Dengue diversity across spatial and temporal scales: Local structure and the effect of host population size

Salje, Henrik,Lessler, Justin,Maljkovic Berry, Irina,Melendrez, Melanie C.,Endy, Timothy,Kalayanarooj, Siripen,A-Nuegoonpipat, Atchareeya,Chanama, Sumalee,Sangkijporn, Somchai,Klungthong, Chonticha,Th American Association for the Advancement of Scienc 2017 Science Vol.355 No.6331

<P>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 the mechanisms by which 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 spatiotemporal structure of endemic transmission. Using geolocated genotype (800 cases) and serotype (17,291 cases) data, we show that in Bangkok, Thailand, 60% of dengue cases living <200 meters apart come from the same transmission chain, as opposed to 3% of cases separated by 1 to 5 kilometers. At distances <200 meters from a case (encompassing an average of 1300 people in Bangkok), the effective number of chains is 1.7. This number rises by a factor of 7 for each 10-fold increase in the population of the 'enclosed' region. This trend is observed regardless of whether population density or area increases, though increases in density over 7000 people per square kilometer 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.</P>

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>

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>

Protection against cholera from killed whole-cell oral cholera vaccines: a systematic review and meta-analysis

Bi, Qifang,Ferreras, Eva,Pezzoli, Lorenzo,Legros, Dominique,Ivers, Louise C,Date, Kashmira,Qadri, Firdausi,Digilio, Laura,Sack, David A,Ali, Mohammad,Lessler, Justin,Luquero, Francisco J,Azman, Andrew Elsevier Science ;, The Lancet Pub. Group 2017 LANCET INFECTIOUS DISEASES Vol.17 No.10

<P><B>Summary</B></P><P><B>Background</B></P><P>Killed whole-cell oral cholera vaccines (kOCVs) are becoming a standard cholera control and prevention tool. However, vaccine efficacy and direct effectiveness estimates have varied, with differences in study design, location, follow-up duration, and vaccine composition posing challenges for public health decision making. We did a systematic review and meta-analysis to generate average estimates of kOCV efficacy and direct effectiveness from the available literature.</P><P><B>Methods</B></P><P>For this systematic review and meta-analysis, we searched PubMed, Embase, Scopus, and the Cochrane Review Library on July 9, 2016, and ISI Web of Science on July 11, 2016, for randomised controlled trials and observational studies that reported estimates of direct protection against medically attended confirmed cholera conferred by kOCVs. We included studies published on any date in English, Spanish, French, or Chinese. We extracted from the published reports the primary efficacy and effectiveness estimates from each study and also estimates according to number of vaccine doses, duration, and age group. The main study outcome was average efficacy and direct effectiveness of two kOCV doses, which we estimated with random-effect models. This study is registered with PROSPERO, number CRD42016048232.</P><P><B>Findings</B></P><P>Seven trials (with 695 patients with cholera) and six observational studies (217 patients with cholera) met the inclusion criteria, with an average two-dose efficacy of 58% (95% CI 42–69, <I>I</I><SUP>2</SUP>=58%) and effectiveness of 76% (62–85, <I>I</I><SUP>2</SUP>=0). Average two-dose efficacy in children younger than 5 years (30% [95% CI 15–42], <I>I</I><SUP>2</SUP>=0%) was lower than in those 5 years or older (64% [58–70], <I>I</I><SUP>2</SUP>=0%; p<0·0001). Two-dose efficacy estimates of kOCV were similar during the first 2 years after vaccination, with estimates of 56% (95% CI 42–66, <I>I</I><SUP>2</SUP>=45%) in the first year and 59% (49–67, <I>I</I><SUP>2</SUP>=0) in the second year. The efficacy reduced to 39% (13 to 57, <I>I</I><SUP>2</SUP>=48%) in the third year, and 26% (−46 to 63, <I>I</I><SUP>2</SUP>=74%) in the fourth year.</P><P><B>Interpretation</B></P><P>Two kOCV doses provide protection against cholera for at least 3 years. One kOCV dose provides at least short-term protection, which has important implications for outbreak management. kOCVs are effective tools for cholera control.</P><P><B>Funding</B></P><P>The Bill & Melinda Gates Foundation.</P>