Single-dose CpG immunization protects against a heterosubtypic challenge and generates antigen-specific memory T cells

Alexander J. Vogel, Deborah M. Brown

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Despite extensive research, influenza A virus (IAV) remains a major cause of morbidity, mortality, and healthcare expenditure. Emerging pandemics from highly pathogenic IAV strains, such as H5N1 and pandemic H1N1, highlight the need for universal, cross-protective vaccines. Current vaccine formulations generate strain-specific neutralizing antibodies primarily against the outer coat proteins, hemagglutinin and neuraminidase. In contrast to these highly mutable proteins, internal proteins of IAV are more conserved and are a favorable target for developing vaccines that induce strong T cell responses in addition to humoral immunity. Here, we found that intranasal administration with a single dose of CpG and inactivated x31 (H3N2) reduced viral titers and partially protected mice from a heterosubtypic challenge with a lethal dose of PR8 (H1N1). Early after immunization, vaccinated mice showed increased innate immune activation with high levels of MHCII and CD86 expression on dendritic cells in both draining lymph nodes and lungs. Three days after immunization, CD4 and CD8 cells in the lung upregulated CD69, suggesting that activated lymphocytes are present at the site of vaccine administration. The ensuing effector Th1 responses were capable of producing multiple cytokines and were present at least 30 days after immunization. Furthermore, functional memory responses were observed, as antigen-specific IFN-γ+ and GrB+ cells were detected early after lethal infection. Together, this work provides evidence for using pattern recognition receptor agonists as a mucosal vaccine platform for inducing robust T cell responses capable of protecting against heterologous IAV challenges.

Original languageEnglish (US)
Article number327
JournalFrontiers in immunology
Volume6
Issue numberJUN
DOIs
StatePublished - Jan 1 2015

Fingerprint

Influenza A virus
Immunization
Vaccines
T-Lymphocytes
Antigens
Pandemics
Pattern Recognition Receptors
Intranasal Administration
Lung
Hemagglutinins
Neuraminidase
Capsid Proteins
Humoral Immunity
Health Expenditures
Neutralizing Antibodies
Dendritic Cells
Proteins
Lymph Nodes
Lymphocytes
Cytokines

Keywords

  • CD4 T lymphocytes
  • CD8 T lymphocytes
  • CpG
  • Cytotoxic T lymphocytes
  • Immunization
  • Influenza A virus
  • Nasal mucosa
  • Vaccines

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Single-dose CpG immunization protects against a heterosubtypic challenge and generates antigen-specific memory T cells. / Vogel, Alexander J.; Brown, Deborah M.

In: Frontiers in immunology, Vol. 6, No. JUN, 327, 01.01.2015.

Research output: Contribution to journalArticle

@article{848cdcbc501e4e78a0258e35c1cc0be8,
title = "Single-dose CpG immunization protects against a heterosubtypic challenge and generates antigen-specific memory T cells",
abstract = "Despite extensive research, influenza A virus (IAV) remains a major cause of morbidity, mortality, and healthcare expenditure. Emerging pandemics from highly pathogenic IAV strains, such as H5N1 and pandemic H1N1, highlight the need for universal, cross-protective vaccines. Current vaccine formulations generate strain-specific neutralizing antibodies primarily against the outer coat proteins, hemagglutinin and neuraminidase. In contrast to these highly mutable proteins, internal proteins of IAV are more conserved and are a favorable target for developing vaccines that induce strong T cell responses in addition to humoral immunity. Here, we found that intranasal administration with a single dose of CpG and inactivated x31 (H3N2) reduced viral titers and partially protected mice from a heterosubtypic challenge with a lethal dose of PR8 (H1N1). Early after immunization, vaccinated mice showed increased innate immune activation with high levels of MHCII and CD86 expression on dendritic cells in both draining lymph nodes and lungs. Three days after immunization, CD4 and CD8 cells in the lung upregulated CD69, suggesting that activated lymphocytes are present at the site of vaccine administration. The ensuing effector Th1 responses were capable of producing multiple cytokines and were present at least 30 days after immunization. Furthermore, functional memory responses were observed, as antigen-specific IFN-γ+ and GrB+ cells were detected early after lethal infection. Together, this work provides evidence for using pattern recognition receptor agonists as a mucosal vaccine platform for inducing robust T cell responses capable of protecting against heterologous IAV challenges.",
keywords = "CD4 T lymphocytes, CD8 T lymphocytes, CpG, Cytotoxic T lymphocytes, Immunization, Influenza A virus, Nasal mucosa, Vaccines",
author = "Vogel, {Alexander J.} and Brown, {Deborah M.}",
year = "2015",
month = "1",
day = "1",
doi = "10.3389/fimmu.2015.00327",
language = "English (US)",
volume = "6",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Media S. A.",
number = "JUN",

