Reconstruction of 60 Years of Chikungunya Epidemiology in the Philippines Demonstrates Episodic and Focal Transmission

Salje, Henrik,Cauchemez, Simon,Alera, Maria Theresa,Rodriguez-Barraquer, Isabel,Thaisomboonsuk, Butsaya,Srikiatkhachorn, Anon,Lago, Catherine B.,Villa, Daisy,Klungthong, Chonticha,Tac-An, Ilya A.,Fern Oxford University Press 2016 The Journal of Infectious Diseases Vol.213 No.4

<P>Proper understanding of the long-term epidemiology of chikungunya has been hampered by poor surveillance. Outbreak years are unpredictable and cases often misdiagnosed. Here we analyzed age-specific data from 2 serological studies (from 1973 and 2012) in Cebu, Philippines, to reconstruct both the annual probability of infection and population-level immunity over a 60-year period (1952–2012). We also explored whether seroconversions during 2012–2013 were spatially clustered. Our models identified 4 discrete outbreaks separated by an average delay of 17 years. On average, 23% (95% confidence interval [CI], 16%–37%) of the susceptible population was infected per outbreak, with >50% of the entire population remaining susceptible at any point. Participants who seroconverted during 2012–2013 were clustered at distances of <230 m, suggesting focal transmission. Large-scale outbreaks of chikungunya did not result in sustained multiyear transmission. Nevertheless, we estimate that >350 000 infections were missed by surveillance systems. Serological studies could supplement surveillance to provide important insights on pathogen circulation.</P>

Epidemiology of Infant Dengue Cases Illuminates Serotype-Specificity in the Interaction between Immunity and Disease, and Changes in Transmission Dynamics

Clapham, Hannah,Cummings, Derek A. T.,Nisalak, Ananda,Kalayanarooj, Siripen,Thaisomboonsuk, Butsaya,Klungthong, Chonticha,Fernandez, Stefan,Srikiatkhachorn, Anon,Macareo, Louis R.,Lessler, Justin,Reis Public Library of Science 2015 PLoS neglected tropical diseases Vol.9 No.12

<▼1><P><B>Background</B></P><P>Infants born to dengue immune mothers acquire maternal antibodies to dengue. These antibodies, though initially protective, decline during the first year of life to levels thought to be disease enhancing, before reaching undetectable levels. Infants have long been studied to understand the interaction between infection and disease on an individual level.</P><P><B>Methods/Findings</B></P><P>Considering infants (cases <1 year old) as a unique group, we analyzed serotype specific dengue case data from patients admitted to a pediatric hospital in Bangkok, Thailand. We show differences in the propensity of serotypes to cause disease in individuals with dengue antibodies (infants and post-primary cases) and in individuals without dengue antibodies (primary cases). The mean age of infant cases differed among serotypes, consistent with previously observed differential waning of maternal antibody titers by serotype. We show that trends over time in epidemiology of infant cases are consistent with those observed in the whole population, and therefore with trends in the force of infection.</P><P><B>Conclusions/Significance</B></P><P>Infants with dengue are informative about the interaction between antibody and the dengue serotypes, confirming that in this population DENV-2 and DENV-4 almost exclusively cause disease in the presence of dengue antibody despite infections occurring in others. We also observe differences between the serotypes in the mean age in infant cases, informative about the interaction between waning immunity and disease for the different serotypes in infants. In addition, we show that the mean age of infant cases over time is informative about transmission in the whole population. Therefore, ongoing surveillance for dengue in infants could provide useful insights into dengue epidemiology, particularly after the introduction of a dengue vaccine targeting adults and older children.</P></▼1><▼2><P><B>Author Summary</B></P><P>Infants born to dengue immune mothers acquire maternal dengue antibodies. These antibodies, though initially protective, decline during the first year of life to levels thought to be disease enhancing, before reaching undetectable levels. We show that in this population, DENV-2 and DENV-4 almost exclusively cause disease in the presence of dengue antibody, despite infections occurring in others. We also observe serotype-specificity in the mean age of infant cases, consistent with differential waning of antibody to each serotype. These results highlight serotype-specificity in the way the immune response interacts with infection to cause disease. In addition, we show that the mean age of infant cases over time is informative about transmission in the whole population. Therefore, ongoing surveillance for dengue in infants could provide useful insights into dengue epidemiology, particularly after the introduction of a dengue vaccine targeting adults and older children.</P></▼2>

Reconstruction of antibody dynamics and infection histories to evaluate dengue risk

Salje, Henrik,Cummings, Derek A. T.,Rodriguez-Barraquer, Isabel,Katzelnick, Leah C.,Lessler, Justin,Klungthong, Chonticha,Thaisomboonsuk, Butsaya,Nisalak, Ananda,Weg, Alden,Ellison, Damon,Macareo, Lou Nature Publishing Group UK 2018 Nature Vol.557 No.7707

<P>As with many pathogens, most dengue infections are subclinical and therefore unobserved(1). Coupled with limited understanding of the dynamic behaviour 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 these change over time, between assay interpretations and with cohort design. Here 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 haemagglutination inhibition assay titre measurements)(2,3). We identify 1,149 infections (95% confidence interval, 1,135-1,163) that were not detected by active surveillance and estimate that 65% of infections are subclinical. After infection, individuals develop a stable set point antibody load after one year that places them within or outside a risk window. Individuals with pre-existing titres of <= 1: 40 develop haemorrhagic fever 7.4 (95% confidence interval, 2.5-8.2) times more often than naive individuals compared to 0.0 times for individuals with titres > 1: 40 (95% confidence interval: 0.0-1.3). Plaque reduction neutralization test titres <= 1: 100 were similarly associated with severe disease. Across the population, variability in the size of epidemics results in large-scale temporal changes in infection and disease risk that correlate poorly with age.</P>

