Category: Publications

Sanchez-Vargas LA, Mathew A, Salje H, Sousa D, Casale NA, Farmer A, Buddhari D, Anderson K, Iamsirithaworn S, Kaewhiran S, Friberg H, Currier JR, Rothman AL

J Infect Dis 2024 Nov;230(5):1147-1156

PMID: 38478732

Abstract

BACKGROUND: Dengue virus (DENV) nonstructural protein 1 (NS1) has multiple functions within infected cells, on the cell surface, and in secreted form, and is highly immunogenic. Immunity from previous DENV infections is known to exert both positive and negative effects on subsequent DENV infections, but the contribution of NS1-specific antibodies to these effects is incompletely understood.

METHODS: We investigated the functions of NS1-specific antibodies and their significance in DENV infection. We analyzed plasma samples collected in a prospective cohort study prior to symptomatic or subclinical secondary DENV infection. We measured binding to purified recombinant NS1 protein and to NS1-expressing CEM cells, antibody-mediated natural killer (NK) cell activation by plate-bound NS1 protein, and antibody-dependent cellular cytotoxicity (ADCC) of NS1-expressing target cells.

RESULTS: We found that antibody responses to NS1 were highly serotype cross-reactive and that subjects who experienced subclinical DENV infection had significantly higher antibody responses to NS1 in preinfection plasma than subjects who experienced symptomatic infection. We observed strong positive correlations between antibody binding and NK activation.

CONCLUSIONS: These findings demonstrate the involvement of NS1-specific antibodies in ADCC and provide evidence for a protective effect of NS1-specific antibodies in secondary DENV infection.

Williams RJ, Brintz BJ, Ribeiro Dos Santos G, Huang AT, Buddhari D, Kaewhiran S, Iamsirithaworn S, Rothman AL, Thomas S, Farmer A, Fernandez S, Cummings DAT, Anderson KB, Salje H, Leung DT

Sci Adv 2024 Feb;10(7):eadj9786

PMID: 38363842

Abstract

The differentiation of dengue virus (DENV) infection, a major cause of acute febrile illness in tropical regions, from other etiologies, may help prioritize laboratory testing and limit the inappropriate use of antibiotics. While traditional clinical prediction models focus on individual patient-level parameters, we hypothesize that for infectious diseases, population-level data sources may improve predictive ability. To create a clinical prediction model that integrates patient-extrinsic data for identifying DENV among febrile patients presenting to a hospital in Thailand, we fit random forest classifiers combining clinical data with climate and population-level epidemiologic data. In cross-validation, compared to a parsimonious model with the top clinical predictors, a model with the addition of climate data, reconstructed susceptibility estimates, force of infection estimates, and a recent case clustering metric significantly improved model performance.

Hamins-Puértolas M, Buddhari D, Salje H, Cummings DAT, Fernandez S, Farmer A, Kaewhiran S, Khampaen D, Iamsirithaworn S, Srikiatkhachorn A, Waickman A, Thomas SJ, Rothman AL, Endy T, Rodriguez-Barraquer I, Anderson KB

Nat Microbiol 2024 Jan;9(1):274-283

PMID: 38110699

Abstract

Although it is known that household infections drive the transmission of dengue virus (DENV), it is unclear how household composition and the immune status of inhabitants affect the individual risk of infection. Most population-based studies to date have focused on paediatric cohorts because more severe forms of dengue mainly occur in children, and the role of adults in dengue transmission is understudied. Here we analysed data from a multigenerational cohort study of 470 households, comprising 2,860 individuals, in Kamphaeng Phet, Thailand, to evaluate risk factors for DENV infection. Using a gradient-boosted regression model trained on annual haemagglutination inhibition antibody titre inputs, we identified 1,049 infections, 90% of which were subclinical. By analysing imputed infections, we found that individual antibody titres, household composition and antibody titres of other members in the same household affect an individual’s risk of DENV infection. Those individuals living in households with high average antibody titres, or households with more adults, had a reduced risk of infection. We propose that herd immunity to dengue acts at the household level and may provide insight into the drivers of the recent change in the shifting age distribution of dengue cases in Thailand.

O’Driscoll M, Buddhari D, Huang AT, Waickman A, Kaewhirun S, Iamsirithaworn S, Khampaen D, Farmer A, Fernandez S, Rodriguez-Barraquer I, Srikiatkhachorn A, Thomas S, Endy T, Rothman AL, Anderson K, Cummings DAT, Salje H

Proc Natl Acad Sci U S A 2023 Oct;120(41):e2308221120

PMID: 37774093

Abstract

Infants less than 1 y of age experience high rates of dengue disease in dengue virus (DENV) endemic countries. This burden is commonly attributed to antibody-dependent enhancement (ADE), whereby concentrations of maternally derived DENV antibodies become subneutralizing, and infection-enhancing. Understanding antibody-related mechanisms of enhanced infant dengue disease risk represents a significant challenge due to the dynamic nature of antibodies and their imperfect measurement processes. Further, key uncertainties exist regarding the impact of long-term shifts in birth rates, population-level infection risks, and maternal ages on the DENV immune landscape of newborns and their subsequent risks of severe dengue disease in infancy. Here, we analyze DENV antibody data from two infant cohorts (N = 142 infants with 605 blood draws) and 40 y of infant dengue hospitalization data from Thailand. We use mathematical models to reconstruct maternally derived antibody dynamics, accounting for discretized measurement processes and limits of assay detection. We then explore possible antibody-related mechanisms of enhanced infant dengue disease risk and their ability to reconstruct the observed age distribution of hospitalized infant dengue cases. We find that ADE mechanisms are best able to reconstruct the observed data. Finally, we describe how the shifting epidemiology of dengue in Thailand, combined with declining birth rates, have decreased the absolute risk of infant dengue disease by 88% over a 40-y period while having minimal impact on the mean age of infant hospitalized dengue disease.

Ribeiro Dos Santos G, Buddhari D, Iamsirithaworn S, Khampaen D, Ponlawat A, Fansiri T, Farmer A, Fernandez S, Thomas S, Rodriguez Barraquer I, Srikiatkhachorn A, Huang AT, Cummings DAT, Endy T, Rothman AL, Salje H, Anderson KB

J Infect Dis 2022 Oct;226(8):1348-1356

PMID: 35512137

Abstract

BACKGROUND: Dengue virus (DENV) often circulates endemically. In such settings with high levels of transmission, it remains unclear whether there are risk factors that alter individual infection risk.

METHODS: We tested blood taken from individuals living in multigenerational households in Kamphaeng Phet province, Thailand for DENV antibodies (N = 2364, mean age 31 years). Seropositivity ranged from 45.4% among those 1-5 years old to 99.5% for those >30 years. Using spatially explicit catalytic models, we estimated that 11.8% of the susceptible population gets infected annually.

RESULTS: We found that 37.5% of the variance in seropositivity was explained by unmeasured household-level effects with only 4.2% explained by spatial differences between households. The serostatus of individuals from the same household remained significantly correlated even when separated by up to 15 years in age.

CONCLUSIONS: These findings show that despite highly endemic transmission, persistent differences in infection risk exist across households, the reasons for which remain unclear.