Interferons (IFNs) are key controllers of viral replication, with intact IFN responses suppressing virus growth and spread. Using the murine norovirus (MNoV) system, we show that IFNs exert selective pressure to limit the pathogenic evolutionary potential of this enteric virus. In animals lacking type I IFN signaling, the nonlethal MNoV strain CR6 rapidly acquired enhanced virulence via conversion of a single nucleotide. This nucleotide change resulted in amino acid substitution F514I in the viral capsid, which led to >10,000-fold higher replication in systemic organs including the brain. Pathogenicity was mediated by enhanced recruitment and infection of intestinal myeloid cells and increased extraintestinal dissemination of virus. Interestingly, the trade-off for this mutation was reduced fitness in an IFN-competent host, in which CR6 bearing F514I exhibited decreased intestinal replication and shedding. In an immunodeficient context, a spontaneous amino acid change can thus convert a relatively avirulent viral strain into a lethal pathogen.

Recent articles have highlighted the importance of incorporating implementation science concepts into pandemic-related research. However, limited research has been documented to date regarding implementation outcomes that may be unique to COVID-19 vaccinations and how to utilize implementation strategies to address vaccine program-related implementation challenges. To address these gaps, we formed a global COVID-19 implementation workgroup of implementation scientists who met weekly for over a year to review the available literature and learn about ongoing research during the pandemic. We developed a hierarchy to prioritize the applicability of “lessons learned” from the vaccination-related implementation literature. We identified applications of existing implementation outcomes as well as identified additional implementation outcomes. We also mapped implementation strategies to those outcomes. Our efforts provide rationale for the utility of using implementation outcomes in pandemic-related research. Furthermore, we identified three additional implementation outcomes: availability, health equity, and scale-up. Results include a list of COVID-19 relevant implementation strategies mapped to the implementation outcomes.