Protective and immunological behavior of chimeric yellow fever dengue vaccine

• Children, ages 5 years and younger, given three doses of CYD vaccine were hospitalized five times more frequently with breakthrough dengue virus infections than were placebo controls.
• Children who were seronegative at the time of CYD vaccination were poorly protected against symptomatic dengue virus infection.
• Seronegative children uniformly developed dengue neutralizing antibodies following vaccination.
• Symptomatic dengue virus infections in individuals circulating non-protective dengue antibodies suggests disease in vaccinated young children is antibody enhanced.
• CYD vaccination protected seropositives from disease, mild or severe, when challenged by a wild-type dengue virus.

.Clinical observations from the third year of the Sanofi Pasteur chimeric yellow fever dengue tetravalent vaccine (CYD) trials document both protection and vaccination-enhanced dengue disease among vaccine recipients. Children who were 5 years-old or younger when vaccinated experienced a DENV disease resulting in hospitalization at 5 times the rate of controls. On closer inspection, hospitalized cases among vaccinated seropositives, those at highest risk to hospitalized disease accompanying a dengue virus (DENV) infection, were greatly reduced by vaccination. But, seronegative individuals of all ages after being vaccinated were only modestly protected from mild to moderate disease throughout the entire observation period despite developing neutralizing antibodies at high rates. Applying a simple epidemiological model to the data, vaccinated seronegative individuals of all ages were at increased risk of developing hospitalized disease during a subsequent wild type DENV infection. The etiology of disease in placebo and vaccinated children resulting in hospitalization during a DENV infection, while clinically similar are of different origin. The implications of the observed mixture of DENV protection and enhanced disease in CYD vaccinees are discussed.