DDO-adjuvanted influenza A virus nucleoprotein mRNA vaccine induces robust humoral and cellular type 1 immune responses and protects mice from challenge

ABSTRACT A challenge in viral vaccine development is to produce vaccines that generate both neutralizing antibodies to prevent infection and cytotoxic CD8+ T-cells that target conserved viral proteins and can eliminate infected cells to control virus spread. mRNA technology offers an opportunity to...

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Main Authors: Victoria Gnazzo, Hanaa Saleh, Ítalo A. Castro, Adrianus C. M. Boon, Amelia K. Pinto, James D. Brien, Carolina B. López
Format: Article
Language:English
Published: American Society for Microbiology 2025-02-01
Series:mBio
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Online Access:https://journals.asm.org/doi/10.1128/mbio.03589-24
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author Victoria Gnazzo
Hanaa Saleh
Ítalo A. Castro
Adrianus C. M. Boon
Amelia K. Pinto
James D. Brien
Carolina B. López
author_facet Victoria Gnazzo
Hanaa Saleh
Ítalo A. Castro
Adrianus C. M. Boon
Amelia K. Pinto
James D. Brien
Carolina B. López
author_sort Victoria Gnazzo
collection DOAJ
description ABSTRACT A challenge in viral vaccine development is to produce vaccines that generate both neutralizing antibodies to prevent infection and cytotoxic CD8+ T-cells that target conserved viral proteins and can eliminate infected cells to control virus spread. mRNA technology offers an opportunity to design vaccines based on conserved CD8-targeting epitopes, but achieving robust antigen-specific CD8+ T-cells remains a challenge. Here, we tested the viral-derived oligonucleotide DDO268 as an adjuvant in the context of a model influenza A virus (IAV) nucleoprotein (NP) mRNA vaccine in C57BL/6 mice. DDO268 when co-packaged with mRNA in lipid nanoparticles is sensed by RIG I-like receptors and safely induces local type I interferon (IFN) production followed by dendritic cells type 1 activation and migration to the draining lymph nodes. This early response triggered by DDO268 improved the generation of IgG2c antibodies and antigen-specific Th1 CD4+ and CD8+ T-cells (IFNγ+TNFα+IL2+) that provided enhanced protection against lethal IAV challenge. In addition, the inclusion of DDO268 reduced the antigen dose required to achieve protection. These results highlight the potential of DDO268 as an effective mRNA vaccine adjuvant and show that an IAV NP mRNA/DDO268 vaccine is a promising approach for generating protective immunity against conserved internal IAV epitopes.IMPORTANCEVaccines that generate neutralizing antibodies and cytotoxic CD8+ T-cells targeting conserved epitopes are ideal for effective protection against viruses. mRNA vaccines combined with the right adjuvant offer a promising solution to this challenge. We show that the virus-derived oligonucleotide DDO268 enhances antibody and T-cell responses to an influenza A virus (IAV) nucleoprotein mRNA vaccine in mice. DDO268 safely induces local type I interferon production and stimulates dendritic cell activation providing enhanced protection against IAV challenge. In addition, the adjuvant activity of DDO268 allows for the use of lower antigen doses during vaccination.
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spelling doaj-art-b0b6963221674176bca137c5104221b12025-02-05T14:00:48ZengAmerican Society for MicrobiologymBio2150-75112025-02-0116210.1128/mbio.03589-24DDO-adjuvanted influenza A virus nucleoprotein mRNA vaccine induces robust humoral and cellular type 1 immune responses and protects mice from challengeVictoria Gnazzo0Hanaa Saleh1Ítalo A. Castro2Adrianus C. M. Boon3Amelia K. Pinto4James D. Brien5Carolina B. López6Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri, USADepartment of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri, USADepartment of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri, USADepartment of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri, USADepartment of Microbiology, Immunology & Molecular Genetics, University of Kentucky, Lexington, Kentucky, USADepartment of Microbiology, Immunology & Molecular Genetics, University of Kentucky, Lexington, Kentucky, USADepartment of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri, USAABSTRACT A challenge in viral vaccine development is to produce vaccines that generate both neutralizing antibodies to prevent infection and cytotoxic CD8+ T-cells that target conserved viral proteins and can eliminate infected cells to control virus spread. mRNA technology offers an opportunity to design vaccines based on conserved CD8-targeting epitopes, but achieving robust antigen-specific CD8+ T-cells remains a challenge. Here, we tested the viral-derived oligonucleotide DDO268 as an adjuvant in the context of a model influenza A virus (IAV) nucleoprotein (NP) mRNA vaccine in C57BL/6 mice. DDO268 when co-packaged with mRNA in lipid nanoparticles is sensed by RIG I-like receptors and safely induces local type I interferon (IFN) production followed by dendritic cells type 1 activation and migration to the draining lymph nodes. This early response triggered by DDO268 improved the generation of IgG2c antibodies and antigen-specific Th1 CD4+ and CD8+ T-cells (IFNγ+TNFα+IL2+) that provided enhanced protection against lethal IAV challenge. In addition, the inclusion of DDO268 reduced the antigen dose required to achieve protection. These results highlight the potential of DDO268 as an effective mRNA vaccine adjuvant and show that an IAV NP mRNA/DDO268 vaccine is a promising approach for generating protective immunity against conserved internal IAV epitopes.IMPORTANCEVaccines that generate neutralizing antibodies and cytotoxic CD8+ T-cells targeting conserved epitopes are ideal for effective protection against viruses. mRNA vaccines combined with the right adjuvant offer a promising solution to this challenge. We show that the virus-derived oligonucleotide DDO268 enhances antibody and T-cell responses to an influenza A virus (IAV) nucleoprotein mRNA vaccine in mice. DDO268 safely induces local type I interferon production and stimulates dendritic cell activation providing enhanced protection against IAV challenge. In addition, the adjuvant activity of DDO268 allows for the use of lower antigen doses during vaccination.https://journals.asm.org/doi/10.1128/mbio.03589-24mRNA vaccineadjuvantstype I IFN
spellingShingle Victoria Gnazzo
Hanaa Saleh
Ítalo A. Castro
Adrianus C. M. Boon
Amelia K. Pinto
James D. Brien
Carolina B. López
DDO-adjuvanted influenza A virus nucleoprotein mRNA vaccine induces robust humoral and cellular type 1 immune responses and protects mice from challenge
mBio
mRNA vaccine
adjuvants
type I IFN
title DDO-adjuvanted influenza A virus nucleoprotein mRNA vaccine induces robust humoral and cellular type 1 immune responses and protects mice from challenge
title_full DDO-adjuvanted influenza A virus nucleoprotein mRNA vaccine induces robust humoral and cellular type 1 immune responses and protects mice from challenge
title_fullStr DDO-adjuvanted influenza A virus nucleoprotein mRNA vaccine induces robust humoral and cellular type 1 immune responses and protects mice from challenge
title_full_unstemmed DDO-adjuvanted influenza A virus nucleoprotein mRNA vaccine induces robust humoral and cellular type 1 immune responses and protects mice from challenge
title_short DDO-adjuvanted influenza A virus nucleoprotein mRNA vaccine induces robust humoral and cellular type 1 immune responses and protects mice from challenge
title_sort ddo adjuvanted influenza a virus nucleoprotein mrna vaccine induces robust humoral and cellular type 1 immune responses and protects mice from challenge
topic mRNA vaccine
adjuvants
type I IFN
url https://journals.asm.org/doi/10.1128/mbio.03589-24
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