Anti-viral therapies are typically designed to target only the current strains of a virus, a myopic response. However, therapy-induced selective pressures drive the emergence of new viral strains, against which the original myopic therapies are no longer effective. This evolutionary response presents an opportunity: our therapies could both defend against and actively influence viral evolution. This motivates our method ADIOS: Antibody Development vIa Opponent Shaping. ADIOS is a meta-learning framework where the process of antibody therapy design, the outer loop, accounts for the virus’s adaptive response, the inner loop. With ADIOS, antibodies are not only robust against potential future variants, they also influence, i.e. shape, which future variants emerge. In line with the opponent shaping literature, we refer to our optimised antibodies as shapers. To demonstrate the value of ADIOS, we build a viral evolution simulator using the Absolut! framework, in which shapers successfully target both current and future viral variants, outperforming myopic antibodies. Furthermore, we show that shapers modify the distribution over viral evolutionary trajectories to result in weaker variants. We believe that our ADIOS paradigm will facilitate the discovery of long-lived vaccines and antibody therapies while also generalising to other domains. Specifically, domains such as antimicrobial resistance, cancer treatment, and others with evolutionarily adaptive opponents. Our code is available at https://github.com/olakalisz/adios.

Directed evolution can enable engineering of biological systems with minimal knowledge of their underlying sequence-to-function relationships. A typical directed evolution process consists of iterative rounds of mutagenesis and selection that are designed to steer changes in a biological system (e.g. a protein) towards some functional goal. Much work has been done, particularly leveraging advancements in machine learning, to optimise the process of directed evolution. Many of these methods, however, require DNA sequencing and synthesis, making them resource-intensive and incompatible with developments in targeted in vivo mutagenesis. Operating within the experimental constraints of established sorting-based directed evolution techniques (e.g. Fluorescence-Activated Cell Sorting, FACS), we explore approaches for optimisation of directed evolution that could in future be implemented without sequencing information. We then expand our methods to the context of emerging experimental techniques in directed evolution, which allow for single-cell selection based on fitness objectives defined from any combination of measurable traits. Finally, we explore these alternative strategies on the GB1 and TrpB empirical landscapes, demonstrating that they could lead to up to 19-fold and 7-fold increases respectively in the probability of attaining the global fitness peak.