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Vaccine development is limited by antibody\u2010dependent enhancement and a lack of good animal models. Thus, the study investigated cross infection based on maternal immunity in BALB\/c mice and assessed the risk of cross infection by DV2\u2010D13113 and DV3\u2010YNWS2 epidemic virus strains. DV replicated within the organs of the BALB\/c infant mice, even causing death. Particularly, DV3\u2010infected infant mice were at higher risk of severe disease if their mothers were infected with DV2. Although BALB\/c adults and pups survived DV2\/DV3 infection and produced anti\u2010DV antibodies after 5\u20138 days, extensive subcutaneous vascular leakage was observed after secondary DV infection. Furthermore, vascular permeability in the lung and kidney significantly increased in offspring born to heterotypic virus\u2010infected mothers. Thus, vascular leakage indicates severe DV infection. The results indicate that maternal immunity increases the severity of subsequent heterotypic infection. Additionally, secondary cross infection by D13113 and YNWS2 represents a risk of serious disease. 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