Subject(s)COVID-19 , Humans , Animals , Mice , Signal Transduction , Complement C5a , Receptor, Anaphylatoxin C5a , Mice, Knockout
OBJECTIVES: Severe COVID-19 is associated with exaggerated complement activation. We assessed the efficacy and safety of avdoralimab (an anti-C5aR1 mAb) in severe COVID-19. DESIGN: FOR COVID Elimination (FORCE) was a double-blind, placebo-controlled study. SETTING: Twelve clinical sites in France (ICU and general hospitals). PATIENTS: Patients receiving greater than or equal to 5 L oxygen/min to maintain Sp o2 greater than 93% (World Health Organization scale ≥ 5). Patients received conventional oxygen therapy or high-flow oxygen (HFO)/noninvasive ventilation (NIV) in cohort 1; HFO, NIV, or invasive mechanical ventilation (IMV) in cohort 2; and IMV in cohort 3. INTERVENTIONS: Patients were randomly assigned, in a 1:1 ratio, to receive avdoralimab or placebo. The primary outcome was clinical status on the World Health Organization ordinal scale at days 14 and 28 for cohorts 1 and 3, and the number of ventilator-free days at day 28 (VFD28) for cohort 2. MEASUREMENTS AND MAIN RESULTS: We randomized 207 patients: 99 in cohort 1, 49 in cohort 2, and 59 in cohort 3. During hospitalization, 95% of patients received glucocorticoids. Avdoralimab did not improve World Health Organization clinical scale score on days 14 and 28 (between-group difference on day 28 of -0.26 (95% CI, -1.2 to 0.7; p = 0.7) in cohort 1 and -0.28 (95% CI, -1.8 to 1.2; p = 0.6) in cohort 3). Avdoralimab did not improve VFD28 in cohort 2 (between-group difference of -6.3 (95% CI, -13.2 to 0.7; p = 0.96) or secondary outcomes in any cohort. No subgroup of interest was identified. CONCLUSIONS: In this randomized trial in hospitalized patients with severe COVID-19 pneumonia, avdoralimab did not significantly improve clinical status at days 14 and 28 (funded by Innate Pharma, ClinicalTrials.gov number, NCT04371367).
Subject(s)COVID-19 , Humans , SARS-CoV-2 , Antibodies, Monoclonal, Humanized/therapeutic use , Oxygen , Treatment Outcome
Subject(s)COVID-19 , Humans , Killer Cells, Natural , SARS-CoV-2
The complement system is an essential component of the innate immune system. Its excessive activation during COVID-19 contributes to cytokine storm, disease-specific endothelial inflammation (endotheliitis) and thrombosis that comes with the disease. Targeted therapies of complement inhibition in COVID-19, in particular blocking the C5a-C5aR1 axis have to be taken into account in the establishment of potential biomarkers and development of therapeutic strategies in the most severe forms of the disease.
TITLE: Implication de la cascade du complément dans les formes sévères de COVID-19. ABSTRACT: Le système du complément est un composant essentiel du système immunitaire inné. Son activation excessive au cours de la COVID-19 participe à l'orage cytokinique, à l'inflammation endothéliale (endothélite) et aux thromboses qui accompagnent la maladie. Bloquer le complément, notamment l'axe C5a-C5aR1, par des thérapies spécifiques représente un espoir thérapeutique dans les formes les plus sévères de la maladie.
Subject(s)COVID-19/immunology , COVID-19/pathology , Complement Activation/physiology , Complement System Proteins/physiology , Animals , COVID-19/metabolism , Complement C5a/immunology , Complement C5a/metabolism , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Humans , Inflammation/complications , Inflammation/immunology , Inflammation/pathology , SARS-CoV-2/immunology , Severity of Illness Index , Signal Transduction/immunology
The complement system is an essential component of the innate immune system. The three complement pathways (classical, lectin, alternative) are directly or indirectly activated by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). In the most severe forms of COVID-19, overactivation of the complement system may contribute to the cytokine storm, endothelial inflammation (endotheliitis) and thrombosis. No antiviral drug has yet been shown to be effective in COVID-19. Therefore, immunotherapies represent a promising therapeutic in the immunopathological phase (following the viral phase) of the disease. Complement blockade, mostly C5a-C5aR axis blockade, may prevent acute respiratory distress syndrome (ARDS) from worsening or progression to death. Clinical trials are underway.
Subject(s)COVID-19/pathology , Complement C5a/antagonists & inhibitors , Cytokine Release Syndrome/pathology , Cytokines/immunology , Immunotherapy/methods , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , COVID-19/immunology , Complement Activation/immunology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Humans , Inflammation/immunology , Inflammation/pathology , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2/immunology , Signal Transduction/immunology , Thrombosis/immunology , Thrombosis/pathology , COVID-19 Drug Treatment
Coronavirus disease 2019 (COVID-19) is a disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic1. The C5a complement factor and its receptor C5aR1 (also known as CD88) have a key role in the initiation and maintenance of several inflammatory responses by recruiting and activating neutrophils and monocytes1. Here we provide a longitudinal analysis of immune responses, including phenotypic analyses of immune cells and assessments of the soluble factors that are present in the blood and bronchoalveolar lavage fluid of patients at various stages of COVID-19 severity, including those who were paucisymptomatic or had pneumonia or acute respiratory distress syndrome. The levels of soluble C5a were increased in proportion to the severity of COVID-19 and high expression levels of C5aR1 receptors were found in blood and pulmonary myeloid cells, which supports a role for the C5a-C5aR1 axis in the pathophysiology of acute respiratory distress syndrome. Anti-C5aR1 therapeutic monoclonal antibodies prevented the C5a-mediated recruitment and activation of human myeloid cells, and inhibited acute lung injury in human C5aR1 knock-in mice. These results suggest that blockade of the C5a-C5aR1 axis could be used to limit the infiltration of myeloid cells in damaged organs and prevent the excessive lung inflammation and endothelialitis that are associated with acute respiratory distress syndrome in patients with COVID-19.