Intranasal Nanovaccine Provides Protection Against Homologous and Heterologous Influenza Virus

Each year influenza A virus (IAV) causes significant illness and economic burden. While current inactivated vaccines may induce production of virus-neutralizing antibodies against antigenically matched strains, their protection is limited against heterologous infection. In addition, intranasally administered live-attenuated influenza vaccines, which were designed to promote cell-mediated immunity, are no longer recommended by the Centers for Disease Control and Prevention due to current poor vaccine efficacy. Therefore, next generation vaccines that can induce protective antibody- and T cell-mediated immunity hold the promise of increasing the breadth of protection against IAV.

Polyanhydride nanoparticles are a versatile platform suitable for the delivery of IAV vaccines that have been demonstrated to promote robust antibody production and T cell responses. In this work, the efficacy of an intranasal polyanhydride nanovaccine encapsulating hemagglutinin, nucleoprotein, and CpG was examined in mice. The nanovaccine provided robust protection during a homologous influenza challenge and induced the formation of germinal centers within the lung, draining lymph nodes, and nasal-associated lymphoid tissue post-vaccination. In addition, influenza-specific and hemagglutination inhibition antibodies were detected in the serum and bronchoalveolar lavage fluid indicating the induction of both local/mucosal and systemic immunity.

While IAV-specific antibodies as well as T cells are protective against homologous influenza viruses, studies suggest that T cells are critical for cross-protection against heterologous infection. Mice administered the polyanhydride nanovaccine demonstrated enhanced accumulation of both CD4⁺ and CD8⁺ influenza-specific T cells within the lungs. Additionally, influenza-specific tissue-resident memory T cells were observed through at least 45 days post-vaccination. Consistent with the induction of IAV-specific T cells after vaccination, we observed that protection against heterologous challenge was greatly enhanced in mice administered the polyanhydride nanovaccine (80% survival) compared to controls (0% survival). Together, these data demonstrate the ability of polyanhydride nanovaccines to induce robust local and systemic adaptive immunity as well as provide protection against homologous and heterologous influenza challenge.