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Guus F Rimmelzwaan - One of the best experts on this subject based on the ideXlab platform.
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virus specific t cells as correlate of cross protective Immunity against influenza
Vaccine, 2015Co-Authors: Arwen F Altenburg, Guus F Rimmelzwaan, Rory D De VriesAbstract:Since inactivated influenza vaccines mainly confer protective Immunity by inducing strain-specific antibodies to the viral hemagglutinin, these vaccines only afford protection against infection with antigenically matching influenza virus strains. Due to the continuous emergence of antigenic drift variants of seasonal influenza viruses and the inevitable future emergence of pandemic influenza viruses, there is considerable interest in the development of influenza vaccines that induce broader protective Immunity. It has long been recognized that influenza virus-specific CD8(+) T cells directed to epitopes located in the relatively conserved internal proteins can cross-react with various subtypes of influenza A virus. This implies that these CD8(+) T cells, induced by prior influenza virus infections or vaccinations, could afford Heterosubtypic Immunity. Furthermore, influenza virus-specific CD4(+) T cells have been shown to be important in protection from infection, either via direct cytotoxic effects or indirectly by providing help to B cells and CD8(+) T cells. In the present paper, we review the induction of virus-specific T cell responses by influenza virus infection and the role of virus-specific CD4(+) and CD8(+) T cells in viral clearance and conferring protection from subsequent infections with homologous or heterologous influenza virus strains. Furthermore, we discuss vector-based vaccination strategies that aim at the induction of a cross-reactive virus-specific T cell response.
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clearance of influenza virus infections by t cells risk of collateral damage
Current Opinion in Virology, 2013Co-Authors: Marine L B Hillaire, Guus F Rimmelzwaan, Joost H C M KreijtzAbstract:Influenza A viruses are a major cause of respiratory infections in humans. To protect against influenza, vaccines mainly aim at the induction of antibodies against the two surface proteins and do not protect against influenza A viruses from other subtypes. There is an increasing interest in Heterosubtypic Immunity that does protect against different subtypes. CD8 and CD4 T cells have a beneficial effect on the course of influenza A virus infection and can recognize conserved IAV epitopes. The T cell responses are tightly regulated to avoid collateral damage due to overreaction. Different studies have shown that an aberrant T cell response to an influenza virus infection could be harmful and could contribute to immunopathology. Here we discuss the recent findings on the balance between the beneficial and detrimental effects of T cell responses in influenza virus infections.
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annual influenza vaccination affects the development of Heterosubtypic Immunity
Vaccine, 2012Co-Authors: Rogier Bodewes, Joost H C M Kreijtz, Martina M Geelhoedmieras, Ron A M Fouchier, Albert D M E Osterhaus, Pieter L A Fraaij, Guus F RimmelzwaanAbstract:Annual vaccination of healthy children >6 months of age against seasonal influenza has been recommended by public health authorities of some countries. However, currently used seasonal vaccines provide only limited protection against (potentially) pandemic influenza viruses. Furthermore, we recently hypothesized that annual vaccination may hamper the development of cross-reactive Immunity against influenza A viruses of novel subtypes, that would otherwise be induced by natural infection. Here we summarize our findings in animal models in which we demonstrated that vaccination against influenza A/H3N2 virus reduced the induction of Heterosubtypic Immunity against highly pathogenic avian influenza A/H5N1 virus, otherwise induced by a prior infection with influenza A/H3N2 virus. The reduction of Heterosubtypic Immunity correlated with reduced virus-specific CD8+ T cell responses. An additional study was performed in humans, in which we collected peripheral blood mononuclear cells from annually vaccinated children with cystic fibrosis (CF) and age-matched unvaccinated healthy control children to study the virus-specific T cell response. An age-related increase of the virus-specific CD8+ T cell response was observed in unvaccinated children that was absent in vaccinated children with CF. These findings highlight the importance of the development of vaccines that provide protection against influenza A viruses of all subtypes.
