Generation of a Live Attenuated Influenza Vaccine that Elicits Broad Protection in Mice and Ferrets

Cell Host Microbe. 2017 Mar 8;21(3):334-343. doi: 10.1016/j.chom.2017.02.007.

Abstract

New influenza vaccines that provide effective and broad protection are desperately needed. Live attenuated viruses are attractive vaccine candidates because they can elicit both humoral and cellular immune responses. However, recent formulations of live attenuated influenza vaccines (LAIVs) have not been protective. We combined high-coverage transposon mutagenesis of influenza virus with a rapid high-throughput screening for attenuation to generate W7-791, a live attenuated mutant virus strain. W7-791 produced only a transient asymptomatic infection in adult and neonatal mice even at doses 100-fold higher than the LD50 of the parent strain. A single administration of W7-791 conferred full protection to mice against lethal challenge with H1N1, H3N2, and H5N1 strains, and improved viral clearance in ferrets. Adoptive transfer of T cells from W7-791-immunized mice conferred heterologous protection, indicating a role for T cell-mediated immunity. These studies present an LAIV development strategy to rapidly generate and screen entire libraries of viral clones.

Keywords: flu vaccine; genome-wide mutagenesis; influenza vaccine; matrix protein.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Cross Protection
  • DNA Transposable Elements
  • Disease Models, Animal
  • Ferrets
  • Genetic Testing
  • Immunity, Heterologous
  • Influenza A Virus, H1N1 Subtype / immunology*
  • Influenza A Virus, H3N2 Subtype / immunology*
  • Influenza A Virus, H5N1 Subtype / immunology*
  • Influenza Vaccines / administration & dosage
  • Influenza Vaccines / immunology*
  • Influenza Vaccines / isolation & purification*
  • Mice
  • Mutagenesis, Insertional
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / prevention & control*
  • Survival Analysis
  • T-Lymphocytes / immunology*
  • Vaccines, Attenuated / administration & dosage
  • Vaccines, Attenuated / immunology
  • Vaccines, Attenuated / isolation & purification

Substances

  • DNA Transposable Elements
  • Influenza Vaccines
  • Vaccines, Attenuated