Study published as pre-print preview in The Journal of Clinical Investigation
"Host immunological responses facilitate development of SARS-CoV-2 mutations in patients receiving monoclonal antibody treatments" is a study showing several significant immunological findings: patients treated with various monoclonal antibodies (mAbs) develop escape spike mutations in SARS-CoV-2 where an anti-inflammatory and pro-healing host milieu facilitates development of such mutations. Furthermore, the scientists developed a score identifying patients at risk for developing mutations in SARS-CoV-2 due to treatment with mAbs. The research was conducted within the EU HORIZON 2020 project ORCHESTRA (Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic) at the University of Antwerp, Belgium, and at the University of Verona, Italy.
Monoclonal antibodies (mAbs) offer a treatment option for individuals at high risk of developing severe COVID-19, and for whom vaccination does not offer optimal protection. For instance, immunosuppressed patients such as those receiving cancer treatment or organ transplant are unable to mount a sufficient antibody response to vaccination. MAbs have the ability to provide an immune response to a specific virus variant that the individual has not been able to generate on their own. The researchers have now discovered that treatment with mAbs comes with a serious trade-off; SARS-CoV-2 mutates in response to the immune-pressure created under mAb-treatment along with host immune responses. This also means that the virus can develop resistance to mAbs – similar to resistance emergence under antibiotic treatments in bacterial infections.
In a clinical trial conducted at the University of Verona, led by Prof. Evelina Tacconelli, Director of the Infectious Diseases section and Coordinator of ORCHESTRA, biological samples were collected from high-risk patients with COVID-19 who were treated with different mAbs. Viral variant analysis performed at the Laboratory of Medical Microbiology, University of Antwerp, led by Prof. Surbhi Malhotra, showed that approximately 8% of mAb-treated patients developed evasive SARS-CoV-2 spike mutations with remarkable speed and high specificity for the targeted mAb binding sites. While most patients cleared the virus over time, immunocompromised patients had significantly higher viral loads for prolonged periods and had 3-fold higher chance to develop SARS-CoV-2 escape mutations.
The authors further developed an index that can predict patients at high risk of developing escape mutations to therapeutic mAbs with >96% accuracy using a combination of circulating immune and growth factors-related biomarkers (CIB) measured in the blood at first contact with the patient before mAb treatment.
“It was intriguing to see that not only the mAb neutralising capacity and host immunity, but also host-healing responses played a crucial role in development of SARS-CoV-2 escape mutants”, says
lead author of the study Prof. Samir Kumar-Singh, Director of Molecular Pathology Group, Laboratory of Cell Biology and Histology, University of Antwerp, who supervised the host response studies.
The CIB-index that the authors identified could help with point-of-care decision to reduce the risk of mAb treatment failure and allow patients to receive other treatment options such as antiviral treatments or convalescent plasma. Even if patients have already received mAb therapy, knowledge of this CIB index can still improve mitigation strategies to avoid possible spread of SARS-CoV-2 escape mutants, especially to individuals at high-risk in the same clinical or close contact setting.
“The study provides innovative data to select high risk patients for early treatment. We believe this will reduce not only COVID-19 mortality but also Long COVID”, says Prof. Evelina Tacconelli.
Coordinated by Prof. Evelina Tacconelli and her team from the University of Verona, ORCHESTRA (ORCHESTRA - EU Horizon 2020 cohort to tackle COVID-19 internationally (orchestra-cohort.eu)), is financed by the HORIZON 2020 programme, the EU research and innovation initiative, and started in December 2020 with the goal to create a clear understanding of the clinical expression of the SARS-CoV-2-Pandemic and to deliver recommendations for future health crises. 37 partners from 15 countries have established a research infrastructure to collaborate according to defined common standards. Research objectives include identifying predictors of COVID-19 presentation, sequelae by virus variants and immunity function status, markers of disease severity, vaccination efficacy and long-term consequences of the disease.