Severe COVID-19 is characterized by a strong inflammatory response and a high incidence of thromboembolic complications. Complement activation may form the common pathway in severe COVID-19, leading to the observed inflammation and coagulopathy.

Complement activation in patients with severe COVID-19

Autopsies of patients with severe COVID-19 showed widespread complement activation in lung and kidney. The complement system is a part of our immune system that enhances the ability of antibodies and other immune cells to clear pathogens, promote inflammation and attack the pathogens by the membrane attack complex (MAC) formation. The complement system consists of small proteins produced by the liver which circulate in an inactive form and can become active after several stimuli.

Treating severe COVID-19 by restoring the balance of the immune system.

COVID-19 studies showed binding of the SARS-CoV-2 virus N-protein to the complement activating mannose-associated serine protease 2 (MASP2), ultimately leading to downstream complement pathway activation and generation of C5a. The potent anaphylatoxin C5a attracts neutrophils and monocytes to the infection site and strongly activates these cells, causing tissue damage by oxidative radical formation and enzyme release. This also induces the release of tissue factor from endothelial cells and neutrophils thereby activating the coagulation system. High concentrations of C5a have been reported in patients with severe COVID-19, and the C5a-C5aR1 signaling axis has been suggested to be crucial in COVID-19-associated inflammation. The complement system is normally a very useful part of our immune system for attacking pathogens. However, in COVID-19 the balance between attacking the virus and collateral damage to the target organs goes wrong. By blocking C5a in severe COVID-19 this balance may be restored and the inflammatory and coagulation cascade slowed down.  

International phase III trial

Until recently, only upstream blockade of complement was possible which resulted in potential side effects due to blocking of C5b-9, and thereby the MAC formation. The MAC formation plays a crucial role in host defense through cell lysis. The pharmaceutical company InflaRx has developed a specific anti-C5a antibody which leaves the MAC formation intact while blocking the potent anaphylatoxin C5a. Vilobelimab is a chimeric monoclonal IgG4 antibody that specifically binds with high affinity to the soluble form of human complement component C5a. InflaRx initiated and funded the current adaptive phase II/III trial, to investigate the effect of anti-C5a treatment in severe COVID-19.

Alexander Vlaar, professor of translational intensive care medicine photo by DigiDaan
Alexander Vlaar, professor of translational intensive care medicine

Prof. Alexander Vlaar is the international principal investigator of this trial, and recently published the first part of the adaptive phase II/III PANAMO trial in The Lancet Rheumatology exploring potential benefit and safety of selectively blocking C5a with the monoclonal antibody vilobelimab in patients with severe COVID-19. The results showed that C5a inhibition with vilobelimab was safe and secondary outcomes were in favor of vilobelimab. There were consistent signals of benefit in the treatment-group including a lower 28-day all-cause mortality rate, lower rate in impaired kidney function, faster normalization in lymphocyte counts and greater reduction in LDH. This warranted investigating C5a inhibition with vilobelimab within a phase III trial. The phase III trial is currently being conducted in several medical centers, world-wide, including Amsterdam UMC.

This article is published in June 2021 in the ACS magazine 2021, page 19

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