Influence of L-leucine as a dispersibility enhancer on inhalation performance and immunogenicity of a dry powder influenza vaccine

Developing dry powder formulations for sensitive biologics such as viral vaccines is not straightforward, with major challenges associated with their aerosolization still to be resolved, though their resulting tolerance for high temperatures makes these biopharmaceuticals easier to stockpile and transport. L-leucine is a known dispersibility enhancer for spray dried food and drug products that may improve the aerosolization of these new vaccines as well, but its full impact has not yet been studied across the supply chain from powder production to administration into a host for the viral actives being encapsulated. To establish better guidelines for formulators with L-leucine as a dispersibility enhancer in spray dried vaccine formulations, the whole supply chain was evaluated from dry powder synthesis and product stability, to aerosolization and delivery into the lungs, and finally whether the immunogenic response of the viral vector in murine models. An enveloped virus, Influenza A virus (IAV) was the targeted model viral vector for the study, stabilized in a binary matrix blend of lactose and trehalose, with and without L-leucine. Appropriately respirable particles (<5 μm) were produced, displaying aerodynamic properties sufficient for insufflation into mice via a custom-made intratracheal delivery device. In vivo immunogenicity was confirmed using a hemagglutination inhibition assay, with the spray dried powders inducing hemagglutinin inhibition (HAI) titers at protective levels. Though concerns were raised with L-leucine in deactivating a percentage of the virus in this study, the overall performance of the dry powder influenza vaccine benefited from its inclusion in the formulation.