DISCUSSION
dengue infections, bleeding, DENV-2 infection, dengue, infections, infection, Active febrile
BLEEDING, DENGUE, THROMBOCYTOPENIA, INFECTIONS, INFECTION, REINFECTION, LEAKAGE
Active febrile surveillance over ∼57 months in this phase 3 efficacy trial enabled the identification of 18 multiple, symptomatic dengue infections. Although this is a small number of cases, the distribution by vaccination group (five in the TAK-003 group versus 13 in the placebo group; 2:1 randomization ratio) provides some evidence of the lower risk of a subsequent symptomatic dengue episode in people who have postvaccination breakthrough cases. This incremental effect of TAK-003 is relevant because people living in dengue-endemic countries are at risk of multiple, sequential dengue infections during their lifetime.In earlier reports from this ongoing trial, we noted a trend of a lower proportion of breakthrough cases in vaccinees presenting with dengue-relevant clinical characteristics compared with the placebo group, such as signs of plasma leakage, thrombocytopenia, or signs of bleeding.Among the 18 sequential episodes, the majority of the cases (i.e., 13 of 18 first episodes and 12 of 18 subsequent episodes) were caused by DENV-1 or -2. This reflects the data in the placebo group over ∼57 months in eight dengue-endemic countries, in which these two serotypes accounted for the majority of dengue cases (423 of 560). This observed serotype distribution pattern also aligns generally with decades of dengue epidemiology globally.Notably, we observed no clear patterns in causative serotype of sequential episodes, but we did record two cases of homotypic reinfection. The first case was a DENV-3 infection in a baseline seropositive participant who most likely had at least one DENV-2 infection prior to enrollment in the trial, based on the baseline neutralizing titers (DENV-1, 105; DENV-2, 4,374; DENV-3, 146; and DENV-4, 330), although this was not confirmed. This observation is particularly interesting because TAK-003 vaccination did not show efficacy against DENV-3 in baseline seronegative participants.The majority of dengue infections tend to be asymptomatic