PROACTIVE generated results that go beyond the current state of the art in coronavirus immunology and antibody discovery. While most existing therapeutic monoclonal antibodies (mAbs) and vaccine approaches target immunodominant and highly variable regions of the SARS-CoV-2 spike protein, PROACTIVE successfully identified a class of human monoclonal antibodies recognizing conserved, subdominant epitopes shared across sarbecoviruses. These epitopes are under lower selective pressure and therefore represent more stable and durable targets for both therapy and prevention.
By exploiting rare immune repertoires derived from SARS-CoV-1 survivors subsequently exposed to SARS-CoV-2 antigens, as well as from individuals with hybrid and super-hybrid immunity, the project demonstrated that broad neutralization breadth can be naturally achieved in humans and systematically isolated. The identified antibodies exhibit very high potency and neutralize all tested SARS-CoV-2 variants as well as SARS-CoV-1, a level of breadth that is not achieved by currently approved mAb therapies.
Beyond antibody discovery, the generation of large, high-quality datasets linking antibody sequence, germline usage, functional breadth, and immune history provides an unprecedented resource to understand how repeated heterologous antigenic exposures shape the human immune repertoire. These results open the way to rational, data-driven design of antibody cocktails and vaccine antigens targeting conserved coronavirus vulnerabilities, thereby advancing pandemic preparedness strategies beyond variant-reactive approaches toward truly proactive and mutation-resistant interventions.
