Intranasal Epitope‐Polymer Vaccine Lodges Resident Memory T Cells Protecting Against Influenza Virus

Abstract Intranasal vaccines, unlike injectable vaccines, boost immunity along the respiratory tract; this can significantly limit respiratory virus replication and shedding. There remains a need to develop mucosal adjuvants and vaccine delivery systems that are both safe and effective following intranasal administration. Here, biopolymer particles (BP) densely coated with repeats of MHC class I restricted immunodominant epitopes derived from influenza A virus namely NP₃₆₆, a nucleoprotein‐derived epitope and PA₂₂₄, a polymerase acidic subunit derived epitope, are bioengineered. These BP‐NP₃₆₆/PA₂₂₄ can be manufactured at a high yield and are obtained at ≈93% purity, exhibiting ambient‐temperature stability. Immunological characterization includes comparing systemic and mucosal immune responses mounted following intramuscular or intranasal immunization. Immunization with BP‐NP₃₆₆/PA₂₂₄ without adjuvant triggers influenza‐specific CD8⁺ T cell priming and memory CD8⁺ T cell development. Co‐delivery with the adjuvant poly(I:C) significantly boosts the size and functionality of the influenza‐specific pulmonary resident memory CD8⁺ T cell pool. Intranasal, but not intramuscular delivery of BP‐NP₃₆₆/PA₂₂₄ with poly(I:C), provides protection against influenza virus challenge. Overall, the BP approach demonstrates as a suitable antigen formulation for intranasal delivery toward induction of systemic protective T cell responses against influenza virus.