Controlling Influenza by Cytotoxic T-Cells: Calling for Help from Destroyers

Schotsaert, Michael; Ibáñez, Lorena Itatí; Fiers, Walter; Saelens, Xavier

doi:10.1155/2010/863985

Cited by 18 publications

(11 citation statements)

References 129 publications

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“…This might be of particular interest, since it was shown that CD4 + and CD8 + T-cell responses to influenza could partially confer protection from heterologous IAV infection [28]–[31]. It is further known that CTL responses play an important role in controlling RSV infection [32]–[34].…”

Section: Discussionmentioning

confidence: 99%

Protective Efficacy and Immunogenicity of a Combinatory DNA Vaccine against Influenza A Virus and the Respiratory Syncytial Virus

et al. 2013

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The Respiratory Syncytial Virus (RSV) and Influenza A Virus (IAV) are both two major causative agents of severe respiratory tract infections in humans leading to hospitalization and thousands of deaths each year. In this study, we evaluated the immunogenicity and efficacy of a combinatory DNA vaccine in comparison to the single component vaccines against both diseases in a mouse model. Intramuscular electroporation with plasmids expressing the hemagglutinin (HA) of IAV and the F protein of RSV induced strong humoral immune responses regardless if they were delivered in combination or alone. In consequence, high neutralizing antibody titers were detected, which conferred protection against a lethal challenge with IAV. Furthermore, the viral load in the lungs after a RSV infection could be dramatically reduced in vaccinated mice. Concurrently, substantial amounts of antigen-specific, polyfunctional CD8+ T-cells were measured after vaccination. Interestingly, the cellular response to the hemagglutinin was significantly reduced in the presence of the RSV-F encoding plasmid, but not vice versa. Although these results indicate a suppressive effect of the RSV-F protein, the protective efficacy of the combinatory vaccine was comparable to the efficacy of both single-component vaccines. In conclusion, the novel combinatory vaccine against RSV and IAV may have great potential to reduce the rate of severe respiratory tract infections in humans without increasing the number of necessary vaccinations.

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Section: Discussionmentioning

confidence: 99%

Protective Efficacy and Immunogenicity of a Combinatory DNA Vaccine against Influenza A Virus and the Respiratory Syncytial Virus

et al. 2013

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“…Cross-protective adaptive immunity is important in antigenically dissimilar influenza viruses, as has been shown in animal studies and limited human studies (8,9,17,(38)(39)(40)(41)(42)(43). There is strong evidence in the literature that CD8+ T cells play a large role in providing such cross-immunity to influenza virus that has drifted enough to evade neutralizing antibodies (13,14,17,38,(44)(45)(46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

CD8+ T cell immunity to 2009 pandemic and seasonal H1N1 influenza viruses

Scheible

Zhang

Baer

et al. 2011

Vaccine

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A novel strain of H1N1 influenza A virus (pH1N1) emerged in 2009, causing a worldwide pandemic. Several studies suggest that this virus is antigenically more closely related to human influenza viruses that circulated prior to 1957 than viruses of more recent seasonal influenza varieties. The extent to which individuals who are naïve to the 2009 pH1N1 virus carry cross-reactive CD8+ T cells is not known, but a certain degree of reactivity would be expected since there is substantial conservation among the internal proteins of the virus. In the present study, we examined production of multiple cytokines in response to virus from CD8+ T cells in healthy adult subjects, between 18 and 50 years of age (born post 1957), who had no evidence of exposure to the 2009 pH1N1 virus, and had blood collected prior to the emergence of the pandemic in April of 2009. Human peripheral blood mononuclear cells (PBMC) were stimulated in vitro with a panel of live viruses, and assayed by intracellular cytokine staining and flow cytometry. Although results were variable, most subjects exhibited cytokine positive CD8+ T cells in response to pH1N1. Cytokine producing cells were predominantly single positive (IL2, IFNγ, or TNFα); triple-cytokine producing cells were relatively rare. This result suggests that although many adults carry cross-reactive T cells against the emergent pandemic virus, these cells are in a functionally limited state, possibly because these subjects have not had recent exposure to either seasonal or pandemic influenza strains.

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“…One strategy to induce heterosubtypic immunity is vaccination with a formulation that has the capacity to induce cross-reactive CD8+ cytotoxic T lymphocyte (CTL) responses against conserved antigens shared by different influenza virus subtypes [5] , [7] , [8] . CTL-mediated heterosubtypic immunity, although unable to neutralize the virus and prevent infection, could facilitate clearance of the virus, thereby controlling the course of infection [5] , [9] .…”

Section: Introductionmentioning

confidence: 99%

Induction of Heterosubtypic Cross-Protection against Influenza by a Whole Inactivated Virus Vaccine: The Role of Viral Membrane Fusion Activity

et al. 2012

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BackgroundThe inability of seasonal influenza vaccines to effectively protect against infection with antigenically drifted viruses or newly emerging pandemic viruses underlines the need for development of cross-reactive influenza vaccines that induce immunity against a variety of virus subtypes. Therefore, potential cross-protective vaccines, e.g., whole inactivated virus (WIV) vaccine, that can target conserved internal antigens such as the nucleoprotein (NP) and/or matrix protein (M1) need to be explored.Methodology/Principal FindingsIn the current study we show that a WIV vaccine, through induction of cross-protective cytotoxic T lymphocytes (CTLs), protects mice from heterosubtypic infection. This protection was abrogated after depletion of CD8+ cells in vaccinated mice, indicating that CTLs were the primary mediators of protection. Previously, we have shown that different procedures used for virus inactivation influence optimal activation of CTLs by WIV, most likely by affecting the membrane fusion properties of the virus. Specifically, inactivation with formalin (FA) severely compromises fusion activity of the virus, while inactivation with β-propiolactone (BPL) preserves fusion activity. Here, we demonstrate that vaccination of mice with BPL-inactivated H5N1 WIV vaccine induces solid protection from lethal heterosubtypic H1N1 challenge. By contrast, vaccination with FA-inactivated WIV, while preventing death after lethal challenge, failed to protect against development of disease and severe body weight loss. Vaccination with BPL-inactivated WIV, compared to FA-inactivated WIV, induced higher levels of specific CD8+ T cells in blood, spleen and lungs, and a higher production of granzyme B in the lungs upon H1N1 virus challenge.Conclusion/SignificanceThe results underline the potential use of WIV as a cross-protective influenza vaccine candidate. However, careful choice of the virus inactivation procedure is important to retain membrane fusion activity and full immunogenicity of the vaccine.

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Controlling Influenza by Cytotoxic T-Cells: Calling for Help from Destroyers

Cited by 18 publications

References 129 publications

Protective Efficacy and Immunogenicity of a Combinatory DNA Vaccine against Influenza A Virus and the Respiratory Syncytial Virus

Protective Efficacy and Immunogenicity of a Combinatory DNA Vaccine against Influenza A Virus and the Respiratory Syncytial Virus

CD8+ T cell immunity to 2009 pandemic and seasonal H1N1 influenza viruses

Induction of Heterosubtypic Cross-Protection against Influenza by a Whole Inactivated Virus Vaccine: The Role of Viral Membrane Fusion Activity

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