al.) was at high risk of bias.
      f . Inconsistency: I2 was 79%
      g . Imprecision: 95%CI of MD from -6.1 to 2.4 days
      h . RoB: Two RCTs (Zhang et al, and Veiga et al.) were at high of bias, and six RCTs had some concerns of bias.
      i . Inconsistency: I2 was 77%
      j . RoB: Two RCTs (Veiga et al., and Vlaar et al.) were at high risk of bias, and eight RCTs had some concerns of bias.
      Figure 2
      Figure 2Effects of monoclonal antibodies on all-cause mortality stratified by type of COVID-19 patients.
      Figure 3
      Figure 3Effects of monoclonal antibodies on COVID-19-related death stratified by type of COVID-19 patients.
      Figure 4
      Figure 4Effects of monoclonal antibodies on serious adverse events stratified by type of COVID-19 patients.

      Effects of monoclonal antibodies in non-hospitalized patients

      Table 3 shows the certainty of evidence of monoclonal antibody effects in non-hospitalized patients. Monoclonal antibodies reduced hospitalizations vs. placebo (RR 0.30, 95%CI 0.17 to 0.53, I2=0%, high certainty of evidence, Figure S7) and may slightly reduce serious adverse events vs. placebo (RR 0.47, 95%CI 0.22 to 1.01, I2=33%, low certainty of evidence, Figure 4). All-cause mortality, COVID-19 related death, mechanical ventilation, length of stay, viral load, bacteremia, and adverse events were not different between monoclonal antibodies and placebo, with certainty of evidence ranging from very low to moderate (Figures 2, 3, S2 to S6).
      Table 3Summary of findings table of effects of monoclonal antibodies in non-hospitalized COVID-19 patients.
      OutcomesAnticipated absolute effects* (95% CI)Relative effect

      (95% CI)
      № of participants

      (studies)
      Certainty of the evidence

      (GRADE)
      Risk with placeboRisk with Monoclonal antibodies
      COVID-19 related hospitalization

      follow-up: median 29 days
      6 per 1002 per 100

      (1 to 3)
      RR 0.30

      (0.17 to 0.53)
      1612

      (2 RCTs)
      ⨁⨁⨁⨁

      High
      All-cause mortality

      follow-up: median 29 days
      1 per 1000 per 100

      (0 to 2)
      RR 0.30

      (0.05 to 1.85)
      2212

      (4 RCTs)
      ⨁◯◯◯

      Very low
      . RoB: Weinreich et al. was at high risk of bias; Gupta et al. had some concerns of bias.
      ,
      . Imprecision: 95%CI was 0.05 to 1.85
      COVID-19 related death

      follow-up: median 29 days
      1 per 1000 per 100

      (0 to 2)
      RR 0.28

      (0.04 to 1.81)
      1829

      (3 RCTs)
      ⨁◯◯◯

      Very low
      . RoB: Weinreich et al. was at high risk of bias
      ,
      . Imprecision: 95%CI was 0.04 to 1.81
      Invasive mechanical ventilation

      follow-up: median 29 days
      1 per 1000 per 100

      (0 to 3)
      RR 0.20

      (0.01 to 4.16)
      583

      (1 RCT)
      ⨁◯◯◯

      Very low
      . RoB: Gupta et al. had high risk of bias
      ,
      . Imprecision: 95%CI was 0.01 to 4.16
      Length of hospital stay

      assessed with: days

      follow-up: median 29 days
      The mean length of hospital stay was 11.2 daysMD 3.9 days lower

      (9.02 lower to 1.22 higher)
      -44

      (1 RCT)
      ⨁⨁◯◯

      Low
      . Imprecision: 95%CI of MD was -9.02 to 1.22 days
      Viral load reduction from baseline

      assessed with: log10

      follow-up: median 29 days
      The mean viral load reduction from baseline was -1.2 log10MD 0.44 log10 lower

