Activation of Tumor Antigen-Specific Cytotoxic T Lymphocytes (CTLs) by Human Dendritic Cells Infected with an Attenuated Influenza A Virus Expressing a CTL Epitope Derived from the HER-2/neu Proto-Oncogene

ABSTRACT The development of cancer vaccines requires approaches to induce expansion and functional differentiation of tumor antigen-specific cytotoxic T lymphocyte (CTL) effectors which posses cytolytic capability and produce cytokines. Efficient induction of such cells is hindered by the poor immunogenicity of tumor antigens and by the poor transduction efficiency of dendritic cells (DCs) with current nonreplicating vectors. We have investigated the use of influenza A virus, a potent viral inducer of CTLs, as a vector expressing the immunodominant HER-2 CTL epitope KIF (E75). For this purpose, an attenuated influenza A/PR8/34 virus with a truncated nonstructural (NS1) gene was generated containing the E75 epitope in its neuraminidase protein (KIF-NS virus). Stimulation of peripheral blood mononuclear cells from healthy donors and of tumor-associated lymphocytes from ovarian and breast cancer patients with DCs infected with KIF-NS virus (KIF-NS DC) induced CTLs that specifically recognized the peptide KIF and HER-2-expressing tumors in cytotoxicity assays and secreted gamma interferon (IFN-γ) and interleukin-2 at recall with peptide. Priming with KIF-NS DCs increased the number of E75+ CD45RO+ cells by more than 10-fold compared to nonstimulated cells. In addition, KIF-NS virus induced high levels of IFN-α in DCs. This is the first report demonstrating induction of human epitope-specific CTLs against a tumor-associated antigen with a live attenuated recombinant influenza virus vector. Such vectors may provide a novel approach for tumor antigen delivery, lymphocyte activation, and differentiation in human cancer vaccine development.

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Dendritic cells and influenza A virus infection

Virulence ◽

10.4161/viru.21864 ◽

2012 ◽

Vol 3 (7) ◽

pp. 603-608 ◽

Cited By ~ 27

Author(s):

Jason Waithman ◽

Justine D. Mintern

Keyword(s):

Dendritic Cells ◽

Virus Infection ◽

Influenza A Virus ◽

Influenza A ◽

Influenza A Virus Infection

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Broad neutralization of H1 and H3 viruses by adjuvanted influenza HA stem vaccines in nonhuman primates

Science Translational Medicine ◽

10.1126/scitranslmed.abe5449 ◽

2021 ◽

Vol 13 (583) ◽

pp. eabe5449

Author(s):

Nicole Darricarrère ◽

Yu Qiu ◽

Masaru Kanekiyo ◽

Adrian Creanga ◽

Rebecca A. Gillespie ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Nonhuman Primates ◽

Vaccine Development ◽

Protective Efficacy ◽

Neutralizing Antibody ◽

Gene Families ◽

Influenza Viruses ◽

Public Health Importance ◽

Water Emulsion

Seasonal influenza vaccines confer protection against specific viral strains but have restricted breadth that limits their protective efficacy. The H1 and H3 subtypes of influenza A virus cause most of the seasonal epidemics observed in humans and are the major drivers of influenza A virus–associated mortality. The consequences of pandemic spread of COVID-19 underscore the public health importance of prospective vaccine development. Here, we show that headless hemagglutinin (HA) stabilized-stem immunogens presented on ferritin nanoparticles elicit broadly neutralizing antibody (bnAb) responses to diverse H1 and H3 viruses in nonhuman primates (NHPs) when delivered with a squalene-based oil-in-water emulsion adjuvant, AF03. The neutralization potency and breadth of antibodies isolated from NHPs were comparable to human bnAbs and extended to mismatched heterosubtypic influenza viruses. Although NHPs lack the immunoglobulin germline VH1-69 residues associated with the most prevalent human stem-directed bnAbs, other gene families compensated to generate bnAbs. Isolation and structural analyses of vaccine-induced bnAbs revealed extensive interaction with the fusion peptide on the HA stem, which is essential for viral entry. Antibodies elicited by these headless HA stabilized-stem vaccines neutralized diverse H1 and H3 influenza viruses and shared a mode of recognition analogous to human bnAbs, suggesting that these vaccines have the potential to confer broadly protective immunity against diverse viruses responsible for seasonal and pandemic influenza infections in humans.

