Vaccinia-based influenza vaccine overcomes previously induced immunodominance hierarchy for heterosubtypic protection

Eur J Immunol. 2014 Aug;44(8):2360-9. doi: 10.1002/eji.201344005. Epub 2014 Jun 16.

Abstract

Growing concerns about unpredictable influenza pandemics require a broadly protective vaccine against diverse influenza strains. One of the promising approaches was a T cell-based vaccine, but the narrow breadth of T-cell immunity due to the immunodominance hierarchy established by previous influenza infection and efficacy against only mild challenge condition are important hurdles to overcome. To model T-cell immunodominance hierarchy in humans in an experimental setting, influenza-primed C57BL/6 mice were chosen and boosted with a mixture of vaccinia recombinants, individually expressing consensus sequences from avian, swine, and human isolates of influenza internal proteins. As determined by IFN-γ ELISPOT and polyfunctional cytokine secretion, the vaccinia recombinants of influenza expanded the breadth of T-cell responses to include subdominant and even minor epitopes. Vaccine groups were successfully protected against 100 LD50 challenges with PR/8/34 and highly pathogenic avian influenza H5N1, which contained the identical dominant NP366 epitope. Interestingly, in challenge with pandemic A/Cal/04/2009 containing mutations in the dominant epitope, only the group vaccinated with rVV-NP + PA showed improved protection. Taken together, a vaccinia-based influenza vaccine expressing conserved internal proteins improved the breadth of influenza-specific T-cell immunity and provided heterosubtypic protection against immunologically close as well as distant influenza strains.

Keywords: Consensus sequence; Heterosubtypic protection; Immunodominance hierarchy; T-cell immunity; Universal influenza vaccine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Female
  • Humans
  • Influenza A Virus, H1N1 Subtype / immunology
  • Influenza A Virus, H5N1 Subtype / immunology
  • Influenza Vaccines / immunology*
  • Influenza Vaccines / pharmacology*
  • Influenza, Human / immunology
  • Influenza, Human / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / prevention & control
  • Swine
  • T-Lymphocytes / immunology
  • Vaccinia / immunology
  • Vaccinia virus / immunology*

Substances

  • Influenza Vaccines