      (1.4 lower to 0.52 higher)
      -1941

      (4 RCTs)
      ⨁◯◯◯

      Very low
      . RoB: Weinreich et al. was at high risk of bias
      ,
      . Inconsistency: I2=91%
      ,
      . Imprecision: 95%CI of MD was -1.4 to 0.52 log10
      Any adverse events

      follow-up: median 29 days
      16 per 10014 per 100

      (12 to 17)
      RR 0.90

      (0.75 to 1.09)
      2749

      (4 RCTs)
      ⨁⨁⨁◯

      Moderate
      . RoB: Weinreich et al. was at high risk of bias; Gupta et al. had some concerns of bias.
      Serious adverse events

      follow-up: median 29 days
      3 per 1001 per 100

      (1 to 3)
      RR 0.47

      (0.22 to 1.01)
      2749

      (4 RCTs)
      ⨁⨁◯◯

      Low
      . RoB: Weinreich et al. was at high risk of bias; Gupta et al. had some concerns of bias.
      ,
      . Imprecision: 95%CI 0.22 to 1.01
      Bacteremia

      follow-up: median 29 days
      1 per 1001 per 100

      (0 to 3)
      RR 1.33

      (0.30 to 5.92)
      1035

      (1 RCT)
      ⨁⨁◯◯

      Low
      . Imprecision: 95%CI 0.30 to 5.92
      Explanations
      a . RoB: Weinreich et al. was at high risk of bias; Gupta et al. had some concerns of bias.
      b . Imprecision: 95%CI was 0.05 to 1.85
      c . RoB: Weinreich et al. was at high risk of bias
      d . Imprecision: 95%CI was 0.04 to 1.81
      e . RoB: Gupta et al. had high risk of bias
      f . Imprecision: 95%CI was 0.01 to 4.16
      g . Imprecision: 95%CI of MD was -9.02 to 1.22 days
      h . Inconsistency: I2=91%
      i . Imprecision: 95%CI of MD was -1.4 to 0.52 log10
      j . Imprecision: 95%CI 0.22 to 1.01
      k . Imprecision: 95%CI 0.30 to 5.92

      Effects of monoclonal antibodies in prophylaxis against COVID-19

      Table 4 shows the certainty of evidence of monoclonal antibody effects in trials of prophylaxis. Symptomatic COVID-19, positive SARS-CoV-2 PCR test, all-cause mortality, COVID-19 related death, adverse events, serious adverse events, and bacteremia were not different between monoclonal antibodies and placebo, with certainty of evidence ranging from very low to moderate (Figures S8, S9, 2 to 4, S5 and S6). Monoclonal antibodies probably reduced viral load slightly vs. placebo (MD -0.8 log10, 95%CI -1.21 to -0.39, one trial, moderate certainty of evidence).
      Table 4Summary of findings table of effects of monoclonal antibodies in individuals exposed to SARS-CoV-2 (prophylaxis).
      OutcomesAnticipated absolute effects* (95% CI)Relative effect

      (95% CI)
      № of participants

      (studies)
      Certainty of the evidence

      (GRADE)
      Risk with placeboRisk with Monoclonal antibodies
      Symptomatic COVID-19

      assessed with: positive PCR test plus COVID-19 symptoms

      follow-up: median 28 days
      7 per 1005 per 100

      (2 to 10)
      RR 0.75

      (0.36 to 1.54)
      2471

      (2 RCTs)
      ⨁◯◯◯

      Very low
      . RoB: O'Brien et al. at high risk of bias due to measurement of the outcome and selection of the reported result.
      ,
      . Inconsistency: I2=60%
      ,
      . Imprecision: 95%CI 0.36 to 1.54
      Symptomatic and asymptomatic COVID-19