Resolution of a Chikungunya Outbreak in a Prospective Cohort, Cebu, Philippines, 2012–2014

Srikiatkhachorn, Anon,Alera, Maria Theresa,Lago, Catherine B.,Tac-An, Ilya A.,Villa, Daisy,Fernandez, Stefan,Thaisomboonsuk, Butsaya,Klungthong, Chonticha,Levy, Jens W.,Velasco, John Mark,Roque Jr., V U.S. Department of Health and Human Services * Cen 2016 Emerging Infectious Diseases Vol.22 No.10

Dengue Virus (DENV) Neutralizing Antibody Kinetics in Children After Symptomatic Primary and Postprimary DENV Infection

Clapham, Hannah E.,Rodriguez-Barraquer, Isabel,Azman, Andrew S.,Althouse, Benjamin M.,Salje, Henrik,Gibbons, Robert V.,Rothman, Alan L.,Jarman, Richard G.,Nisalak, Ananda,Thaisomboonsuk, Butsaya,Kalay Oxford University Press 2016 The Journal of Infectious Diseases Vol.213 No.9

<P>The immune response to dengue virus (DENV) infection is complex and not fully understood. Using longitudinal data from 181 children with dengue in Thailand who were followed for up to 3 years, we describe neutralizing antibody kinetics following symptomatic DENV infection. We observed that antibody titers varied by serotype, homotypic vs heterotypic responses, and primary versus postprimary infections. The rates of change in antibody titers over time varied between primary and postprimary responses. For primary infections, titers increased from convalescence to 6 months. By comparing homotypic and heterotypic antibody titers, we saw an increase in type specificity from convalescence to 6 months for primary DENV3 infections but not primary DENV1 infections. In postprimary cases, there was a decrease in titers from convalescence up until 6 months after infection. Beginning 1 year after both primary and postprimary infections, there was evidence of increasing antibody titers, with greater increases in children with lower titers, suggesting that antibody titers were boosted due to infection and that higher levels of neutralizing antibody may be more likely to confer a sterilizing immune response. These findings may help to model virus transmission dynamics and provide baseline data to support the development of vaccines and therapeutics.</P>

Incidence of Dengue Virus Infection in Adults and Children in a Prospective Longitudinal Cohort in the Philippines

Alera, Maria Theresa,Srikiatkhachorn, Anon,Velasco, John Mark,Tac-An, Ilya A.,Lago, Catherine B.,Clapham, Hannah E.,Fernandez, Stefan,Levy, Jens W.,Thaisomboonsuk, Butsaya,Klungthong, Chonticha,Macare Public Library of Science 2016 PLoS neglected tropical diseases Vol.10 No.2

<▼1><P><B>Background</B></P><P>The mean age of dengue has been increasing in some but not all countries. We sought to determine the incidence of dengue virus (DENV) infection in adults and children in a prospective cohort study in the Philippines where dengue is hyperendemic.</P><P><B>Methodology/Principal Findings</B></P><P>A prospective cohort of subjects ≥6 months old in Cebu City, Philippines, underwent active community-based surveillance for acute febrile illnesses by weekly contact. Fever history within the prior seven days was evaluated with an acute illness visit followed by 2, 5, and 8-day, and 3-week convalescent visits. Blood was collected at the acute and 3-week visits. Scheduled visits took place at enrolment and 12 months that included blood collections. Acute samples were tested by DENV PCR and acute/convalescent samples by DENV IgM/IgG ELISA to identify symptomatic infections. Enrolment and 12-month samples were tested by DENV hemagglutination inhibition (HAI) assay to identify subclinical infections. Of 1,008 enrolled subjects, 854 completed all study activities at 12 months per-protocol undergoing 868 person-years of surveillance. The incidence of symptomatic and subclinical infections was 1.62 and 7.03 per 100 person-years, respectively. However, in subjects >15 years old, only one symptomatic infection occurred whereas 27 subclinical infections were identified. DENV HAI seroprevalence increased sharply with age with baseline multitypic HAIs associated with fewer symptomatic infections. Using a catalytic model, the historical infection rate among dengue naïve individuals was estimated to be high at 11–22%/year.</P><P><B>Conclusions/Significance</B></P><P>In this hyperendemic area with high seroprevalence of multitypic DENV HAIs in adults, symptomatic dengue rarely occurred in individuals older than 15 years. Our findings demonstrate that dengue is primarily a pediatric disease in areas with high force of infection. However, the average age of dengue could increase if force of infection decreases over time, as is occurring in some hyperendemic countries such as Thailand.</P></▼1><▼2><P><B>Author Summary</B></P><P>The average age of dengue has been increasing in some but not all dengue endemic countries. To investigate the age pattern of dengue in people of all ages ≥6 months old, a prospective community-based cohort study was undertaken in Cebu City, Philippines where dengue virus has been circulating for many decades. Active surveillance for acute fevers was performed, and acute/convalescent blood samples were tested for evidence of symptomatic dengue. Blood was also collected at enrolment and one year later, and tested serologically to identify subclinical infections. Overall, 1.62 symptomatic and 7.03 subclinical infections per 100 person-years of surveillance were detected. Among people older than 15 years, only one symptomatic dengue case occurred while 27 subclinical infections were identified. By analyzing age-specific dengue serology data, the historical infection rate among people with no prior dengue virus infection was found to be high at around 11–22% per year. Our results show that dengue is primarily a childhood disease in endemic settings where the historical infection rate has been high. However, the average age of dengue could increase if the infection rate decreases over time as is happening in some endemic countries like Thailand.</P></▼2>