Optimizing Humoral Immunity for Durable and Broad Protection in Flavivirus Vaccines.

Flavivirus infections, including dengue, Zika, West Nile, and Japanese encephalitis, remain a major global health concern. Although several vaccines are licensed, the durability and qualitative features of vaccine-induced antibodies differ substantially across platforms, leading to incomplete cross-protection and the risk of antibody-dependent enhancement. Long-term durability is exemplified by YF-17D, which induces protective antibodies that have been detectable for decades, whereas the JE SA14-14-2 vaccine has achieved program-level reductions in disease in endemic regions. In contrast, CYD-TDV shows serostatus-dependent outcomes, and the investigational TAK-003 vaccine has demonstrated antibody persistence for at least four years. Recent studies have clarified how preserving quaternary envelope epitopes, minimizing prM-associated non-neutralizing specificity, and sustaining germinal center activity determine antibody affinity, breadth, and persistence. Advances in adjuvant formulations and delivery platforms have shown that engaging defined innate pathways and prolonging antigen availability enhance affinity maturation and long-lived plasma cell formation. Booster scheduling and baseline serostatus further shape the antibody quality, highlighting the importance of immune imprinting and cross-reactivity in vaccine design. Together, these findings outline the design principles for next-generation flavivirus vaccines, including stabilization of neutralization-sensitive epitopes, use of adjuvants that sustain germinal center responses, optimization of antigen persistence, and tailoring of dosing strategies to immune history to elicit durable and broadly protective humoral immunity.