An Optimised Live Attenuated Influenza Vaccine Ferret Efficacy Model Successfully Translates H1N1 Clinical Data

Between 2013 and 2016, the A/H1N1pdm09 component of the live attenuated influenza vaccine (LAIV) produced instances of lower-than-expected vaccine effectiveness. Standard pre-clinical ferret models, using a human-like vaccine dose and focusing on antigenic match to circulating wildtype (<i>wt</i>) strains, were unable to predict these fluctuations. By optimising the vaccine dose and utilising clinically relevant endpoints, we aimed to develop a ferret efficacy model able to reproduce clinical observations. Ferrets were intranasally vaccinated with 4 Log₁₀ FFU/animal (1000-fold reduction compared to clinical dose) of seven historical LAIV formulations with known (19-90%) H1N1 vaccine efficacy or effectiveness (VE). Following homologous H1N1 <i>wt</i> virus challenge, protection was assessed based on primary endpoints of <i>wt</i> virus shedding in the upper respiratory tract and the development of fever. LAIV formulations with high (82-90%) H1N1 VE provided significant protection from <i>wt</i> challenge, while formulations with reduced (19-32%) VE tended not to provide significant protection. The strongest correlation observed was between reduction in <i>wt</i> shedding and VE (R² = 0.75). Conversely, serum immunogenicity following vaccination was not a reliable indicator of protection (R² = 0.37). This demonstrated that, by optimisation of the vaccine dose and the use of non-serological, clinically relevant protection endpoints, the ferret model could successfully translate clinical H1N1 LAIV VE data.