Article Impact Level: HIGH Data Quality: STRONG Summary of eBioMedicine, 116, 105770. https://doi.org/10.1016/j.ebiom.2025.105770 Dr. Matthias Bruhn et al.
Points
- This study showed that SARS-CoV-2 can develop escape mutations during monoclonal antibody treatment, especially when a single antibody is used, due to rapid viral evolution and somatic hypermutation.
- Researchers found that combining monoclonal antibodies targeting non-overlapping viral sites significantly reduced the emergence of resistant mutations in both in vivo and in vitro models.
- Adding a third, non-neutralizing antibody enhanced immune system engagement through Fc-mediated effects, mimicking natural immune responses and improving overall treatment efficacy.
- These findings support the design of antibody therapies that anticipate viral evolution and leverage diverse immune mechanisms to prevent therapeutic failure.
- The study highlights the importance of using strategic monoclonal antibody combinations to maintain treatment effectiveness and reduce the risk of viral escape in COVID-19 management.
Summary
This study investigated the risk of viral escape mutations during monoclonal antibody (mAb) treatment for SARS-CoV-2 and explored strategies to prevent these mutations, particularly in the context of ongoing viral evolution. Using a hamster model, the researchers treated animals with SARS-CoV-2 neutralizing mAbs and observed breakthrough infections due to viral mutations that emerged in vivo. The team developed an in vitro antibody escape assay, which mimicked the in vivo situation, and identified that somatic hypermutations (SHM) in the virus affected the profile of viral escape hotspots targeted by the mAbs. These findings underscore the rapid emergence of viral variants when a single mAb is used and the importance of SHM in preventing viral escape.
The researchers tested various combinations of mAbs to suppress the emergence of viral mutants. They found that pairing mAbs targeting non-overlapping epitopes significantly reduced the formation of escape variants. Furthermore, adding a third, non-neutralizing mAb to the combination enhanced the Fc-mediated effector functions of the treatment, providing an additive effect. This approach aimed to replicate the natural polyclonal immune response, where multiple antibodies act together to neutralize the virus, reducing the chances of escape. These findings suggest that anticipatory B cell memory could be leveraged to design more effective mAb combinations with a reduced risk of viral escape.
The study emphasizes that combining multiple mAbs is a promising strategy to mitigate the risk of escape mutations and enhance the effectiveness of monoclonal antibody therapies for SARS-CoV-2. The results provide valuable insights for future mAb development and therapy, particularly in managing viral evolution and improving long-term treatment outcomes for COVID-19 patients. These findings are crucial for optimizing mAb use in preventing and treating COVID-19, offering potential strategies to combat viral mutations.
Link to the article: https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(25)00214-2/fulltext
References Bruhn, M., Obara, M., Gonzalez-Hernandez, M., Reineking, W., Salam, A., Mirolo, M., Hinrichs, I., Mergani, A., Bartsch, Y., Schambach, A., Zimmer, G., Baumgärtner, W., Osterhaus, A. D. M. E., & Kalinke, U. (2025). Somatic hypermutation shapes the viral escape profile of SARS-CoV-2 neutralising antibodies. eBioMedicine, 116, 105770. https://doi.org/10.1016/j.ebiom.2025.105770
