LAUSR

Abstract Despite remarkable successes of immunization in protecting public health, safe and effective vaccines against a number of life‐threatening pathogens such as HIV, ebola, influenza, and SARS‐CoV‐2 remain urgently needed. Subunit vaccines can avoid potential toxicity associated with traditional whole virion‐inactivated and live‐attenuated vaccines; however, the immunogenicity of subunit vaccines is often poor. A facile method is here reported to produce lipid nanoparticle subunit vaccines that exhibit high immunogenicity and elicit protection against influenza virus. Influenza hemagglutinin (HA) immunogens are functionalized on the surface of liposomes via stable metal chelation chemistry, using a scalable advanced microfluidic mixing technology (NanoAssemblr). Immunization of mice with HA‐liposomes elicits increased serum antibody titers and superior protection against highly pathogenic virus challenge compared with free HA protein. HA‐liposomal vaccines display enhanced antigen deposition into germinal centers within the draining lymph nodes, driving increased HA‐specific B cell, and follicular helper T cell responses. This work provides mechanistic insights into highly protective HA‐liposome vaccines and informs the rational design and rapid production of next generation nanoparticle subunit vaccines.