      assessed with: Positive PCR test with or without COVID-19 symptoms

      follow-up: median 28 days
      18 per 1009 per 100

      (4 to 21)
      RR 0.52

      (0.23 to 1.17)
      2471

      (2 RCTs)
      ⨁◯◯◯

      Very low
      . RoB: O'Brien et al. at high risk of bias due to measurement of the outcome and selection of the reported result.
      ,
      . Inconsistency: I2=93%
      ,
      . Imprecision: 95%CI 0.23 to 1.17
      All-cause mortality

      follow-up: median 28 days
      1 per 1001 per 100

      (0 to 3)
      RR 0.83

      (0.25 to 2.70)
      966

      (1 RCT)
      ⨁⨁◯◯

      Low
      . Imprecision: 95%CI 0.25 to 2.70
      COVID-19 related death

      follow-up: median 28 days
      1 per 1000 per 100

      (0 to 2)
      RR 0.11

      (0.01 to 2.05)
      966

      (1 RCT)
      ⨁⨁◯◯

      Low
      . Imprecision: 95%CI 0.01 to 2.05
      Viral load reduction from baseline

      assessed with: log10

      follow-up: median 28 days
      The mean viral load reduction from baseline was -0.39 log10MD 0.8 log10 lower

      (1.21 lower to 0.39 lower)
      -132

      (1 RCT)
      ⨁⨁⨁◯

      Moderate
      . Imprecision: 95%CI -1.21 to -0.39 log10
      Any adverse events

      follow-up: median 28 days
      26 per 10022 per 100

      (14 to 33)
      RR 0.85

      (0.56 to 1.28)
      3792

      (2 RCTs)
      ⨁◯◯◯

      Very low
      . RoB: O'Brien et al. at high risk of bias due to measurement of the outcome and selection of the reported result.
      ,
      . Inconsistency: I2=89%
      Serious adverse events

      follow-up: median 28 days
      2 per 1002 per 100

      (1 to 3)
      RR 0.93

      (0.55 to 1.58)
      3792

      (2 RCTs)
      ⨁⨁⨁◯

      Moderate
      . RoB: O'Brien et al. at high risk of bias due to measurement of the outcome and selection of the reported result.
      Bacteremia

      follow-up: median 28 days
      2 per 1001 per 100

      (1 to 2)
      RR 0.70

      (0.37 to 1.33)
      2680

      (2 RCTs)
      ⨁⨁⨁◯

      Moderate
      . RoB: O'Brien et al. at high risk of bias due to measurement of the outcome and selection of the reported result.
      Explanations
      a . RoB: O'Brien et al. at high risk of bias due to measurement of the outcome and selection of the reported result.
      b . Inconsistency: I2=60%
      c . Imprecision: 95%CI 0.36 to 1.54
      d . Inconsistency: I2=93%
      e . Imprecision: 95%CI 0.23 to 1.17
      f . Imprecision: 95%CI 0.25 to 2.70
      g . Imprecision: 95%CI 0.01 to 2.05
      h . Imprecision: 95%CI -1.21 to -0.39 log10
      i . Inconsistency: I2=89%

