An Innovative, Prospective, Hybrid Cohort-Cluster Study Design to Characterize Dengue Virus Transmission in Multigenerational Households in Kamphaeng Phet, Thailand

Abstract

Difficulties inherent in the identification of immune correlates of protection or severe disease have challenged the development and evaluation of dengue vaccines. There persist substantial gaps in knowledge about the complex effects of age and sequential dengue virus (DENV) exposures on these correlations. To address these gaps, we were conducting a novel family-based cohort-cluster study for DENV transmission in Kamphaeng Phet, Thailand. The study began in 2015 and is funded until at least 2023. As of May 2019, 2,870 individuals in 485 families were actively enrolled. The families comprise at least 1 child born into the study as a newborn, 1 other child, a parent, and a grandparent. The median age of enrolled participants is 21 years (range 0-93 years). Active surveillance is performed to detect acute dengue illnesses, and annual blood testing identifies subclinical seroconversions. Extended follow-up of this cohort will detect sequential infections and correlate antibody kinetics and sequence of infections with disease outcomes. The central goal of this prospective study is to characterize how different DENV exposure histories within multigenerational family units, from DENV-naive infants to grandparents with multiple prior DENV exposures, affect transmission, disease, and protection at the level of the individual, household, and community.

Keywords: Thailand; dengue virus; pathogenesis; prospective cohort study; transmission.

Figure 1

Flowchart of study activities for a prospective family cohort study in Kamphaeng Phet, Thailand, 2015–2019. DENV, dengue virus; RT-PCR, reverse-transcriptase polymerase chain reaction.

Figure 2

Map of Kamphaeng Phet province, indicating location within Thailand (A) (source: Wikipedia) and the locations of enrolled households (B) (source: Google Earth Pro) for a prospective family cohort study in Kamphaeng Phet, Thailand, 2015–2019. Spatial resolution of the map image is intentionally low, to preclude identification of individual homes.

Figure 3

Age and sex composition of the actively enrolled participants in the study, as of May 2019, for a prospective family cohort study in Kamphaeng Phet, Thailand, 2015–2019. NB, newborn.

Figure 4

Enrollment serostatus of 416 study participants enrolled in 2015, based upon flow-based cytometry testing for neutralizing antibodies to dengue virus (DENV)-1–4 serotypes, Kamphaeng Phet, Thailand, 2015–2019. “Naive" indicates that an individual lacked detectable antibodies to all 4 serotypes (titer: <1:40); “monotypic” indicates a positive titer to a single DENV serotype; “multitypic” indicates a positive titer for ≥2 DENV serotypes.

Figure 5

Results from illness and household investigations, including dengue virus (DENV) serotype and primary/secondary infection status of detected infections, Kamphaeng Phet, Thailand, 2015–2019. Note that 4 reverse-transcriptase polymerase chain reaction (RT-PCR)-positive individuals resided in the same house as other tested-positive individuals; thus, 29 household investigations from 33 cases.

Figure 6

Seroconversion rate (per 100 person-months) according to age group and enrollment cohort, Kamphaeng Phet, Thailand, 2015–2019. Seroconversion was defined as a 4-fold or greater rise in antibody titers to any dengue virus serotype by hemagglutination inhibition (without a higher rise in Japanese encephalitis virus titers) when comparing 2 routinely collected specimens collected, on average, 1 year apart. Error bars represent 95% confidence intervals for estimated rates.

Figure 7

Lessons learned from the Kamphaeng Phet family cohort study for dengue virus (DENV) transmission in households, Thailand, 2015–2019.