A tetravalent live
attenuated vaccine composed of chimeras of
yellow fever 17D and the four dengue viruses (chimeric
yellow fever dengue [CYD]) manufactured by Sanofi Pasteur has completed phase III clinical testing in over 35,000 children 2-16 years of age. The
vaccine was recently licensed in four countries. During the first 2 years of observation, CYD
vaccine efficacy ranged between 30% and 79% in 10 different countries with an overall efficacy of 56.8%. During year 3, there was an overall efficacy against hospitalization of 16.7%, but a relative risk of hospitalization of 1.6 among children younger than 9 years and 4.95 in children 5 years of age and younger. Vaccination of seronegative children resulted in universal broad
dengue neutralizing antibody responses, but poor protection against breakthrough
dengue cases. Unless proven otherwise, such breakthrough cases in vaccinated subjects should be regarded as
vaccine antibody-enhanced (ADE). The provenance of these cases can be studied serologically using original antigenic sin immune responses in convalescent sera. In conventional
dengue vaccine efficacy clinical trials, persons vaccinated as seronegatives may be hospitalized with breakthrough ADE
infections, whereas in the placebo group,
dengue infection of monotypic immunes results in hospitalization.
Vaccine efficacy trial design must identify
dengue disease etiology by separately measuring efficacy in seronegatives and seropositives. The reason(s) why CYD
vaccine failed to raise protective dengue virus immunity are unknown. To achieve a safe and protective
dengue vaccine, careful studies of monotypic CYD
vaccines in humans should precede field trials of tetravalent formulations.