Insidious Insights: Implications of viral vector engineering for pathogen enhancement

Abstract

Optimizing viral vectors and their properties will be important for improving the effectiveness and safety of clinical gene therapy. However, such research may generate dual-use insights relevant to the enhancement of pandemic pathogens. In particular, reliable and generalizable methods of immune evasion could increase viral fitness sufficient to cause a new pandemic. High potential for misuse is associated with (1) the development of universal genetic elements for immune modulation, (2) specific insights on capsid engineering for antibody evasion applicable to viruses with pandemic potential, and (3) the development of computational methods to inform capsid engineering. These risks may be mitigated by prioritizing non-viral delivery systems, pharmacological immune modulation methods, non-genetic vector surface modifications, and engineering methods specific to AAV and other viruses incapable of unassisted human-to-human transmission. We recommend that computational vector engineering and the publication of associated code and data be limited to AAV until a technical solution for preventing malicious access to viral engineering tools has been established.

Fig. 1. Vector enhancement approaches and associated potential for misuse.

a Non-viral vector delivery approaches feature the least dual-use potential compared to approaches that involve the modification of viral vectors. b, c Compared to heritable viral vector enhancement, non-heritable enhancement approaches, such as PEGylation, feature less potential for misuse as they are not passed onto viral progeny. d Heritable approaches for enhancement of vectors based on viruses incapable of unassisted transmission, such as AAV, feature less potential for misuse than similar approaches applied to vectors based on viruses capable of unassisted transmission. e Compared to other approaches for the enhancement of viral vectors, highest potential for misuse features heritable enhancement of vectors based on viruses capable of unassisted transmission, such as capsid-engineered AdV or chimeric IAV. AAV adeno-associated virus, AdV adenovirus, IAV influenza a virus.