Harnessing conserved epitopes and multivalent antigen strategies for vaccine design: Lessons learned and opportunities

Vaccination remains a cornerstone of global disease prevention, yet outcomes differ markedly across pathogens. For antigenically stable viruses such as hepatitis B virus (HBV), vaccines have achieved durable, cross-genotype protection and have substantially reduced disease burden worldwide. In contrast, extensive antigenic diversity in other pathogens enables immune escape, narrows protective responses, and complicates the development of broadly effective vaccines. Lessons from HBV suggest that targeting conserved, immunodominant antigens can underpin durable immunity. It has, however, proven difficult to translate this to highly variable pathogens. Conserved epitopes are often structurally masked or immunologically subdominant, limiting their ability to elicit robust protective responses. In addition, determinants that govern whether conserved epitope responses translate into durable protection remain poorly understood. This narrative review examines current progress, challenges, and opportunities and highlights how conserved epitopes and multivalent vaccine strategies can inform the next generation of broadly protective vaccines against antigenically diverse pathogens.