Vaughn (1) has contributed valuably to enrich an understanding of important phenomena uncovered during our retrospective seroepidemiologic study of the 1997 dengue epidemic in Santiago de Cuba. We were quite unprepared to find that most primary dengue virus type 2 (DEN-2) infections in adults as well as in children were, as Vaughn has put it, “naturally attenuated” (1, p. 801). His commentary has extended our discussion (2) to a more comprehensive search for large virgin-soil DEN-2 and dengue virus type 4 outbreaks. Seldom have these been reported.
Vaughn has identified the alarming implications of naturally attenuated dengue viral strains that produce overt disease in heterotypically immune individuals. What about purposely attenuated viruses? The safety of dengue vaccines must be judged and tested in dengue-immune subjects.
Because population-based studies of dengue infection and disease are rare, it is good to underscore the power of neutralizing antibodies to quantify past dengue infections. As our report (2) and the commentary by Vaughn (1) make clear, studies directed at hospitalized cases can be expected to miss many important attributes of a dengue epidemic. Yet, hospitalized cases have been the principal focus of dengue research during the dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) era. Looking for correlates of “virulence,” many researchers compare the genomic or phenotypic properties of viruses that have been isolated from overt disease that varies in severity. This approach, however, ignores the only available measure of viral virulence, the incidence rate of disease to total infections. For secondary infection dengue, this means the ratio of clinical disease due to a specific viral strain to total secondary dengue infections with that strain. Virulence is recognized when ratios with genotypically or phenotypically distinct viruses are not the same. Just this phenomenon was recognized during the 1980 population-based study in Rayong, Thailand (3). There, the numerous dengue virus type 1 (DEN-1) infections that occurred in children immune to DEN-2 resulted in no cases of DHF/DSS, while as many as 20 percent of the children infected with DEN-1 and then DEN-2 developed DHF/DSS. A similar approach in Iquitos, Peru, in 1995 provided the first hard evidence that the American genotype of DEN-2 lacks virulence, i.e., no DHF/DSS accompanied the thousands of DEN-2 infections in subjects immune to DEN-1 (4). It appears that in 1980 a similar phenomenon was described for DEN-1. To date, appropriate genotyping studies on DEN-1 strains have not been reported. That such data may be difficult to attain should not deter the field from balancing gene sequencing with a greater or equal emphasis on carefully designed seroepidemiologic studies.