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cross protective Immunity against influenza ph1n1 2009 viruses induced by seasonal influenza a h3n2 virus is mediated by virus specific t cells
Journal of General Virology, 2011Co-Authors: Marine L B Hillaire, Rogier Bodewes, Joost H C M Kreijtz, Martina M Geelhoedmieras, Ron A M Fouchier, Albert D M E Osterhaus, S E Van Trierum, Thijs Kuiken, Nella J Nieuwkoop, Guus F RimmelzwaanAbstract:Influenza A (H1N1) viruses of swine origin were introduced into the human population in 2009 and caused a pandemic. The disease burden in the elderly was relatively low, which was attributed to the presence of cross-reacting serum antibodies in this age group, which were raised against seasonal influenza A (H1N1) viruses that circulated before 1957. It has also been described how infection with Heterosubtypic influenza viruses can induce some degree of protection against infection by a novel strain of influenza virus. Here, we assess the extent of protective Immunity against infection with the 2009 influenza A (H1N1) pandemic influenza virus that is afforded by infection with a seasonal influenza A (H3N2) virus in mice. Mice that experienced a primary A (H3N2) influenza virus infection displayed reduced weight loss after challenge infection and cleared the 2009 influenza A (H1N1) virus infection more rapidly. To elucidate the correlates of protection of this Heterosubtypic Immunity to pandemic H1N1 virus infection, adoptive transfer experiments were carried out by using selected post-infection lymphocyte populations. Virus-specific CD8+ T-cells in concert with CD4+ T-cells were responsible for the observed protection. These findings may not only provide an explanation for epidemiological differences in the incidence of severe pandemic H1N1 infections, they also indicate that the induction of cross-reactive virus-specific CD8+ and CD4+ T-cell responses may be a suitable approach for the development of universal influenza vaccines.
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vaccination against seasonal influenza a h3n2 virus reduces the induction of Heterosubtypic Immunity against influenza a h5n1 virus infection in ferrets
Journal of Virology, 2011Co-Authors: Rogier Bodewes, Joost H C M Kreijtz, Martina M Geelhoedmieras, Ron A M Fouchier, Albert D M E Osterhaus, G Van Amerongen, R J Verburgh, S E Van Trierum, Thijs Kuiken, Guus F RimmelzwaanAbstract:Infection with seasonal influenza viruses induces a certain extent of protective Immunity against potentially pandemic viruses of novel subtypes, also known as Heterosubtypic Immunity. Here we demonstrate that infection with a recent influenza A/H3N2 virus strain induces robust protection in ferrets against infection with a highly pathogenic avian influenza virus of the H5N1 subtype. Prior H3N2 virus infection reduced H5N1 virus replication in the upper respiratory tract, as well as clinical signs, mortality, and histopathological changes associated with virus replication in the brain. This protective Immunity correlated with the induction of T cells that cross-reacted with H5N1 viral antigen. We also demonstrated that prior vaccination against influenza A/H3N2 virus reduced the induction of Heterosubtypic Immunity otherwise induced by infection with the influenza A/H3N2 virus. The implications of these findings are discussed in the context of vaccination strategies and vaccine development aiming at the induction of Immunity to pandemic influenza.
Joost H C M Kreijtz - One of the best experts on this subject based on the ideXlab platform.
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Heterosubtypic Immunity to h7n9 influenza virus in isogenic guinea pigs after infection with pandemic h1n1 virus
Vaccine, 2015Co-Authors: Lidewij Wiersma, Joost H C M Kreijtz, Ron A M Fouchier, G Van Amerongen, Stella Vogelzangvan E Trierum, Peter Van Run, Mechtild Ladwig, Stefanie Banneke, Hubert Schaefer, Thijs KuikenAbstract:Heterosubtypic Immunity is defined as immune-mediated (partial) protection against an influenza virus induced by an influenza virus of another subtype to which the host has not previously been exposed. This cross-protective effect has not yet been demonstrated to the newly emerging avian influenza A viruses of the H7N9 subtype. Here, we assessed the induction of protective Immunity to these viruses by infection with A(H1N1)pdm09 virus in a newly developed guinea pig model. To this end, ten female 12-16 week old strain 2 guinea pigs were inoculated intratracheally with either A(H1N1)pdm09 influenza virus or PBS (unprimed controls) followed 4 weeks later with an A/H7N9 influenza virus challenge. Nasal swabs were taken daily and animals from both groups were sacrificed on days 2 and 7 post inoculation (p.i.) with A/H7N9 virus and full necropsies were performed. Nasal virus excretion persisted until day 7 in unprimed control animals, whereas only two out of seven H1N1pdm09-primed animals excreted virus via the nose. Infectious virus was recovered from nasal turbinates, trachea and lung of all animals at day 2 p.i., but titers were lower for H1N1pdm09-primed animals, especially in the nasal turbinates. By day 7 p.i., relatively high virus titers were found in the nasal turbinates of all unprimed control animals but infectious virus was isolated from the nose of only one of four H1N1pdm09-primed animals. Animals of both groups developed inflammation of variable severity in the entire respiratory tract. Viral antigen positive cells were demonstrated in the nasal epithelium of both groups at day 2. The bronchi(oli) and alveoli of unprimed animals showed a moderate to strong positive signal at day 2, whereas H1N1pdm09-primed animals showed only minimal positivity. By day 7, only viral antigen positive cells were found after H7N9 virus infection in the nasal turbinates and the lungs of unprimed controls. Thus infection with H1N1pdm09 virus induced partially protective Heterosubtypic Immunity to H7N9 virus in (isogenic) guinea pigs that could not be attributed to cross-reactive virus neutralizing antibodies.