      Discussion

      Our systematic review suggests that monoclonal antibodies had limited effects on most of the outcomes in hospitalized and non-hospitalized COVID-19 patients, and in individuals exposed to SARS-CoV-2, with certainty of evidence ranging from very low to moderate for most outcomes. In particular there were no effects of monoclonal antibodies on all-cause mortality or COVID-19-related mortality across trials. In 20 trials of hospitalized COVID-19 patients, monoclonal antibodies slightly reduced mechanical ventilation and bacteremia, and the evidence was very uncertain about the effect on adverse events. In five placebo-controlled trials of non-hospitalized COVID-19 patients, monoclonal antibodies reduced COVID-19 related hospitalization, and may slightly reduce serious adverse events. In two placebo-controlled prophylaxis trials of individuals exposed to SARS-CoV-2, monoclonal antibodies probably reduced viral load slightly.
      The anti-inflammatory monoclonal antibodies in our systematic review included inhibitors of interleukin-6 (tocilizumab, sarilumab), interleukin-1 (canakinumab), complement-5 (vilobelimb), surface glycoprotein CD-6 (itolizumab), CD-147 (meplazumab), and granulocyte-monocyte colony stimulating factor (mavrilimumab). While more robust reductions in all-cause mortality were seen for non-tolicizumab anti-inflammatory monoclonal antibodies vs. control as compared to tolicizumab vs. control, whether alternative mechanisms of blocking inflammation provide superior benefits needs future verification in randomized trials. Finding a smaller magnitude of benefit for some outcomes in hospitalized patients receiving monoclonal antibodies vs. standard of care than when monoclonal antibodies were compared vs. placebo may suggest that the weaknesses in blinding when standard of care is used might have biased the results.
      The use of anti-SARS-CoV-2 monoclonal antibodies in hospitalized COVID-19 patients has only been evaluated in one trial
      • Lundgren JD
      • Grund B
      • et al.
      ACTIV-3/TICO LY-CoV555 Study Group
      A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.
      and the results were not promising. Unfortunately, this trial evaluated bamlanivimab alone where the emergency authorization approved product now contains bamlanivimab + etesevimab, so the monoclonal antibodies assessed might have been suboptimal. It is pharmacologically plausible that suppressing excessive inflammation is more important than suppressing viral replication in hospitalized patients
      • Cantini F
      • Goletti D
      • Petrone L
      • Najafi Fard S
      • Niccoli L
      • Foti R.
      Immune Therapy, or Antiviral Therapy, or Both for COVID-19: A Systematic Review.
      .
      In non-hospitalized COVID-19 patients, anti-inflammatory monoclonal antibodies have not been assessed and there is pharmacologic reason to believe that they would not be effective
      • Cantini F
      • Goletti D
      • Petrone L
      • Najafi Fard S
      • Niccoli L
      • Foti R.
      Immune Therapy, or Antiviral Therapy, or Both for COVID-19: A Systematic Review.
      . At this stage of the disease, the suppression of viral replication may be more effective since excessive inflammation is not commonly seen in non-hospitalized patients. In our study, we found that the anti-SARS-CoV-2 monoclonal antibodies reduced COVID-19-related hospitalization, with no significant effects on all-cause mortality, COVID-19 related death, mechanical ventilation, and length of stay but the literature base only has five randomized trials. Importantly, there were no increases in adverse events or serious adverse events in our systematic review which is very promising.
      In patients at high risk of developing COVID-19, the patient population assessing the impact of anti-SARS-CoV-2 monoclonal antibodies on patient outcomes is small. That means that the promising reductions in viral load, and the absence of effects on developing symptomatic and/or asymptomatic COVID-19 disease, all-cause mortality, COVID-19 related deaths, and bacteremia with anti-SARS-CoV-2 monoclonal antibodies are underpowered to show statistical significance. Further research in this area is encouraged as these potential benefits could occur without increases in adverse events or serious adverse events.
      In Winter 2022, the omicron variant became the dominant subvariant (99%) in the United States
      • Takashita E
      • Kinoshita N
      • Yamayoshi S
      • et al.
      Efficacy of Antibodies and Antiviral Drugs against Covid-19 Omicron Variant.
      . The anti-SARS-CoV-2 monoclonal antibodies casirivimab + imdevimab, bamlanivimab + etesevimab, and sotrovimab were not effective against the omicron subvariant in vitro and therapy with these drugs were therefore discouraged by the FDA

      Food and Drug Administration. Emergency Use Authorization of drugs and non-vaccine biological products. Available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs Accessed 28 March 2022.