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Transcriptomic profile of chicken bone marrow-derive dendritic cells in response to H9N2 avian influenza A virus

Veterinary Immunology and Immunopathology ◽

10.1016/j.vetimm.2019.109992 ◽

2020 ◽

Vol 220 ◽

pp. 109992

Author(s):

Qingtao Liu ◽

Jing Yang ◽

Xinmei Huang ◽

Yuzhuo Liu ◽

Kaikai Han ◽

...

Keyword(s):

Bone Marrow ◽

Dendritic Cells ◽

Avian Influenza ◽

Influenza A Virus ◽

Influenza A ◽

Transcriptomic Profile ◽

Chicken Bone ◽

Avian Influenza A Virus

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Massive Mobilization of Dendritic Cells During Influenza A Virus Subtype H5N1 Infection of Nonhuman Primates

The Journal of Infectious Diseases ◽

10.1093/infdis/jiu009 ◽

2014 ◽

Vol 209 (12) ◽

pp. 2012-2016 ◽

Cited By ~ 9

Author(s):

Adam C. Soloff ◽

Stephanie J. Bissel ◽

Beth Fallert Junecko ◽

Brendan M. Giles ◽

Todd A. Reinhart ◽

...

Keyword(s):

Dendritic Cells ◽

Influenza A Virus ◽

Influenza A ◽

Nonhuman Primates ◽

H5n1 Infection ◽

Virus Subtype

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Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells

Blood ◽

10.1182/blood.v96.9.3102.h8003102_3102_3108 ◽

2000 ◽

Vol 96 (9) ◽

pp. 3102-3108

Author(s):

Peter Brossart ◽

Stefan Wirths ◽

Gernot Stuhler ◽

Volker L. Reichardt ◽

Lothar Kanz ◽

...

Keyword(s):

Ovarian Cancer ◽

Dendritic Cells ◽

T Lymphocytes ◽

Tumor Antigen ◽

Cytotoxic T Lymphocyte ◽

B Cell Lymphoma ◽

Breast And Ovarian Cancer ◽

Her 2 ◽

Single Tumor

Vaccination of patients with cancer using dendritic cells (DCs) was shown to be effective for B-cell lymphoma and malignant melanoma. Here we provide evidence that patients with advanced breast and ovarian cancer can be efficiently vaccinated with autologous DCs pulsed with HER-2/neu– or MUC1-derived peptides. Ten patients were included in this pilot study. The DC vaccinations were well tolerated with no side effects. In 5 of 10 patients, peptide-specific cytotoxic T lymphocytes (CTLs) could be detected in the peripheral blood using both intracellular IFN-γ staining and 51Cr-release assays. The major CTL response in vivo was induced with the HER-2/neu–derived E75 and the MUC1-derived M1.2 peptide, which lasted for more than 6 months, suggesting that these peptides might be immunodominant. In addition, in one patient vaccinated with the MUC1-derived peptides, CEA- and MAGE-3 peptide-specific T-cell responses were detected after several vaccinations. In a second patient immunized with the HER-2/neu peptides, MUC1-specific T lymphocytes were induced after 7 immunizations, suggesting that antigen spreading in vivo might occur after successful immunization with a single tumor antigen. Our results show that vaccination of DCs pulsed with a single tumor antigen may induce immunologic responses in patients with breast and ovarian cancer. This study may be relevant to the design of future clinical trials of other peptide-based vaccines.

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Avian influenza A virus PB2 promotes interferon type I inducing properties of a swine strain in porcine dendritic cells

Virology ◽

10.1016/j.virol.2012.01.037 ◽

2012 ◽

Vol 427 (1) ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Manuela Ocaña-Macchi ◽

Meret E. Ricklin ◽

Sylvie Python ◽

Gsell-Albert Monika ◽

Jürgen Stech ◽

...

