Recombinant vector vaccines and within-host evolution

Abstract

4Many recombinant vector vaccines are capable of replication within the host. They consist of a 5 fully competent vector backbone engineered to express an antigen from a foreign transgene. From the 6 perspective of viral replication, the transgene is not only dispensable but may even be intrinsically 7 detrimental. Thus vaccine revertants that delete the transgene may evolve to dominate the within-8 host population and in doing so reduce the antigenicity of the vaccine. We apply mathematical and 9 computational models to study this process, including the dynamics of vaccine and revertant growth 10 plus the dynamics of innate and adaptive immunity. Although the selective basis of vaccine evolution is 11 easy to comprehend, the immunological consequences are not. One complication is that, despite possible 12 fitness differences between vaccine and revertant, the opportunity for vaccine evolution is limited by the 13 short period of growth before the viral population is cleared. Even less obvious, revertant per se does not 14 interfere with immunity to vaccine except as the revertant suppresses vaccine abundance; the magnitude 15 of this interference depends on mechanisms and timing of viral suppression. Adaptive immunity targeting 16 the foreign antigen is also a possible basis of vaccine inferiority, but it is not worsened by vaccine evolution. 17Overall, we find that within-host vaccine evolution can sometimes matter to the adaptive immune response 18 targeting the foreign antigen, but even when it does matter, simple principles of vaccine design and the 19 control of inoculum composition can largely mitigate the effects. 20 Author Summary 21 Recombinant vector vaccines are live replicating viruses that are engineered to carry extra genes derived from 22a pathogen -and these produce proteins against which we want to generate immunity. These genes may 23 evolve to be lost during the course of replication within an individual, and there is a concern that this can 24 severely limit the vaccine's efficacy. The dynamics of this process are studied here with mathematical models. 25The potential for vaccine evolution is somewhat reduced by the short-term growth of the vaccine population 26 before it is suppressed by the immune response. Even when within-host evolution can be a problem, the 27 1 . CC-BY 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/545087 doi: bioRxiv preprint models show that increasing the vaccine inoculum size or ensuring that the inoculum is mostly pure vaccine 28 can largely avoid the loss of immunity arising from evolution. 29