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Declining levels of maternal antibodies were shown to sensitize infants born to dengue immune mothers to severe disease during primary infection, through the process of antibody-dependent enhancement of infection (ADE). With the recent approval for human use of Sanofi-Pasteur’s chimeric dengue vaccine CYD-TDV and several vaccine candidates in clinical development, the scenario of infants born to vaccinated mothers has become a reality. This raises two questions: will declining levels of maternal vaccine-induced antibodies will cause ADE? and, will maternal antibodies interfere with vaccination efficacy in the infant? To address these questions, the above scenario was modelled in mice. Type I interferon-deficient female mice were immunized with live attenuated DENV2 PDK53, the core component of tetravalent DENVax candidate currently under clinical development. Pups born to PDK53-immunized dams acquired maternal antibodies that strongly neutralized parental strain 16681, but not the heterologous DENV2 strain D2Y98P-PP1, and instead caused ADE during primary infection with this strain. Furthermore, pups failed to seroconvert after PDK53 vaccination owing to maternal antibody interference. However, a cross-protective multifunctional CD8+ T cell response did develop. Thus, our work advocates for the development of dengue vaccine candidates that induce protective CD8+ T cells despite the presence of enhancing, interfering maternal antibodies.

This work has been accepted for publication in JCI Insights.

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