      . This suggests that anti-SARS-CoV2 monoclonal antibodies will be even less effective than what we found in our systematic review when the omicron variant or other resistant subvariants predominate. Our literature search was through November 3, 2021 and would not have included predominant omicron subvariant patient populations. However, the efficacy of the anti-inflammatory monoclonal antibodies would be less likely than the anti-SARS-CoV-2 monoclonal antibodies to vary given the circulating subvariant at the time. The anti-SARS-CoV-2 monoclonal antibody bebtelovimab received an emergency authorization from the FDA on February 11, 2022 for the treatment of mild to moderate COVID-19 as it retained activity against omicron variant

      Food and Drug Administration. Emergency Use Authorization of drugs and non-vaccine biological products. Available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs Accessed 28 March 2022.

      ,

      Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes New Monoclonal Antibody for Treatment of COVID-19 that Retains Activity Against Omicron Variant. Available at: www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-new-monoclonal-antibody-treatment-covid-19-retains#:∼:text=Today%2C%20the%20U.S.%20Food%20and,activity%20against%20the%20omicron%20variant. Accessed 4/1/ 2022

      . With the progress of research on pathogenesis of SARS-CoV-2 infection, new monoclonal antibodies (such as anti-inflammasomes or monocyte/macrophage entry inhibitors
      • Junqueira C
      • Crespo Â
      • Ranjbar S
      • et al.
      FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation.
      ) should be evaluated in randomized trials to assess their efficacy and safety.
      The increase in vaccination against SARS-CoV-2 could support earlier and more robust creation of a patient's own antibody response to COVID-19 infection. Whether this attenuates some of the benefits of providing monoclonal antibody therapy is unknown. Importantly, there were no reporting on the proportion of fully vaccinated individuals in our included randomized controlled trials. This potential confounding factor should be assessed in future studies.
      Our study had some limitations. First, most of the randomized trials were conducted in hospitalized COVID-19 patients, and effects for non-hospitalized and prophylaxis randomized trials were less conclusive. Second, certainty of evidence was low or very low for most of the outcomes in the three populations. Third, we did not assess effects of individual monoclonal antibodies on outcomes in non-hospitalized and prophylaxis due to the scarcity of studies; we did evaluate the effects tocilizumab vs. other monoclonal antibodies for hospitalized patients. Fourth, randomized trial data for hospitalized patients were almost entirely comprised of anti-inflammatory monoclonal antibodies while for non-hospitalized patients and those at high risk of developing COVID-19, only anti-SARS-CoV-2 monoclonal antibody data were available. Finally, all monoclonal antibodies in non-hospitalized and prophylaxis were evaluated against placebo, but no active treatment or standard of care.

      Conclusions

      Monoclonal antibodies had limited effects on most of the outcomes in hospitalized and non-hospitalized COVID-19 patients, and in individuals exposed to SARS-CoV-2. There were no effects of monoclonal antibodies on all-cause mortality or COVID-19-related mortality. In hospitalized COVID-19 patients, monoclonal antibodies slightly reduce mechanical ventilation and bacteremia, and the evidence was very uncertain on adverse events. In non-hospitalized COVID-19 patients, monoclonal antibodies reduced COVID-19 related hospitalization, and may slightly reduce serious adverse events. In randomized trials of individuals exposed to SARS-CoV-2, monoclonal antibodies probably reduced viral load slightly.
      Anti-inflammatory monoclonal antibodies in hospitalized COVID-19 patients and anti-SARS-CoV-2 monoclonal antibodies in non-hospitalized COVID-19 patients or those at high risk of developing COVID-19 are promising, but additional data are needed to determine their efficacy and safety.

      Clinical significance

      • A systematic review of randomized controlled trials assessing monoclonal antibodies in COVID-19.
      • In hospitalized, monoclonal antibodies slightly reduced mechanical ventilation and bacteremia.
      • In non-hospitalized, monoclonal antibodies reduced hospitalization, and may slightly reduce SAEs.
      • In individuals exposed to SARS-CoV-2, monoclonal antibodies probably reduced viral load slightly.
      • There were no effects of monoclonal antibodies on all-cause mortality or COVID-19-related mortality.

      Funding

      No funding was received for this study.

      Declarations of Interest

      None for all authors.

