Injectable and Pathogen-Mimicking Hydrogels for Enhanced Protective Immunity against Emerging and Highly Pathogenic Influenza Virus

Seasonal emerging infectious diseases such as influenza A impose substantial risk and need new translational strategies to achieve active immunomodulation. Here, a novel injectable pathogen‐mimicking hydrogel (iPMH) that can enhance both cellular and humoral immune responses is suggested. By the help of poly(γ‐glutamic acid) that has abundant carboxylate groups and dispersion helper function, hydrophobic immunostimulatory 3‐O‐desacyl‐4′‐monophosphoryl lipid A (MPLA) molecules and viral antigens (PR8, W150) can be successfully combined as pathogen‐mimicking adjuvants. Polyelectrolyte complex between the poly(γ‐glutamic acid)‐based adjuvants and collagens generate in situ gel‐forming hydrogel at physiological temperature. When the iPMH are immunized, they act as a pathogen‐mimicking (MPLA, H1N1, H5N1) immune priming center and a depot for continuous stimulation of immune system, resulting in the induction of high levels (8.5 times higher) of antigen‐specific IgG titers in the sera of mice and the increased number of IFN‐γ‐producing cells (7.3 times higher) compared with those in the groups immunized with antigen plus clinically used aluminum gels. Following the intranasal infection of the mouse adapted virus (emerging infectious 2009 H1N1 and highly pathogenic 2006 H5N1) at 50 times the 50% lethal dose, the mice immunized with viral antigens plus iPMH exhibit 100% protective immunity against lethal virus challenge.