Flaviviruses cause a spectrum of potentially severe diseases. Most flaviviruses are transmitted by mosquitoes or ticks and are widely distributed all over the world. Among them, several mosquito-borne flaviviruses are co-epidemic, and the similarity of their antigenicity creates abundant cross-reactive immune responses which complicate their prevention and control. At present, only effective vaccines against yellow fever and Japanese encephalitis have been used clinically, while the optimal vaccines against other flavivirus diseases are still under development. The antibody-dependent enhancement generated by cross-reactive immune responses against different serotypes of dengue virus makes the development of the dengue fever vaccine a bottleneck. It has been proposed that the cross-reactive immunity elicited by prior infection of mosquito-borne flavivirus could also affect the outcome of the subsequent infection of heterologous flavivirus. In this review, we focused on five medically important flaviviruses, and rearranged and recapitulated their cross-reactive immunity in detail from the perspectives of serological experiments in vitro, animal experiments in vivo, and human cohort studies. We look forward to providing references and new insights for the research of flavivirus vaccines and specific prevention.
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