Keyword(s):

Dendritic Cells ◽

Avian Influenza ◽

Influenza A Virus ◽

Influenza A ◽

Type I ◽

Avian Influenza A Virus ◽

Swine Strain

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A new strategy of immune evasion by influenza A virus: Inhibition of monocyte differentiation into dendritic cells

Veterinary Immunology and Immunopathology ◽

10.1016/j.vetimm.2010.03.004 ◽

2010 ◽

Vol 136 (3-4) ◽

pp. 201-210 ◽

Cited By ~ 10

Author(s):

Saikat Boliar ◽

Thomas M. Chambers

Keyword(s):

Dendritic Cells ◽

Influenza A Virus ◽

Immune Evasion ◽

Influenza A ◽

Monocyte Differentiation ◽

Virus Inhibition ◽

New Strategy

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Avian Influenza A Virus Pandemic Preparedness and Vaccine Development

Vaccines ◽

10.3390/vaccines6030046 ◽

2018 ◽

Vol 6 (3) ◽

pp. 46 ◽

Cited By ~ 7

Author(s):

Rory de Vries ◽

Sander Herfst ◽

Mathilde Richard

Keyword(s):

Avian Influenza ◽

Influenza A Virus ◽

Influenza A ◽

Vaccine Development ◽

Influenza Pandemic ◽

Broad Host Range ◽

Influenza A Viruses ◽

Vaccination Strategies ◽

Pandemic Virus ◽

Wide Range

Influenza A viruses can infect a wide range of hosts, creating opportunities for zoonotic transmission, i.e., transmission from animals to humans, and placing the human population at constant risk of potential pandemics. In the last hundred years, four influenza A virus pandemics have had a devastating effect, especially the 1918 influenza pandemic that took the lives of at least 40 million people. There is a constant risk that currently circulating avian influenza A viruses (e.g., H5N1, H7N9) will cause a new pandemic. Vaccines are the cornerstone in preparing for and combating potential pandemics. Despite exceptional advances in the design and development of (pre-)pandemic vaccines, there are still serious challenges to overcome, mainly caused by intrinsic characteristics of influenza A viruses: Rapid evolution and a broad host range combined with maintenance in animal reservoirs, making it near impossible to predict the nature and source of the next pandemic virus. Here, recent advances in the development of vaccination strategies to prepare against a pandemic virus coming from the avian reservoir will be discussed. Furthermore, remaining challenges will be addressed, setting the agenda for future research in the development of new vaccination strategies against potentially pandemic influenza A viruses.

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Influenza A Virus Subpopulations and Their Implication in Pathogenesis and Vaccine Development

Annual Review of Animal Biosciences ◽

10.1146/annurev-animal-021419-083756 ◽

2020 ◽

Vol 8 (1) ◽

pp. 247-267 ◽

Cited By ~ 1

Author(s):

Amir Ghorbani ◽

John M. Ngunjiri ◽

Chang-Won Lee

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Vaccine Development ◽

Current Knowledge ◽

Genomic Diversity ◽

Biologically Active ◽

Virus Particles ◽

Live Attenuated Influenza Vaccine ◽

Minor Portion ◽

A Minor

The concept of influenza A virus (IAV) subpopulations emerged approximately 75 years ago, when Preben von Magnus described “incomplete” virus particles that interfere with the replication of infectious virus. It is now widely accepted that infectious particles constitute only a minor portion of biologically active IAV subpopulations. The IAV quasispecies is an extremely diverse swarm of biologically and genetically heterogeneous particle subpopulations that collectively influence the evolutionary fitness of the virus. This review summarizes the current knowledge of IAV subpopulations, focusing on their biologic and genomic diversity. It also discusses the potential roles IAV subpopulations play in virus pathogenesis and live attenuated influenza vaccine development.

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