Genomic and transcriptomic determinants of host susceptibility, protection, and viral mutation in experimental SARS CoV-2 infection

This project aims to use samples collected during the world's first SARS-CoV-2 human challenge studies to investigate in depth how pre-existing immunity and virus-host interactions affect the outcome of infection. Two SARS-CoV-2 human challenge studies are currently underway that together are enrolling naïve, previously infected and vaccinated young adults for controlled infection with a well-characterised viral inoculum. This proposal will investigate the genomic and cell-specific variations in host response that may be responsible for differential clinical outcome and within-host viral variation. Since in- host mutation is the mechanism by which viruses escape vaccine-mediated protection, further understanding of its drivers is an urgent priority to help anticipate the emergence of vaccine-resistant variants. Single-cell RNAseq will be used to analyse the transcriptional patterns of blood and nasal cells over the course of infection. These will be correlated with the transcriptional responses of the virus in concurrent nasal samples and whole genome sequencing to identify stable mutants that arise. Incorporating each participant's genomic sequence, integrative analysis of virus and host factors that correlate with susceptibility and protection from infection and disease will be achieved. Thus, we will maximise the value of the human challenge programme and identify specific targets for vaccine improvement.