Target Product Profiles for Mosquito Gene Drives: Incorporating Insights From Mathematical Models

Abstract

Mosquito-borne diseases such as malaria continue to pose a major global health burden, and the impact of currently-available interventions is stagnating. Consequently, there is interest in novel tools to control these diseases, including gene drive-modified mosquitoes. As these tools continue to be refined, decisions on whether to implement them in the field depend on their alignment with target product profiles (TPPs) that define product characteristics required to achieve desired entomological and epidemiological outcomes. TPPs are increasingly being used for malaria and vector control interventions, such as attractive targeted sugar baits and long-acting injectable drugs, as they progress through the development pipeline. For mosquito gene drive products, reliable predictions from mathematical models are an essential part of these analyses, as field releases could potentially be irreversible. Here, we review the prior use of mathematical models in developing TPPs for malaria and vector control tools and discuss lessons from these analyses that may apply to mosquito gene drives. We recommend that, as gene drive technology gets closer to field release, discussions regarding target outcomes engage a wide range of stakeholders and account for settings of interest and vector species present. Given the relatively large number of parameters that describe gene drive products, machine learning approaches may be useful to explore parameter space, and an emphasis on conservative fitness estimates is advisable, given the difficulty of accurately measuring these parameters prior to field studies. Modeling may also help to inform the risk, remediation and cost dimensions of mosquito gene drive TPPs.

Manipulating the Destiny of Wild Populations Using CRISPR

“…Regulatory approval for environmental releases will depend on demonstrations of safety and efficacy, both of which require modeling to extrapolate knowledge of molecular mechanisms to the population level. To address efficacy, modeling can inform target product profiles (TPPs) that determine parameter value ranges for which a product is likely to have its desired impact (119,162), and, to address safety, some questions in an environmental risk assessment will be suited to modeling analyses, for example, the risk of releasing an only transiently successful genetic biocontrol system that would reduce malaria immunity in the human population and result in increased susceptibility and incidence upon technology failure (60,114). Models can also inform the design of field trials and interventions (140,169), requirements of monitoring efforts to assess gene drive establishment and persistence, and requirements of surveillance programs to detect either unintended spread of gene drive alleles beyond a trial site or drive-resistant alleles within a trial site (187).…”

MGDrivE 3: A decoupled vector-human framework for epidemiological simulation of mosquito genetic control tools and their surveillance

“…We are continuing development of the MGDrivE 3 software package and welcome suggestions and requests from the research community regarding future directions. As gene drive mosquito projects advance from the lab to the field, we intend our software to address the evolving modeling needs of the technology [42] - from contributing to TPPs [4] and environmental risk assessments [43], to planning field trials, interventions [6, 7] and surveillance programs [14]. The epidemiological extensions offered in MGDrivE 3 will enable more accurate predictions of implications of mosquito genetic control for disease transmission, which are relevant as an outcome for TPPs, and field trial and intervention planning.…”

“…gambiae [3]. As the prospect of environmental releases of constructs like these nears, there is a need for increasingly detailed mathematical models to predict the spread of genes through populations, as well as their epidemiological and biosafety implications [4].…”

“…Meanwhile, detailed models of malaria transmission have been developed by several groups [10][11][12] incorporating symptomatic and asymptomatic infection, variable parasite density in humans, age structure, mosquito biting heterogeneity, and interventions such as vector control utilizing long-lasting insecticide-treated nets (LLINs) and indoor residual spraying with insecticides (IRS), and antimalarial drug therapy. Incorporating this level of epidemiological detail into mosquito genetic control models would be of great utility considering that genetic control tools will likely be implemented alongside other interventions, expected epidemiological impacts should be a focus in developing these products [4], and initial field trials are expected to have a measured entomological outcome alongside a modeled epidemiological one [13].…”

Dual effector population modification gene-drive strains of the African malaria mosquitoes, Anopheles gambiae and Anopheles coluzzii

“…Furthermore, an expert panel recommended a reduction of 20 to 50% in human incidence as the minimally acceptable target for a population modification strain to be eligible for field testing ( 35 ). These thresholds are not likely to be related linearly to epidemiological impacts, and with the difficulty of testing them in human challenge trials, modeling should provide a practical alternative ( 36 ). The laboratory analyses and modeling done here support the further development of TP13-based strains for population modification as part of a comprehensive malaria control strategy.…”