In patients with Covid-19 treated with monoclonal antibodies, a specific anti-inflammatory response can develop which facilitates the Sars-CoV-2 virus to develop evasive mutations of the Spike protein. This means that the virus can develop resistance to monoclonal antibodies similar to bacteria developing resistance to antibiotics. This is what emerged from a study, coordinated by the University of Verona, which led to the development of an algorithm that early identifies patients in which the virus can develop mutations.
The research, conducted as part of the collaboration between the University of Verona and the University of Antwerp, in Belgium, within the European project ‘Orchestra’ and financed with European funds from the Horizon 2020 programme, was published in pre-print on ‘Journal of Clinical Investigation’. Monoclonal antibodies – it is explained – significantly reduce the risk of developing severe forms of Covid-19 and are used in unvaccinated or immunocompromised high-risk patients, suffering from neoplasms or undergoing transplantation. Monoclonal antibodies provide, in these patients, a rapid immune response to a specific virus variant, which the individual patient is unable to develop on his own. The researchers have now discovered that the treatment may be able to promote mutations of the SARS-CoV-2 virus as a response to the substantial immune pressure created by monoclonal treatment, coupled with the patient’s immune response.
In the clinical study conducted at the University of Verona and led by Evelina Tacconelli, director of the infectious diseases section and coordinator of the Orchestra project, patients at high risk of developing severe Covid-19 who received monoclonal antibody therapy were studied. The analysis of the viral variants, performed in the Medical Microbiology laboratory of the University of Antwerp led by Surbhi Malhotra, shows that in approximately 8% of patients treated with monoclonals, the virus develops evasive mutations of the Spike protein with considerable speed. While most patients clear the virus over time, immunocompromised patients have significantly higher viral loads over longer periods and are 3 times more likely to develop evasive mutations of the Spike protein.
The authors of the study therefore developed an algorithm capable of predicting with 96% accuracy in which patients are at highest risk of mutations evasive to monoclonal antibody therapy, using a combination of immunological tests measured in the patient’s blood before the initiation of monoclonal antibody therapy. “The study provides innovative data useful in the selection of high-risk patients for early treatments”, explains Tacconelli, “and allows us to keep the efficacy of monoclonals high by using them only in patients who can have a benefit. We believe that the use of monoclonals on the basis of the circulating variants and the correct selection of patients to be treated reduces not only the mortality from Covid-19, but also the risk of Long Covid”.
“It was interesting to discover that in the development of evasive mutations, not only the neutralizing capacity of the monoclonals and the patient’s immune system count, but also the entire healing process”, continues Samir Kumar-Singh, co-author of the study and director of the study. from the Molecular Pathology group in the Cell Biology and Histology laboratory of the University of Antwerp, who supervised the host response studies.
The developed algorithm will help in making decisions at the individual patient level to reduce the risk of treatment failure with monoclonals, allowing patients to receive other therapeutic options, such as oral antivirals. The application of the algorithm will also be able to improve risk reduction strategies, decreasing the possible circulation of evasive mutations of Sars-CoV-2, especially among high-risk close contacts of patients with Covid-19.
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