Particulate characteristics of engineered nanoparticle vaccines modulate vaccine immunogenicity in an intranasal route

Abstract The intranasal route is an ideal vaccination route for preventing infectious respiratory diseases due to its capability of generating both mucosal immunity—the first line of defense against respiratory virus invasion—and systemic immunity. Protein antigens are poorly immunogenic when administered intranasally. Previously we found that polycationic polyethyleneimine (PEI)-hemagglutinin (HA) nanoparticles significantly enhanced influenza HA immunogenicity in an intranasal route. Herein, we prepared hybrid PEI-HA-lipid nanoparticles and investigated how particulate features influence their immunogenicity. We found that a phosphatidylserine-based lipid layer coating around PEI-HA nanoparticles made the particle negatively charged and eliminated the induced antibody responses, reflecting the importance of surface charges in the antibody induction. However, further incorporation of PAMP adjuvants (MPLA and cGAMP) substantially boosted humoral and cellular responses both mucosally and systemically. MPLA and cGAMP-co-loaded hybrid nanoparticles generated the most lung-resident CD8+ T memory cells among all groups. These nanoparticles showed distinct antigen delivery behavior and early immune responses in mouse lungs and NALTs. Only adjuvanted particles induced significant BMDC maturation and inflammatory cytokines secretion in vitro cultures. Studies on these particle vaccines’ protective efficacy are ongoing in mice. The role of particulate features in programming the immune responses would be further analyzed. Our study will provide perspectives for the development of intranasal particulate vaccines against infectious respiratory diseases. Supported by grants from NIH/NIAID (R01AI101047, R01AI116835, R01AI143844)