      Declaration of authorship

      All authors had access to the data and a role in writing the manuscript.

      Supplement

      Pubmed search strategy
      Figure S1. Risk of bias of included RCTs
      Figure S2. Effects of monoclonal antibodies on length of hospital stay stratified by type of COVID-19 patients.
      Figure S3. Effects of monoclonal antibodies on invasive mechanical ventilation stratified by type of COVID-19 patients.
      Figure S4. Effects of monoclonal antibodies on viral load stratified by type of COVID-19 patients.
      Figure S5. Effects of monoclonal antibodies on adverse events stratified by type of COVID-19 patients.
      Figure S6. Effects of monoclonal antibodies on bacteremia stratified by type of COVID-19 patients.
      Figure S7. Effects of monoclonal antibodies on COVID-19 related hospitalization in non-hospitalized RCTs
      Figure S8. Effects of monoclonal antibodies on symptomatic COVID-19 incidence in prophylaxis RCTs
      Figure S9. Effects of monoclonal antibodies on symptomatic or asymptomatic COVID-19 incidence in prophylaxis RCTs
      Figure S10: Subgroup analyses
      Figure S10A: Subgroup analyses by type of drug: tocilizumab vs. other MAbs in hospitalized patients
      S10A1. All-cause mortality
      S10A2. COVID-19-related death
      S10A3. Serious adverse events
      S10A4. Length of hospital stay
      S10A5. Invasive mechanical ventilation
      S10A6. Adverse events
      S10A7. Bacteremia
      Figure S10B: Subgroup analyses by type of control in hospitalized patients
      S10B1. All-cause mortality
      S10B2. COVID-19-related death
      S10B3. Serious adverse events
      S10B4. Length hospital stay
      S10B5. Invasive mechanical ventilation
      S10B6. Adverse events
      S10B7. Bacteremia
      Figure S10C: Subgroup analyses by type of control in hospitalized patients receiving tocilizumab
      S10C1. All-cause mortality
      S10C2. Serious adverse events
      S10C3. Length hospital stay
      S10C4. Invasive mechanical ventilation
      S10C5. Adverse events
      S10C6. Bacteremia
      Pubmed search strategy
      ("antibodies, monoclonal"[MeSH Terms] OR ("antibodies"[All Fields] AND "monoclonal"[All Fields]) OR "monoclonal antibodies"[All Fields] OR ("monoclonal"[All Fields] AND "antibodies"[All Fields]) OR ("antibodies, neutralizing"[MeSH Terms] OR ("antibodies"[All Fields] AND "neutralizing"[All Fields]) OR "neutralizing antibodies"[All Fields] OR ("neutralizing"[All Fields] AND "antibodies"[All Fields])) OR ("bamlanivimab"[Supplementary Concept] OR "bamlanivimab"[All Fields]) OR ("etesevimab"[Supplementary Concept] OR "etesevimab"[All Fields]) OR ("sotrovimab"[Supplementary Concept] OR "sotrovimab"[All Fields]) OR ("meplazumab"[Supplementary Concept] OR "meplazumab"[All Fields]) OR ("itolizumab"[Supplementary Concept] OR "itolizumab"[All Fields]) OR ("sarilumab"[Supplementary Concept] OR "sarilumab"[All Fields]) OR (("casirivimab"[Supplementary Concept] OR "casirivimab"[All Fields]) AND ("imdevimab"[Supplementary Concept] OR "imdevimab"[All Fields])) OR ("tocilizumab"[Supplementary Concept] OR "tocilizumab"[All Fields])) AND ("covid 19"[All Fields] OR "covid 19"[MeSH Terms] OR "covid 19 vaccines"[All Fields] OR "covid 19 vaccines"[MeSH Terms] OR "covid 19 serotherapy"[All Fields] OR "covid 19 serotherapy"[Supplementary Concept] OR "covid 19 nucleic acid testing"[All Fields] OR "covid 19 nucleic acid testing"[MeSH Terms] OR "covid 19 serological testing"[All Fields] OR "covid 19 serological testing"[MeSH Terms] OR "covid 19 testing"[All Fields] OR "covid 19 testing"[MeSH Terms] OR "sars cov 2"[All Fields] OR "sars cov 2"[MeSH Terms] OR "severe acute respiratory syndrome coronavirus 2"[All Fields] OR "ncov"[All Fields] OR "2019 ncov"[All Fields] OR (("coronavirus"[MeSH Terms] OR "coronavirus"[All Fields] OR "cov"[All Fields]) AND 2019/11/01:3000/12/31[Date - Publication]) OR ("coronavirus"[MeSH Terms] OR "coronavirus"[All Fields] OR "coronaviruses"[All Fields]) OR (("coronavirus"[MeSH Terms] OR "coronavirus"[All Fields] OR "coronaviruses"[All Fields]) AND ("disease"[MeSH Terms] OR "disease"[All Fields] OR "diseases"[All Fields] OR "disease s"[All Fields] OR "diseased"[All Fields])) OR ("covid 19"[MeSH Terms] OR "covid 19"[All Fields] OR "coronavirus disease 19"[All Fields]) OR ("severe acute respiratory syndrome"[MeSH Terms] OR ("severe"[All Fields] AND "acute"[All Fields] AND "respiratory"[All Fields] AND "syndrome"[All Fields]) OR "severe acute respiratory syndrome"[All Fields]) OR ("sars cov 2"[MeSH Terms] OR "sars cov 2"[All Fields] OR "sars cov 2"[All Fields])) AND ("random allocation"[MeSH Terms] OR ("random"[All Fields] AND "allocation"[All Fields]) OR "random allocation"[All Fields] OR "random"[All Fields] OR "randomization"[All Fields] OR "randomized"[All Fields] OR "randomisation"[All Fields] OR "randomisations"[All Fields] OR "randomise"[All Fields] OR "randomised"[All Fields] OR "randomising"[All Fields] OR "randomizations"[All Fields] OR "randomize"[All Fields] OR "randomizes"[All Fields] OR "randomizing"[All Fields] OR "randomness"[All Fields] OR "randoms"[All Fields] OR ("random allocation"[MeSH Terms] OR ("random"[All Fields] AND "allocation"[All Fields]) OR "random allocation"[All Fields] OR "random"[All Fields] OR "randomization"[All Fields] OR "randomized"[All Fields] OR "randomisation"[All Fields] OR "randomisations"[All Fields] OR "randomise"[All Fields] OR "randomised"[All Fields] OR "randomising"[All Fields] OR "randomizations"[All Fields] OR "randomize"[All Fields] OR "randomizes"[All Fields] OR "randomizing"[All Fields] OR "randomness"[All Fields] OR "randoms"[All Fields]))
      Figure S1. Risk of bias of included RCTs
      Figure S2. Effects of monoclonal antibodies on length of hospital stay stratified by type of COVID-19 patients.
      Figure S3. Effects of monoclonal antibodies on invasive mechanical ventilation stratified by type of COVID-19 patients.
      Figure S4. Effects of monoclonal antibodies on viral load stratified by type of COVID-19 patients.
      Figure S5. Effects of monoclonal antibodies on adverse events stratified by type of COVID-19 patients.
      Figure S6. Effects of monoclonal antibodies on bacteremia stratified by type of COVID-19 patients.
      Figure S7. Effects of monoclonal antibodies on COVID-19 related hospitalization in non-hospitalized RCTs
      Figure S8. Effects of monoclonal antibodies on symptomatic COVID-19 incidence in prophylaxis RCTs
      Figure S9. Effects of monoclonal antibodies on symptomatic or asymptomatic COVID-19 incidence in prophylaxis RCTs
      Figure S10: Subgroup analyses
      In subgroup analyses of hospitalized patients, we were unable to find any significant reductions associated with tocilizumab vs. control therapy for any primary or secondary outcome aside from mechanical ventilation (Figure S10A5), which was reduced by 20% (RR 0.80; 95%CI 0.70 to 0.91, I2=0%, p for interaction <0.01). When we assessed monoclonal antibodies other than tolicizumab vs. controls, the magnitude of the reductions was larger for all-cause mortality (Figure S10A1), COVID-19 related death (Figure S10A2), mechanical ventilation (Figure S10A5), and bacteremia (Figure S10A7) than what was seen with tocilizumab vs. controls, but none of the non-tocilizumab vs. control assessments were significantly different (all p for interaction >0.1). However, when tocilizumab trials and the single bamlanivimab trial by Lundgren et al.
