Defining design rules for next-generation snakebite antivenoms

Snakebite is a neglected tropical disease which causes over 100,000 deaths and 400,000 cases of disability each year. Snakebite is treated using antivenoms, which are currently produced by hyper-immunising horses against a venom and harvesting their toxin-neutralising antibodies. There is an urgent need to improve the way that we design and produce antivenoms, owing to limitations in their cost, efficacy, and safety. In recent years, in vitro antibody selection has made new antivenom scaffolds accessible for researchers. There is currently no consensus as to the pharmacokinetic properties of an optimised antivenom, and whether these change depending on the type of venom being treated. To address this question computationally, we built a compartmental model of snakebite envenomation and treatment. The model tracks the movement of venom, antivenom, and neutralised venom through blood and tissue. The model was parameterised with experimental data from rabbits. It enables user-control of several treatment scenario parameters and antivenom design parameters (antivenom size, dose, affinity, and valency). We have applied our model to explore the impact of different antivenom design features on treatment outcome. We simulated treatment of two model venoms with a set of theoretical antivenoms, across a range of treatment time delays. Global parameter optimisation and global sensitivity analysis show kon to primarily mediate treatment efficacy. While molecular weight has a negligible direct impact on treatment outcome, low molecular weight scaffolds can be more easily designed for optimised treatment, particularly when treatment is delayed. The same underlying trends are seen for both venom types tested. This approach can be used to elucidate the dynamics of envenomation-treatment systems, and inform the development of next-generation antivenoms.