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clearance of influenza virus infections by t cells risk of collateral damage
Current Opinion in Virology, 2013Co-Authors: Marine L B Hillaire, Guus F Rimmelzwaan, Joost H C M KreijtzAbstract:Influenza A viruses are a major cause of respiratory infections in humans. To protect against influenza, vaccines mainly aim at the induction of antibodies against the two surface proteins and do not protect against influenza A viruses from other subtypes. There is an increasing interest in Heterosubtypic Immunity that does protect against different subtypes. CD8 and CD4 T cells have a beneficial effect on the course of influenza A virus infection and can recognize conserved IAV epitopes. The T cell responses are tightly regulated to avoid collateral damage due to overreaction. Different studies have shown that an aberrant T cell response to an influenza virus infection could be harmful and could contribute to immunopathology. Here we discuss the recent findings on the balance between the beneficial and detrimental effects of T cell responses in influenza virus infections.
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infection of the upper respiratory tract with seasonal influenza a h3n2 virus induces protective Immunity in ferrets against infection with a h1n1 pdm09 virus after intranasal but not intratracheal inoculation
Journal of Virology, 2013Co-Authors: Rogier Bodewes, Joost H C M Kreijtz, Marine L B Hillaire, Ron A M Fouchier, G Van Amerongen, Thijs Kuiken, Nella J Nieuwkoop, Stella Vogelzangvan E Trierum, Peter Van Run, Albert D M E OsterhausAbstract:The clinical symptoms caused by infection with influenza A virus vary widely and depend on the strain causing the infection, the dose and route of inoculation, and the presence of preexisting Immunity. In most cases, seasonal influenza A viruses cause relatively mild upper respiratory tract disease, while sometimes patients develop an acute severe pneumonia. Heterosubtypic Immunity induced by previous infections with influenza A viruses may dampen the development of clinical symptoms caused by infection with influenza A viruses of another subtype, as is the case during influenza pandemics. Here we show that ferrets acquire protective Immunity after infection of the upper respiratory tract with a seasonal influenza A(H3N2) virus against subsequent infection with influenza A(H1N1)pdm09 virus inoculated by the intranasal route. However, protective Heterosubtypic Immunity was afforded locally, since the prior infection with the A(H3N2) virus did not provide protection against the development of pneumonia induced after intratracheal inoculation with the A(H1N1)pdm09 virus. Interestingly, some of these animals developed more severe disease than that observed in naive control animals. These findings are of interest in light of the development of so-called universal influenza vaccines that aim at the induction of cross-reactive T cell responses.
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annual influenza vaccination affects the development of Heterosubtypic Immunity
Vaccine, 2012Co-Authors: Rogier Bodewes, Joost H C M Kreijtz, Martina M Geelhoedmieras, Ron A M Fouchier, Albert D M E Osterhaus, Pieter L A Fraaij, Guus F RimmelzwaanAbstract:Annual vaccination of healthy children >6 months of age against seasonal influenza has been recommended by public health authorities of some countries. However, currently used seasonal vaccines provide only limited protection against (potentially) pandemic influenza viruses. Furthermore, we recently hypothesized that annual vaccination may hamper the development of cross-reactive Immunity against influenza A viruses of novel subtypes, that would otherwise be induced by natural infection. Here we summarize our findings in animal models in which we demonstrated that vaccination against influenza A/H3N2 virus reduced the induction of Heterosubtypic Immunity against highly pathogenic avian influenza A/H5N1 virus, otherwise induced by a prior infection with influenza A/H3N2 virus. The reduction of Heterosubtypic Immunity correlated with reduced virus-specific CD8+ T cell responses. An additional study was performed in humans, in which we collected peripheral blood mononuclear cells from annually vaccinated children with cystic fibrosis (CF) and age-matched unvaccinated healthy control children to study the virus-specific T cell response. An age-related increase of the virus-specific CD8+ T cell response was observed in unvaccinated children that was absent in vaccinated children with CF. These findings highlight the importance of the development of vaccines that provide protection against influenza A viruses of all subtypes.
