Vaccine efficacy (VE) estimates are crucial for assessing the suitability of dengue vaccine candidates for public health implementation, but efficacy trials are subject to a known bias to estimate VE toward the null if heterogeneous exposure is not accounted for in the analysis of trial data. In light of many well-characterized sources of heterogeneity in dengue virus (DENV) transmission, our goal was to estimate the potential magnitude of this bias in VE estimates for a hypothetical dengue vaccine. To ensure that we realistically modeled heterogeneous exposure, we simulated city-wide DENV transmission and vaccine trial protocols using an agent-based model calibrated with entomological and epidemiological data from long-term field studies in Iquitos, Peru. By simulating a vaccine with a true VE of 0.8 in 1,000 replicate trials each designed to attain 90% power, we found that conventional methods underestimated VE by as much as 21% due to heterogeneous exposure. Accounting for the number of exposures in the vaccine and placebo arms eliminated this bias completely, and the more realistic option of including a frailty term to model exposure as a random effect reduced this bias partially. We also discovered a distinct bias in VE estimates away from the null due to lower detectability of primary DENV infections among seronegative individuals in the vaccinated group. This difference in detectability resulted from our assumption that primary infections in vaccinees who are seronegative at baseline resemble secondary infections, which experience a shorter window of detectable viremia due to a quicker immune response. This resulted in an artefactual finding that VE estimates for the seronegative group were approximately 1% greater than for the seropositive group. Simulation models of vaccine trials that account for these factors can be used to anticipate the extent of bias in field trials and to aid in their interpretation.

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Biased efficacy estimates in phase-III dengue vaccine trials due to heterogeneous exposure and differential detectability of primary infections across trial arms.

Background: Climate influences dengue ecology by affecting vector dynamics, agent development, and mosquito/human interactions. Although these relationships are known, the impact climate change wil...

Climate and dengue transmission: evidence and implications.

Background
The survival of adult female Aedes mosquitoes is a critical component of their ability to transmit pathogens such as dengue viruses. One of the principal determinants of Aedes survival is temperature, which has been associated with seasonal changes in Aedes populations and limits their geographical distribution. The effects of temperature and other sources of mortality have been studied in the field, often via mark-release-recapture experiments, and under controlled conditions in the laboratory. Survival results differ and reconciling predictions between the two settings has been hindered by variable measurements from different experimental protocols, lack of precision in measuring survival of free-ranging mosquitoes, and uncertainty about the role of age-dependent mortality in the field.

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Modelling adult Aedes aegypti and Aedes albopictus survival at different temperatures in laboratory and field settings

Vector-borne disease is one of the greatest contributors to human mortality and morbidity throughout the tropics. Mosquito-transmitted diseases such as malaria, dengue, yellow fever and filariasis are the main contributors to this burden. Although insecticides have historically been used to try to control vector populations, over the past 15 years, substantial progress has been made in developing alternative vector control strategies ranging from biocontrol methods through to genetic modification of wild insect populations. Here, we review recent advances concerning these strategies and consider the potential impediments to their deployment, including the challenges of obtaining regulatory approval and community acceptance.

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Beyond insecticides: new thinking on an ancient problem

Dengue in a changing climate

Dengue viruses are major contributors to illness and death globally. Here we analyze the extrinsic and intrinsic incubation periods (EIP and IIP), in the mosquito and human, respectively. We identified 146 EIP observations from 8 studies and 204 IIP observations from 35 studies. These data were fitted with censored Bayesian time-to-event models. The best-fitting temperature-dependent EIP model estimated that 95% of EIPs are between 5 and 33 days at 25°C, and 2 and 15 days at 30°C, with means of 15 and 6.5 days, respectively. The mean IIP estimate was 5.9 days, with 95% expected between days 3 and 10. Differences between serotypes were not identified for either incubation period. These incubation period models should be useful in clinical diagnosis, outbreak investigation, prevention and control efforts, and mathematical modeling of dengue virus transmission.

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Miranda Chan

Papers

The Incubation Periods of Dengue Viruses