Optimizing the live attenuated influenza A vaccine backbone for high-risk patient groups

The live attenuated influenza vaccine (LAIV) is approved for intranasal spray application in 2-49 year-old patients with safety concerns limiting its use in younger children and immunocompromised patients, mainly from the higher incidence of adverse events and the possibility of uncontrolled replication and reversion to a pathogenic strain, respectively. Further attenuation of the LAIV could generally improve its safety profile, which might come at the cost of reduced immunogenicity. To solve this dilemma, we took advantage of a recently defined mechanism of ER stress induction by modifying IAV non-structural protein 1 (NS1). The modified LAIV (AAmut/PR8) showed stronger ER stress activation in vitro and replicated to lower titers in vivo compared to its parental strain, without affecting protection against homo-subtypic or hetero-subtypic IAV strains. AAmut/PR8 could pose as a suitable strategy to attend the gap to the current LAIV recommendation guidelines in susceptible target populations.