Abstract
Currently licensed vaccines against the influenza A virus (IAV) need to be updated annually to match the constantly evolving antigenicity of the influenza virus glycoproteins, hemagglutinin (HA), and neuramidiase (NA). Attempts to develop universal vaccines that provide broad protection have resulted in some success. Herein, we have shown that a replication-deficient adenovirus expressing H5/M2e induced significant humoral immunity against the conserved HA stalk. Compared to the humoral responses induced by an inactivated influenza vaccine, the humoral responses induced by the adenovirus-vectored vaccine against the conserved stalk domain mediated cross-protection against heterosubtypic influenza viruses. Importantly, virus inactivation by formaldehyde significantly reduced the binding of monoclonal antibodies (mAbs) to the conserved nucleoprotein (NP), M2e, and HA stalk. These results suggest that inactivation by formaldehyde significantly alters the antigenicity of the HA stalk, and suggest that the conformation of the intact HA stalk provided by vector-based vaccines is important for induction of HA stalk-binding Abs. Our study provides insight into the mechanism by which a vector-based vaccine induces broad protection by stimulation of cross-protective Abs targeting conserved domains of viral proteins. The findings support further strategies to develop a vectored vaccine as a universal influenza vaccine for the control of influenza epidemics and unpredicted pandemics.
Highlights
Available influenza A virus (IAV) vaccines require frequent changes in viral strain composition to address the continuous antigenic evolution of seasonal influenza viruses
To examine the antibody responses induced by our adenovirus-vectored influenza vaccine, mice were immunized with formalin-inactivated PR8 plus cholera toxin adjuvant (FiPR8+CT), live PR8, or adenovirus-vectored influenza vaccine, rAdH5/Matrix protein 2 ectodomain (M2e)
Recombinant adenovirus vectored vaccines are an attractive immunization approach given these vectors can express the antigen of interest and produce pathogen associated molecular patterns (PAMPS) that stimulate protective immune responses in the respiratory tract
Summary
Available influenza A virus (IAV) vaccines require frequent changes in viral strain composition to address the continuous antigenic evolution of seasonal influenza viruses. These vaccines often provide poor immunity and are often not effective at preventing severe illness. Single or prime/boost vaccinations with inactivated vaccine did not induce a robust cross-reactive immune response, nor did they provide protection against heterologous influenza virus challenge in either mice or ferrets [2,3,4]. While a trivalent inactivated vaccine (TIV) fails to provide broad protection [3,5], live attenuated influenza vaccines (LAIV) have been shown to induce cross-protection. A robust immune response and protection conferred by LAIV was attributed to serum and mucosal antibody
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