      • Lundgren JD
      • Grund B
      • et al.
      ACTIV-3/TICO LY-CoV555 Study Group
      A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.
      were removed, the trials of other anti-inflammatory monoclonal antibodies did significantly reduce all-cause mortality vs. control (RR 0.64; 95%CI 0.42 to 0.98, I2=0%).
      In subgroup analyses by control group (Figures S10B1-S10B7), monoclonal antibodies had differential effects on all-cause mortality according to the type of control, although none of the subgroup effects was significant (Figure S10B1, p for interaction <0.01). Subgroup analyses for other outcomes did not show differential effects of monoclonal antibodies vs. types of controls (Figures S10B2 to S10B7, all p for interaction>0.1). In subgroup analyses by type of control in tocilizumab-only trials (Figures S10C1-S10C6), monoclonal antibodies had differential effects on all-cause mortality according to the type of control, although none of the subgroup effects was significant (Figure S10C1, p for interaction <0.01). Subgroup analyses for other outcomes did not show differential effects of monoclonal antibodies vs. types of controls (Figures S10C2 to S10C6, all p for interaction>0.1).
      11.1 Figure S10A: Subgroup analyses by type of drug: tocilizumab vs. other MAbs in hospitalized patients
      S10A1. All-cause mortality
      S10A2. COVID-19-related death
      S10A3. Serious adverse events
      S10A4. Length of hospital stay
      S10A5. Invasive mechanical ventilation
      S10A6. Adverse events
      S10A7. Bacteremia
      11.2 Figure S10B: Subgroup analyses by type of control in hospitalized patients
      S10B1. All-cause mortality
      S10B2. COVID-19-related death
      S10B3. Serious adverse events
      S10B4. Length of hospital stay
      S10B5. Invasive mechanical ventilation
      S10B6. Adverse events
      S10B7. Bacteremia
      11.3 Figure S10C: Subgroup analyses by type of control in hospitalized patients receiving tocilizumab
      S10C1. All-cause mortality
      S10C2. Serious adverse events
      S10C3. Length hospital stay
      S10C4. Invasive mechanical ventilation
      S10C5. Adverse events
      S10C6. Bacteremia

      CRediT authorship contribution statement

      Adrian V. Hernandez: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. Alejandro Piscoya: Conceptualization, Data curation, Investigation, Resources, Supervision, Writing – original draft, Writing – review & editing. Vinay Pasupuleti: Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. Mi T. Phan: Data curation, Formal analysis, Investigation, Writing – review & editing. Sreya Julakanti: Data curation, Formal analysis, Investigation, Writing – review & editing. Phirin Khen: Data curation, Formal analysis, Investigation, Writing – review & editing. Yuani M. Roman: Conceptualization, Formal analysis, Investigation, Resources, Writing – original draft, Writing – review & editing. César O. Carranza-Tamayo: Data curation, Formal analysis, Investigation, Writing – review & editing. Angel A. Escobedo: Data curation, Formal analysis, Investigation, Writing – review & editing. C. Michael White: Conceptualization, Data curation, Investigation, Supervision, Writing – original draft, Writing – review & editing.

      Conflict of Interest

      The authors declare that there are no conflicts of interest.
      Acknowledgment
      None.

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