Although neither sex nor age were significantly associated with disease outcome in any model for DENV-3, we ran a paired case-control analysis, matching on these variables. a 4-fold rise in IgM titer between acute and convalescent samples (18%). Although symptomatic illness was more common with naive or monotypic serostatus than with multitypic serostatus (Table ?(Table2),2), the latter accounted for 45% of all detected cases of disease due to DENV-4. Overall, the ratio of apparent to inapparent DENV-4 infections was 1:9. Estimates of Disease Risk In a multivariable model, contamination history and Lck Inhibitor participant age were significantly associated with risk of disease due to DENV-4 contamination (Table ?(Table33 and Supplementary Tables 1 and 2). Monotypic DENV-1 antibodies were associated with reduced odds of disease, whereas monotypic DENV-2 or DENV-3 antibodies were not (Table ?(Table3).3). Disease risk was significantly reduced for individuals with multitypic serostatus (OR, 0.22; 95% CI, .13C.38), with additional protective effects beyond that of DENV-1 antibodies alone (= .0069 by the Lck Inhibitor Wald test). Disease risk appeared to vary nonlinearly with age (Physique ?(Figure2),2), with the highest risk between 25 and 30 years of age. As with DENV-3, when city block was included as a random effect, no impact on the relationship between age, serostatus, and disease was observed. Matched-pairs case-control analysis also showed that the presence of antibodies to 2 DENV serotypes was associated with reduced disease, independent of age and sex (OR, 0.2; 95% CI, .086C.41). Open in a separate window Physique 2. Predicted risk of disease due to contamination with dengue computer virus serotype 4 (DENV-4), as a function of age and serostatus. Naive and monotypic exposures were combined because they were statistically indistinguishable ( .05). Curves were estimated from the best fit model (Table 3) and plotted with standard error of the mean. DISCUSSION Disease in Iquitos was significantly reduced among individuals with postsecondary DENV-3 and DENV-4 infections. Relative to average disease rates during primary and secondary infections, the incidence among postsecondary infections was reduced by 93% for DENV-3 Lck Inhibitor and 64% for DENV-4, even though contamination rates were not reduced among people with prior exposures to DENV. To our knowledge, this is the first population-based evidence quantifying a cumulative protective effect of heterologous DENV neutralizing antibodies against disease, which has been hypothesized for 40 years . Previous studies investigating cross-protection in sequential infections have provided evidence for a short period of protection against classic dengue fever  and long-term protection against severe disease in third and fourth infections . Although we did not attempt to estimate a short-term effect and we did not observe any cases of severe dengue, we were able to show that the effect of heterologous antibody was cumulative, resulting in a reduced incidence of disease during postsecondary contamination with DENV-3 or DENV-4. Cross-protection was not uniform across serotypes. People with DENV-1 neutralizing antibodies were less likely to develop disease, pointing to an epidemiologically important role of the sequence of infecting serotypes in determining clinical outcome [9, 29, 38C40]. This obtaining, however, is usually discordant Rabbit Polyclonal to SLC6A15 with the observation made in Cuba that infections with DENV-3 were more pathogenic in the presence of preexisting DENV-1 antibody than with DENV-2 antibody , which underscores the need to exercise caution in generalizing epidemiological observations between different populations. Previously, cross-reactive DENV-1 antibodies were hypothesized to protect against severe disease during secondary contamination with American genotype DENV-2 . Together, these data indicate that, in the context of the study populace in Iquitos, DENV-1 antibodies may be broadly cross-protective but that antibodies to American DENV-2 and genotype III of DENV-3 are not, although they do contribute to a cumulative effect of reduced disease. In contrast to reduced rates of Lck Inhibitor disease, contamination rates were higher among people with neutralizing antibody to 2 DENV serotypes. Studies in Cuba of 1981 and 1997 dengue epidemics also found higher contamination rates in individuals with prior DENV exposure [42, 43], which the authors hypothesized was due to household-level heterogeneities in mosquito populations. In Iquitos, we have observed consistent spatial variation in populace densities  that correlates well with patterns of seroprevalence on broad spatial scales [19, 30] and supports the premise that seroconversion rates are attributable at least in part to variation in individual exposure to mosquito bites..