As with many pathogens, most dengue infections are subclinical and therefore unobserved1. Coupled with limited understanding of the dynamical behavior of potential serological markers of infection, this observational problem has wide-ranging implications, including hampering our understanding of individual- and population-level correlates of infection and disease risk and how they change over time, assay interpretation and cohort design. We develop a framework that simultaneously characterizes antibody dynamics and identifies subclinical infections via Bayesian augmentation from detailed cohort data (3,451 individuals with blood draws every 91 days, 143,548 hemagglutination inhibition assay titer measurements)2,3. We identify 1,149 infections (95% CI: 1,135–1,163) that were not detected by active surveillance and estimate that 65% of infections are subclinical. Post infection, individuals develop a stable setpoint antibody load after 1y that places them within or outside a risk window. Individuals with pre-existing titers of ≤1:40 develop hemorrhagic fever 7.4 (95% CI: 2.5–8.2) times as often as naïve individuals compared to 0.0 times for individuals with titers >1:40 (95% CI: 0.0–1.3). PRNT titers ≤1:100 were similarly associated with severe disease. Across the population, variability in the force of infection results in large-scale temporal changes in infection and disease risk that correlate poorly with age.

The evolution of dengue virus (DENV) is characterized by phylogenetic trees that have a strong temporal structure punctuated by dramatic changes in clade frequency. To determine the cause of these large-scale phylogenetic patterns, we examined the evolutionary history of DENV serotype 1 (DENV-1) and DENV-3 in Thailand, where gene sequence and epidemiological data are relatively abundant over a 30-year period. We found evidence for the turnover of viral clades in both serotypes, most notably in DENV-1, where a major clade replacement event took place in genotype I during the mid-1990s. Further, when this clade replacement event was placed in the context of changes in serotype prevalence in Thailand, a striking pattern emerged; an increase in DENV-1 clade diversity was associated with an increase in the abundance of this serotype and a concomitant decrease in DENV-4 prevalence, while clade replacement was associated with a decline in DENV-1 prevalence and a rise of DENV-4. We postulate that intraserotypic genetic diversification proceeds at times of relative serotype abundance and that replacement events can result from differential susceptibility to crossreactive immune responses.Dengue is one of the most important reemerging viral diseases, promulgated by increases in human population size and the expansion of global travel networks (10), coupled with the possibility that global climatic changes alter the distribution of the mosquito vector (11,14). Although most cases of dengue virus (DENV) infection are subclinical or cause a febrile illness that is rarely fatal (dengue fever [DF]), increasingly large numbers of patients experience the more severe form of the illness, dengue hemorrhagic fever (DHF), associated with plasma leakage and hemorrhage. With a tendency to progress into fatal shock (dengue shock syndrome), case fatality rates of DHF/dengue shock syndrome vary from 1 to 5% (42). DENV is transmitted among humans primarily by the peridomestic mosquito species Aedes aegypti, although a transmission cycle involving sylvatic Aedes species and nonhuman primates has been described in parts of Africa and Asia (8,21,29). Genetically, DENV is a single-stranded, positive-sense RNA virus with a genome of approximately 11 kb that encodes 10 proteins translated as a single open reading frame and classified within the Flaviviridae. It is subdivided into four serotypes, denoted DENV-1 to DENV-4, that now cocirculate in many parts of the tropical and subtropical world. Importantly, there is growing epidemiological evidence that synergistic host interactions in response to these serotypes following sequential infection, vis-à-vis "antibody-dependent enhancement," are instrumental in the pathophysiology of DHF (16, 34). As such, the study of epidemiological dynamics in populations in which DENV serotypes cocirculate is of special significance.In recent years, there has been considerable interest in describing the genetic structures of DENV populations and determining their underlying evolutionary processes (13,27). These ...

Zika virus (ZIKV) is an emerging mosquito-borne pathogen with reported cases in Africa, Asia, and large outbreaks in the Pacific. No autochthonous ZIKV infections have been confirmed in Thailand. However, there have been several cases reported in travelers returning from Thailand. Here we report seven cases of acute ZIKV infection in Thai residents across the country confirmed by molecular or serological testing including sequence data. These endemic cases, combined with previous reports in travelers, provide evidence that ZIKV is widespread throughout Thailand.

A fundamental mystery for dengue and other infectious pathogens is how observed patterns of cases relate to actual chains of individual transmission events. These pathways are intimately tied to how strains interact and compete across spatial scales. Phylogeographic methods have been used to characterize pathogen dispersal at global and regional scales, but have yielded few insights into the local spatio-temporal structure of endemic transmission. Using geolocated genotype (N=800) and serotype (N=17,291) data, we show that in Bangkok, Thailand, 60% of cases living <200m apart come from the same transmission chain, versus 3% of cases separated by 1–5km. At distances <200m from a case (enclosing an average of 1,300 people in Bangkok) the effective number of chains is 1.7. This increases by 7-fold for each 10-fold increase in enclosed population, whether due to density or increased area; though increases in density over 7,000 people per km2 do not lead to additional chains. Within Thailand these chains quickly mix, and by the next dengue season viral lineages are no longer highly spatially structured within the country. In contrast, viral flow to neighboring countries is limited. These findings are consistent with local, density dependent transmission; and implicate densely populated communities as key sources of viral diversity with home location the focal point of transmission. These findings have important implications for targeted vector control and active surveillance.

BackgroundChikungunya virus (CHIKV) is a globally re-emerging arbovirus for which previous studies have indicated the majority of infections result in symptomatic febrile illness. We sought to characterize the proportion of subclinical and symptomatic CHIKV infections in a prospective cohort study in a country with known CHIKV circulation.Methods/FindingsA prospective longitudinal cohort of subjects ≥6 months old underwent community-based active surveillance for acute febrile illness in Cebu City, Philippines from 2012-13. Subjects with fever history were clinically evaluated at acute, 2, 5, and 8 day visits, and at a 3-week convalescent visit. Blood was collected at the acute and 3-week convalescent visits. Symptomatic CHIKV infections were identified by positive CHIKV PCR in acute blood samples and/or CHIKV IgM/IgG ELISA seroconversion in paired acute/convalescent samples. Enrollment and 12-month blood samples underwent plaque reduction neutralization test (PRNT) using CHIKV attenuated strain 181/clone25. Subclinical CHIKV infections were identified by ≥8-fold rise from a baseline enrollment PRNT titer <10 without symptomatic infection detected during the intervening surveillance period. Selected CHIKV PCR-positive samples underwent viral isolation and envelope protein-1 gene sequencing. Of 853 subjects who completed all study procedures at 12 months, 19 symptomatic infections (2.19 per 100 person-years) and 87 subclinical infections (10.03 per 100 person-years) occurred. The ratio of subclinical-to-symptomatic infections was 4.6:1 varying with age from 2:1 in 6 month-5 year olds to 12:1 in those >50 years old. Baseline CHIKV PRNT titer ≥10 was associated with 100% (95%CI: 46.1, 100.0) protection from symptomatic CHIKV infection. Phylogenetic analysis demonstrated Asian genotype closely related to strains from Asia and the Caribbean.ConclusionsSubclinical infections accounted for a majority of total CHIKV infections. A positive baseline CHIKV PRNT titer was associated with protection from symptomatic CHIKV infection. These findings have implications for assessing disease burden, understanding virus transmission, and supporting vaccine development.