Counteracting Influenza Virus Evolution Through the Full Spectrum of Broadly Protective Antibodies

Despite the presence of licensed vaccines and therapeutics, influenza viruses remain a major public health concern, as they cause seasonal respiratory infections and pose a pandemic threat through the emergence of zoonotic strains. Although neutralizing antibodies elicited by seasonal vaccination constitute a primary defense against infection, their protective capacity is often limited because they frequently target the epitopes that are highly susceptible to structural changes through viral evolution. To overcome this challenge, broadly protective antibodies have been intensively investigated in both humans and animal models. These antibodies recognize conserved epitopes and confer protection through multiple mechanisms beyond conventional neutralization. Recent advances in antibody discovery technologies and structural biology have enabled high-resolution mapping of conserved epitopes and the on-target antibodies that bind them. Furthermore, although broadly protective antibodies are typically elicited only at low frequencies following standard vaccination, several settings have been reported in which their induction is enhanced. Those findings increase the feasibility of epitope-focused vaccine strategies for enhancing the breadth and durability of antibody responses. In this review, we summarize current knowledge of broadly protective flu antibodies and discuss how mechanistic and structural insights can guide the development of next-generation influenza vaccines that offer broad-spectrum protection against antigenically diverse viruses.