Gene drives for schistosomiasis transmission control

Abstract

Schistosomiasis is one of the most important and widespread neglected tropical diseases (NTD), with over 200 million people infected in more than 70 countries; the disease has nearly 800 million people at risk in endemic areas. Although mass drug administration is a cost-effective approach to reduce occurrence, extent, and severity of the disease, it does not provide protection to subsequent reinfection. Interventions that target the parasites' intermediate snail hosts are a crucial part of the integrated strategy required to move toward disease elimination. The recent revolution in gene drive technology naturally leads to questions about whether gene drives could be used to efficiently spread schistosome resistance traits in a population of snails and whether gene drives have the potential to contribute to reduced disease transmission in the long run. Responsible implementation of gene drives will require solutions to complex challenges spanning multiple disciplines, from biology to policy. This Review Article presents collected perspectives from practitioners of global health, genome engineering, epidemiology, and snail/schistosome biology and outlines strategies for responsible gene drive technology development, impact measurements of gene drives for schistosomiasis control, and gene drive governance. Success in this arena is a function of many factors, including gene-editing specificity and efficiency, the level of resistance conferred by the gene drive, how fast gene drives may spread in a metapopulation over a complex landscape, ecological sustainability, social equity, and, ultimately, the reduction of infection prevalence in humans. With combined efforts from across the broad global health community, gene drives for schistosomiasis control could fortify our defenses against this devastating disease in the future.

Fig 1. Traffic light model for the development of an antischistosome gene drive in snails.

Model for the responsive technology development strategy is discussed in this review. At stage 1, research is small scale and takes place in secure laboratories. Data are communicated widely and can lead to further experimentation or, potentially, advancement to stage 2. These controlled field trials incorporate efforts from additional disciplines, including ecological impact modeling and public health, and depend on broad stakeholder engagement. As before, data are broadly disseminated, leading to iteration or potential advancement to stage 3. Regional transmission control depends on the previous alliances as well as coordination with co-occurring public health strategies such as MDA and international strategies by groups such as WHO. MDA, mass drug administration; NGO, nongovernmental organization; WHO, World Health Organization.

Fig 2. Snail gene drive schematic.

A gene drive with the goal of replacing wild populations could be modeled similarly to drives under development in arthropods—given a high enough transmission rate and a low enough fitness cost, a trait can eventually be driven to fixation. However, in hermaphroditic snails like Biomphalaria glabrata and other schistosome-transmitting intermediate hosts, the ability to self-fertilize needs to be taken into account. Most schistosome-transmitting snails can perform both self- and cross-fertilization, but preferences by distinct species or strains have been observed, and these will need to be considered in future modeling and implementation efforts. Potential cross-fertilization between 2 wild-type and 2 modified snails is not shown.

Fig 3. Simulated impact of engineered snail release on worm burden in humans.

Reduction from endemic equilibrium in infection intensity (as measured by per human egg shedding rate, approximately, w_t), prevalence of infection in humans (Ω_t), and effective reproductive number (R_t) of the schistosomes. (A) Percent reduction over 10 years when engineered snails are maintained at 50% frequency (ρ = 0.5) in the population. (B) Percent reduction after maintaining engineered snails at frequency ρ for 10 years.