Report of four volunteers with primary, secondary and tertiary dengue infections during a prospective cohort study

A prospective study of dengue fever (DF) and dengue haemorrhagic fever (DHF) in adults was conducted at two factories in Bandung, Indonesia, between August 2000 and July 2004. A total of 2978 employees were followed for the development of fever and clinical signs of DF/DH E Among 1431 patients reporting a febrile illness, dengue infections were detected in 177 individuals. Four enrollees with evidence of previous dengue exposure experienced two consecutive episodes of dengue infection. Analysis of pre-illness sera revealed that one patient had neutralizing antibodies (nAbs) to DENY-1, two had nAbs to DENV-2, and another had nabs to DENV-2, 3 and 4. The individual with pre-illness neutralizing antibodies to DENV-1 experienced a DENV-3 secondary infection, followed by a third infection with an unknown serotype. One of the two individuals with pre-illness neutralizing antibodies to DENY-2 experienced a DENV-3 and then a DENV-1 infection. The other DENV-2 immune patient experienced sequential infections with DENV-4 and DENV-3 viruses. Finally, the individual with pre-illness neutralizing antibodies against three dengue viruses had a subsequent infection with DENV-4, followed one year later by DENY-3. In this instance, the patient acquired grade II DHF (WHO criteria) from the subsequent DENY-4 infection. These data provide confirmatory evidence that humans can experience three sequential heterologous dengue infections. Importantly, the occurrence of a second and third infection in individuals with pre-illness antibodies against multiple dengue serotypes indicates that neutralizing antibodies are cross-reactive in vitro but not cross-protective in vivo.