Katie Tiley: Using models and maps to inform Target Product Profiles and Preferred Product Characteristics: the example of Wolbachia replacement

Dengue incidence has been rising and the WHO Global Vector Control Response 2017 – 2030 reports an annual 96 million cases, 1.9 million DALYs and 9,110 deaths1. Vaccines are only available for yellow fever and are not currently widely used for dengue, though there are other dengue and chikungunya vaccine candidates in clinical trials2,3. There are no drugs available to combat these infections and so there is a reliance on prevention through vector control. Effective control of this vector is difficult to achieve and sustain given the mosquito’s high reproductive rate and adaptation to urban habitats, with an egg stage that can survive desiccation and a larval phase that can develop in small, temporary water volumes (e.g., water containers and roof gutters). The rapid growth of cities has also favoured this mosquito4. As a result, existing vector control tools alone have generally been unable to sustainably control Ae. aegypti or the diseases it transmits over the long term. A range of novel technologies are under development5, including biocontrol through use of Wolbachia spp. for population replacement or reduction/suppression, the release of genetically modified mosquitoes (such as Oxitec's 1st generation self-limiting technology (1gSLT)6), and other forms of sterile insect technique (SIT).

Ae. aegypti mosquitoes infected with Wolbachia strains show reduced rates of virus dissemination, making them less capable of transmitting arboviruses7. Wolbachia infection is also dominantly maternally inherited and leads to inviable progeny when Wolbachia males and wild-type females mate. This means that Wolbachia can be used to either replace the existing mosquito population with a lower competence phenotype by releasing females (or males and females) or suppress the existing population by releasing only males.

Wolbachia population replacement involves regular releases of Wolbachia-infected mosquitoes into a wild mosquito population over a period of several months. Modelling has shown that once a critical proportion of mosquitoes in the population have Wolbachia, prevalence should continue to increase to fixation without further releases, but below this threshold Wolbachia prevalence may decline (possibly to zero) once releases stop due to fitness costs associated with released mosquito strains8. Operationally, the chance and speed of exceeding this threshold and achieving self-sustaining coverage defined as the percentage of Ae. aegpti population infected with Wolbachia, can be achieved by: increasing the number of releases, decreasing the time gap between releases and increasing the ratio of Wolbachia-infected Ae. aegypti in relation to wild-type Ae. aegypti in each release. All of these options increases cost and can also lead to undesirable temporary increases in the Ae. aegypti mosquito population which should be addressed during community engagement to avoid it becoming could be a key barrier to community acceptability9,10. It should be noted that in practice, Wolbachia frequencies may fluctuate seasonally and still decline to zero after reaching fixation depending on environmental variables such as temperature, rainfall, and physical barriers11,12.

A growing range of entomological, epidemiological and modelling evidence supports the widespread, long-term effectiveness of Wolbachia replacement13–15, and research continues to identify environmental conditions associated with spatially and temporally heterogeneous Wolbachia establishment11. This includes a randomised controlled trial (RCT) of wMel Wolbachia in Yogyakarta City, Indonesia which demonstrated a 77% reduction in dengue incidence and an 86% reduction in hospitalizations16. To date, however, Wolbachia replacement programmes have only been conducted in specific mid-sized cities or specific neighbourhoods of cities. Thirteen countries have implemented replacement programmes at various levels of scale, with 12 through the World Mosquito Program (WMP) and an independent programme in Malaysia17,18. Meanwhile, China (with Ae. albopictus), Singapore, and the USA have so far chosen to use suppression-based programs due to perceived greater compatibility with their existing intensive and long-term efforts to suppress mosquito populations19–21.

These novel technologies (Wolbachia replacement, Wolbachia suppression, 1gSLT and SIT) are subjects of ongoing development, evaluation, demonstration and scale-up in various high-burden programmatic and private settings. While not currently practiced, in theory, combining a prior programme of mosquito suppression followed by Wolbachia population replacement could offer community acceptance or dengue incidence reduction advantages9,22.

Development and transition to scale of new products and strategies can be accelerated by the development of internationally recognised Target Product Profiles (TPPs) and Preferred Product Characteristics (PPCs) documents23. TPPs provide specific quantitative guidance on the key characteristics a product must (minimum target), or should ideally (preferred target), meet when developed into a deployable mass market product. PPCs identify broader areas of unmet need and aim to stimulate new products or product combinations that can address these needs. In early 2022 the WHO convened a Technical Advisory Group (TAG) to develop a draft TPP for Wolbachia replacement and a draft PPC for a hybrid mosquito suppression then Wolbachia replacement strategy. The TPP for Wolbachia replacement began with the development of a “use case characterisation”, following which specific TPP criteria were established under the categories of product performance, product characteristics, production and delivery and intellectual property. For each of these, a minimum and preferred target was established with the former intended to inform a go / no go product development decision point. A combination of different types of evidence from the field, laboratory and modelling studies were used to inform these targets, with the modelling work focused on release and cost-related characteristics. The final WHO TPP was published February 202224. 

TAG members decided that a core premise of the TPP and PPC was that they should closely align with the WHO’s strategy and goals to control dengue globally. As such the WHO’s goal to reduce dengue incidence by 25% by 2030 (2010 – 2020 baseline25) provided a basis to understand the scale and range of settings in which these TPPs, PPCs and the products they ultimately produce are relevant. Computational models can play a key role in the development of TPPs and PPCs due to their ability to generalise beyond areas where data have been collected and make predictions if aspects of the product were to change. Here we describe a dynamic compartmental entomological model and a global geospatial economic model that we developed and used to explore how operational and economic aspects of Wolbachia replacement are likely to change once the technology is used at scale.

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