Polyanhydride Nanovaccine Induces Robust Pulmonary B and T Cell Immunity and Confers Protection Against Homologous and Heterologous Influenza A Virus Infections.

Zeb R Zacharias,Kevin L Legge,Kathleen A Ross,Thomas J Waldschmidt,Jonathan T Goodman,Emma E Hornick,Balaji Narasimhan

doi:10.3389/fimmu.2018.01953

Zeb R Zacharias, Kevin L Legge + Show 5 more

Open Access

https://doi.org/10.3389/fimmu.2018.01953

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Abstract

Influenza A virus (IAV) is a major cause of respiratory illness. Given the disease severity, associated economic costs, and recent appearance of novel IAV strains, there is a renewed interest in developing novel and efficacious “universal” IAV vaccination strategies. Recent studies have highlighted that immunizations capable of generating local (i.e., nasal mucosa and lung) tissue-resident memory T and B cells in addition to systemic immunity offer the greatest protection against future IAV encounters. Current IAV vaccines are designed to largely stimulate IAV-specific antibodies, but do not generate the lung-resident memory T and B cells induced during IAV infections. Herein, we report on an intranasally administered biocompatible polyanhydride nanoparticle-based IAV vaccine (IAV-nanovax) capable of providing protection against subsequent homologous and heterologous IAV infections in both inbred and outbred populations. Our findings also demonstrate that vaccination with IAV-nanovax promotes the induction of germinal center B cells within the lungs, both systemic and lung local IAV-specific antibodies, and IAV-specific lung-resident memory CD4 and CD8 T cells. Altogether our findings show that an intranasally administered nanovaccine can induce immunity within the lungs, similar to what occurs during IAV infections, and thus could prove useful as a strategy for providing “universal” protection against IAV.

Highlights

Influenza A virus (IAV) is a common respiratory pathogen that undergoes seasonal antigenic drift continually giving rise to variant strains that can escape existing immune protection
The spread of IAV has been prevented by two vaccination strategies: inactivated influenza vaccine (IIV) and live-attenuated influenza vaccine (LAIV)
These results suggest that i.n. administration of IAV-nanovax induces lung-resident germinal center (GC) B cell responses capable of producing class-switched B cells to levels commensurate to those found in IAV-infected mice at 45 days following infection/vaccination

Summary

Introduction

Influenza A virus (IAV) is a common respiratory pathogen that undergoes seasonal antigenic drift continually giving rise to variant strains that can escape existing immune protection. The spread of IAV has been prevented by two vaccination strategies: inactivated influenza vaccine (IIV) and live-attenuated influenza vaccine (LAIV) Both IIV and LAIV primarily provide systemic immunity by inducing IAV-specific antibody responses [3, 4]. It is less clear if these vaccination strategies generate robust de novo IAV-specific CD4 or CD8 T cell responses within the lower lung mucosa [4,5,6,7]. LAIV has been shown to induce T cell responses within the lungs of mice following whole lung inoculation [6], when LAIV vaccination has been limited to the upper respiratory tract in animal models, similar to its replication location in humans, it does not induce T cell responses within the lower lung mucosa [7]

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