Considerations in the Design of Clinical Trials to Test Novel Entomological Approaches to Dengue Control

Abstract

Dengue is the most important arboviral infection of humans. In endemic countries the scale of the dengue disease burden imparts an economic cost [1] and strains fragile health care systems. There are no licensed vaccines for prevention of dengue, and the public health response in endemic countries relies mostly on combating the principal mosquito vector, Aedes aegypti, via insecticides and breeding site removal. The sustained transmission of dengue in endemic settings together with its increasing global footprint indicates existing disease control strategies have been unsuccessful [2]. Novel vector control approaches to limit dengue virus (DENV) transmission include release of Ae. aegypti that carry transgenes that result in highly penetrant, dominant, late-acting, female-specific lethality [3]. In field cage experiments, the release of such mosquitoes in sufficient numbers results in eradication of the mosquito population [4]. Another strategy involves embryonic introduction of the obligate intracellular insect bacterium, Wolbachia, into strains of Ae. aegypti [5]. Strikingly, Wolbachia-infected Ae. aegypti are partially resistant to infection with DENV [6], and by virtue of the intrinsic capacity of some strains of Wolbachia to invade insect populations [6], [7], there is the prospect of achieving widespread biological resistance to DENV amongst Ae. aegypti populations. The life-shortening impact of some Wolbachia strains could also contribute to reductions in disease transmission [5]. The first entomological field trials of mosquitoes infected with Wolbachia (wMel and wMelPop strains) have now been successfully carried out in Cairns, Australia and have demonstrated that Wolbachia can establish itself at very high prevalence in field populations of Ae. aegypti [7]. However, the prospects of demonstrating reduction in DENV transmission in Cairns are slim given the episodic, imported nature of dengue outbreaks in this region. A critical challenge for all entomological approaches to control of vector-borne disease is how best to demonstrate efficacy in reducing disease transmission [8]. In principal, the high force of infection in dengue endemic countries should assist an evidence-gathering approach to this challenge. However, a feature of dengue epidemiology is that it is spatially and temporally heterogeneous [9]–[11]. Thus oscillations in disease incidence over time are common for a given region of transmission, and within each region it is common for focal “hot spots” of transmission to exist [3]. This heterogeneity in transmission means that uncontrolled observational studies of dengue transmission in a community where, for example, Wolbachia-infected Ae. aegypti have been released could take many years or decades to yield evidence that is suggestive of a benefit. Equally, the heterogeneity of dengue transmission poses challenges to traditional clinical trial approaches, as does the non-stationary nature of mosquito populations [8]. Here we review design and statistical considerations relevant to the conduct of clinical trials of these novel interventions and the practical challenges posed by the epidemiology of dengue in endemic settings. Whilst our discussion of trial design is focused on Wolbachia-infected Ae. aegypti, it is also relevant to other vector control interventions, such as genetically engineered male mosquitoes carrying a dominant lethal gene [4], insecticide-impregnated nets [12], or larvacides [13].