Optimising genomic RNA RNA interactions for development of flexible influenza virus vector backbones for co vaccination

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The Live Attenuated Influenza Vaccine (LAIV), marketed as FluMist/Fluenz by AstraZeneca forms the backbone of the United Kingdom's childhood influenza vaccination programme and is given as a nasal spray annually to all 2-12 year-olds. Unlike inactivated vaccines, LAIVs are unique in generating significant mucosal immunity (Barria et al., J Infect Dis, 2013), offering the possibility of pre-empting virus spread from the upper to lower respiratory tract and consequent risk of severe disease.In the 2013-14 and 2015-16 influenza seasons, low vaccine effectiveness was observed for the H1N1 component of FluMist in the USA, attributed to decreased LAIV replication in human nasal epithelial cells (Hawksworth et al., Vaccine, 2020), rather than decreased HA antigen stability (Parker et al., Vaccine 2019). One potential contributing factor to this reduced fitness was a decrease in the production of infectious virus particles carrying all eight genome segments. Observations also suggest that the ability of the historic MDV genome to incorporate HA and NA genes from different, contemporary influenza A viruses can vary, resulting in LAIV strains with unexpected replicative differences.This project aims to understand how the genome segments of LAIVs are assembled in order to bioengineer a next-generation of LAIVs suitable as flexible vectors for all seasonal or pandemic influenza strains and co-vaccination against viruses such as SARS-CoV-2 - to which we have no vaccine that confers mucosal immunity. Such a vaccine would be invaluable, since existing vaccines are largely ineffective at halting transmission.This project aims to (1) map RNA:RNA interactions that drive assembly of LAIV strains and (2) to use this knowledge to engineer a flexible MDV backbone enabling efficient generation of either seasonal or pandemic LAIV, that (3) can also act as a flexible platform for co-vaccination of influenza along with other respiratory pathogens.