}

TY - JOUR

T1 - Single-dose CpG immunization protects against a heterosubtypic challenge and generates antigen-specific memory T cells

AU - Vogel, Alexander J.

AU - Brown, Deborah M.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Despite extensive research, influenza A virus (IAV) remains a major cause of morbidity, mortality, and healthcare expenditure. Emerging pandemics from highly pathogenic IAV strains, such as H5N1 and pandemic H1N1, highlight the need for universal, cross-protective vaccines. Current vaccine formulations generate strain-specific neutralizing antibodies primarily against the outer coat proteins, hemagglutinin and neuraminidase. In contrast to these highly mutable proteins, internal proteins of IAV are more conserved and are a favorable target for developing vaccines that induce strong T cell responses in addition to humoral immunity. Here, we found that intranasal administration with a single dose of CpG and inactivated x31 (H3N2) reduced viral titers and partially protected mice from a heterosubtypic challenge with a lethal dose of PR8 (H1N1). Early after immunization, vaccinated mice showed increased innate immune activation with high levels of MHCII and CD86 expression on dendritic cells in both draining lymph nodes and lungs. Three days after immunization, CD4 and CD8 cells in the lung upregulated CD69, suggesting that activated lymphocytes are present at the site of vaccine administration. The ensuing effector Th1 responses were capable of producing multiple cytokines and were present at least 30 days after immunization. Furthermore, functional memory responses were observed, as antigen-specific IFN-γ+ and GrB+ cells were detected early after lethal infection. Together, this work provides evidence for using pattern recognition receptor agonists as a mucosal vaccine platform for inducing robust T cell responses capable of protecting against heterologous IAV challenges.

AB - Despite extensive research, influenza A virus (IAV) remains a major cause of morbidity, mortality, and healthcare expenditure. Emerging pandemics from highly pathogenic IAV strains, such as H5N1 and pandemic H1N1, highlight the need for universal, cross-protective vaccines. Current vaccine formulations generate strain-specific neutralizing antibodies primarily against the outer coat proteins, hemagglutinin and neuraminidase. In contrast to these highly mutable proteins, internal proteins of IAV are more conserved and are a favorable target for developing vaccines that induce strong T cell responses in addition to humoral immunity. Here, we found that intranasal administration with a single dose of CpG and inactivated x31 (H3N2) reduced viral titers and partially protected mice from a heterosubtypic challenge with a lethal dose of PR8 (H1N1). Early after immunization, vaccinated mice showed increased innate immune activation with high levels of MHCII and CD86 expression on dendritic cells in both draining lymph nodes and lungs. Three days after immunization, CD4 and CD8 cells in the lung upregulated CD69, suggesting that activated lymphocytes are present at the site of vaccine administration. The ensuing effector Th1 responses were capable of producing multiple cytokines and were present at least 30 days after immunization. Furthermore, functional memory responses were observed, as antigen-specific IFN-γ+ and GrB+ cells were detected early after lethal infection. Together, this work provides evidence for using pattern recognition receptor agonists as a mucosal vaccine platform for inducing robust T cell responses capable of protecting against heterologous IAV challenges.

KW - CD4 T lymphocytes

KW - CD8 T lymphocytes

KW - CpG

KW - Cytotoxic T lymphocytes

KW - Immunization

KW - Influenza A virus

KW - Nasal mucosa

KW - Vaccines

UR - http://www.scopus.com/inward/record.url?scp=84935089355&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84935089355&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2015.00327

DO - 10.3389/fimmu.2015.00327

M3 - Article

C2 - 26161083

AN - SCOPUS:84935089355

VL - 6

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

IS - JUN

M1 - 327

ER -