Influenza A virus (IAV) is a globally distributed pathogen that causes seasonal winter epidemics and frequent pandemics in humans and birds. Each respiratory season, new vaccines need to be formulated, manufactured at scale (typically by growing the virus in chicken eggs) and administered to hundreds of millions of people. Providing effective vaccines in sufficient quantities to protect against influenza is a massive ongoing global challenge.
CpG dinucleotide enrichment of a virus genome is an appealing live attenuated vaccine development strategy. In the IAV genome, CpGs are markedly suppressed (i.e., cytosine immediately followed by guanine occurs rarely [1]). This is because an antiviral protein made by the host, ZAP, binds CpG sites in viral RNA to target it for degradation. We have shown that adding CpGs into the genome of IAV results in ZAP-mediated virus attenuation [2]. We found that infection of mice with a sub-clinical dose CpG-high IAV offers protection from subsequent infection with a lethal dose of IAV, demonstrating the potential of this approach in influenza vaccinology.
The goal of this project is to advance our technology by addressing the following aims:
1. Determine whether CpG enrichment can be applied as an attenuation strategy to multiple IAV strains from a range of species, including avian influenza
2. Optimise parameters for CpG enrichment, including testing CpG enrichment in multiple viral segments
3. Test approaches for making virally encoded CpGs more visible to the host cell by performing experiments to test RNA structure, integrating bioinformatics and SHAPE-MaP approaches in the lab.
In this interdisciplinary project you will learn a range of laboratory methods including cell culture, virus infections, reverse genetics, and SHAPE-MaP. In silico, you will design CpG-enriched viruses. You will regularly present at lab meetings and have the opportunity to present more widely at conferences.
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