Targeting of non-dominant antigens as a vaccine strategy to broaden T-cell responses during chronic viral infection

PLoS One. 2015 Feb 13;10(2):e0117242. doi: 10.1371/journal.pone.0117242. eCollection 2015.

Abstract

In this study, we compared adenoviral vaccine vectors with the capacity to induce equally potent immune responses against non-dominant and immunodominant epitopes of murine lymphocytic choriomeningitis virus (LCMV). Our results demonstrate that vaccination targeting non-dominant epitopes facilitates potent virus-induced T-cell responses against immunodominant epitopes during subsequent challenge with highly invasive virus. In contrast, when an immunodominant epitope was included in the vaccine, the T-cell response associated with viral challenge remained focussed on that epitope. Early after challenge with live virus, the CD8+ T cells specific for vaccine-encoded epitopes, displayed a phenotype typically associated with prolonged/persistent antigenic stimulation marked by high levels of KLRG-1, as compared to T cells reacting to epitopes not included in the vaccine. Notably, this association was lost over time in T cells specific for the dominant T cell epitopes, and these cells were fully capable of expanding in response to a new viral challenge. Overall, our data suggests a potential for broadening of the antiviral CD8+ T-cell response by selecting non-dominant antigens to be targeted by vaccination. In addition, our findings suggest that prior adenoviral vaccination is not likely to negatively impact the long-term and protective immune response induced and maintained by a vaccine-attenuated chronic viral infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Antigens, Viral / immunology*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Chronic Disease
  • Disease Models, Animal
  • Epitopes, T-Lymphocyte / immunology*
  • Genetic Vectors / genetics
  • Genetic Vectors / immunology
  • Immunodominant Epitopes / immunology
  • Immunologic Memory
  • Immunophenotyping
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • T-Lymphocytes / immunology*
  • Vaccination
  • Viral Proteins / immunology
  • Viral Vaccines / immunology*
  • Virus Diseases / immunology*
  • Virus Diseases / metabolism
  • Virus Diseases / prevention & control

Substances

  • Antigens, Viral
  • Epitopes, T-Lymphocyte
  • Immunodominant Epitopes
  • Viral Proteins
  • Viral Vaccines

Grants and funding

The authors thank The Danish Research Council, The Novo Nordisk Foundation, Aase and Einar Danielsens Fond, The Hede Nielsen Family Foundation and the Foundation for the Advancement of Medical Sciences for funding the study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.