Neutralization of Dengue Virus Serotypes by Sera from Dengue-Infected Individuals Is Preferentially Directed to Heterologous Serotypes and Not against the Autologous Serotype Present in Acute Infection

Sequential infections of humans by the four different dengue serotypes (DENV-1-4) lead to neutralizing antibodies with group, cross, and type specificity. Virus neutralization of serotypes showed monotypic but mostly multitypic neutralization profiles due to multiple virus exposures. We have studied neutralization to heterologous, reference DENV serotypes using paired sera collected between days 6 and 37 after onset of fever. The DENV-primed neutralization profile of the first serum sample, which was monitored by a foci reduction neutralization test (FRNT), was boosted but the neutralization profile stayed unchanged in the second serum sample. In 45 of 47 paired serum samples, the predominant neutralization was directed against DENV serotypes distinct from the infecting serotype. Homologous neutralization studies using sera and viruses from the same area, 33 secondary sera from DENV-1 infected Cambodian patients and eight virus isolates from Cambodia, showed that the FRNT assay accurately predicted the lack of a predominant antibody response against the infecting DENV-1 serotype in contrast to FRNT results using the WHO set of DENV viruses. This report provides evidence that DENV-primed multitypic neutralizing antibody profiles were mainly boosted and stayed unchanged after secondary infection and that DENV neutralization was predominantly directed to heterologous DENV but not against the infecting homologous serotype.