Tailored to two targets: Engineering antiviral bispecific antibodies

Viruses pose major global health challenges because of their rapid evolution and potential to spill over into humans. This thesis explores strategies to design novel antibody-based antiviral therapeutics and multivalent vaccines that aim to improve preparedness for future outbreaks and can overcome viral diversity. Focusing on two clinically important viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and hepatitis C virus (HCV), several protein engineering approaches were used to enhance antiviral breadth and potency. Bispecific antibodies were generated by combining distinct neutralizing antibodies into a single molecule, resulting in improved activity against diverse SARS-CoV-2 variants, related sarbecoviruses, and HCV strains. Additionally, a nanoparticle-based vaccine candidate for HCV was developed, which elicited stronger and broader neutralizing antibody responses than conventional immunogens. The studies described in this thesis demonstrate how multivalent design strategies can provide powerful tools to counteract both rapidly emerging viral threats and persistent chronic infections. The findings contribute to the development of next-generation antibody therapeutics and vaccines and highlight the importance of antibody engineering for global pandemic preparedness.