Role of quaternary epitopes in eliciting broad neutralization response against multiple flaviviruses

Flaviviruses, or orthoflaviviruses, are arthropod-borne RNA viruses that pose a significant global health threat and co-circulate in many regions across the world. Neutralizing antibodies against specific pathogenic flaviviruses, such as dengue virus, Zika virus, and West Nile virus, are well-known. However, vaccine and therapeutic development against many flaviviruses remains challenging due to their antigenic diversity and complex humoral responses. Recent studies have reported patient-derived neutralizing antibodies that are active against multiple flaviviruses. Structural characterization of these pan-flavivirus antibodies has identified quaternary epitopes that are conserved across multiple flaviviruses, emphasizing the importance of quaternary epitopes on native flaviviruses, which, in some cases, are also preserved across different virus morphologies. Understanding the basis of quaternary structural epitope recognition can aid in the design of immunogens that elicit broad protection, with a lower risk of infection enhancement. In this review, we discuss mechanistic insights of bnAbs targeting different quaternary epitopes found on pathogenic flaviviruses, and implications for next-generation pan-flavivirus vaccine strategies.