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cross protective Immunity against influenza ph1n1 2009 viruses induced by seasonal influenza a h3n2 virus is mediated by virus specific t cells
Journal of General Virology, 2011Co-Authors: Marine L B Hillaire, Rogier Bodewes, Joost H C M Kreijtz, Martina M Geelhoedmieras, Ron A M Fouchier, Albert D M E Osterhaus, S E Van Trierum, Thijs Kuiken, Nella J Nieuwkoop, Guus F RimmelzwaanAbstract:Influenza A (H1N1) viruses of swine origin were introduced into the human population in 2009 and caused a pandemic. The disease burden in the elderly was relatively low, which was attributed to the presence of cross-reacting serum antibodies in this age group, which were raised against seasonal influenza A (H1N1) viruses that circulated before 1957. It has also been described how infection with Heterosubtypic influenza viruses can induce some degree of protection against infection by a novel strain of influenza virus. Here, we assess the extent of protective Immunity against infection with the 2009 influenza A (H1N1) pandemic influenza virus that is afforded by infection with a seasonal influenza A (H3N2) virus in mice. Mice that experienced a primary A (H3N2) influenza virus infection displayed reduced weight loss after challenge infection and cleared the 2009 influenza A (H1N1) virus infection more rapidly. To elucidate the correlates of protection of this Heterosubtypic Immunity to pandemic H1N1 virus infection, adoptive transfer experiments were carried out by using selected post-infection lymphocyte populations. Virus-specific CD8+ T-cells in concert with CD4+ T-cells were responsible for the observed protection. These findings may not only provide an explanation for epidemiological differences in the incidence of severe pandemic H1N1 infections, they also indicate that the induction of cross-reactive virus-specific CD8+ and CD4+ T-cell responses may be a suitable approach for the development of universal influenza vaccines.
Rogier Bodewes - One of the best experts on this subject based on the ideXlab platform.
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infection of the upper respiratory tract with seasonal influenza a h3n2 virus induces protective Immunity in ferrets against infection with a h1n1 pdm09 virus after intranasal but not intratracheal inoculation
Journal of Virology, 2013Co-Authors: Rogier Bodewes, Joost H C M Kreijtz, Marine L B Hillaire, Ron A M Fouchier, G Van Amerongen, Thijs Kuiken, Nella J Nieuwkoop, Stella Vogelzangvan E Trierum, Peter Van Run, Albert D M E OsterhausAbstract:The clinical symptoms caused by infection with influenza A virus vary widely and depend on the strain causing the infection, the dose and route of inoculation, and the presence of preexisting Immunity. In most cases, seasonal influenza A viruses cause relatively mild upper respiratory tract disease, while sometimes patients develop an acute severe pneumonia. Heterosubtypic Immunity induced by previous infections with influenza A viruses may dampen the development of clinical symptoms caused by infection with influenza A viruses of another subtype, as is the case during influenza pandemics. Here we show that ferrets acquire protective Immunity after infection of the upper respiratory tract with a seasonal influenza A(H3N2) virus against subsequent infection with influenza A(H1N1)pdm09 virus inoculated by the intranasal route. However, protective Heterosubtypic Immunity was afforded locally, since the prior infection with the A(H3N2) virus did not provide protection against the development of pneumonia induced after intratracheal inoculation with the A(H1N1)pdm09 virus. Interestingly, some of these animals developed more severe disease than that observed in naive control animals. These findings are of interest in light of the development of so-called universal influenza vaccines that aim at the induction of cross-reactive T cell responses.
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annual influenza vaccination affects the development of Heterosubtypic Immunity
Vaccine, 2012Co-Authors: Rogier Bodewes, Joost H C M Kreijtz, Martina M Geelhoedmieras, Ron A M Fouchier, Albert D M E Osterhaus, Pieter L A Fraaij, Guus F RimmelzwaanAbstract:Annual vaccination of healthy children >6 months of age against seasonal influenza has been recommended by public health authorities of some countries. However, currently used seasonal vaccines provide only limited protection against (potentially) pandemic influenza viruses. Furthermore, we recently hypothesized that annual vaccination may hamper the development of cross-reactive Immunity against influenza A viruses of novel subtypes, that would otherwise be induced by natural infection. Here we summarize our findings in animal models in which we demonstrated that vaccination against influenza A/H3N2 virus reduced the induction of Heterosubtypic Immunity against highly pathogenic avian influenza A/H5N1 virus, otherwise induced by a prior infection with influenza A/H3N2 virus. The reduction of Heterosubtypic Immunity correlated with reduced virus-specific CD8+ T cell responses. An additional study was performed in humans, in which we collected peripheral blood mononuclear cells from annually vaccinated children with cystic fibrosis (CF) and age-matched unvaccinated healthy control children to study the virus-specific T cell response. An age-related increase of the virus-specific CD8+ T cell response was observed in unvaccinated children that was absent in vaccinated children with CF. These findings highlight the importance of the development of vaccines that provide protection against influenza A viruses of all subtypes.
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cross protective Immunity against influenza ph1n1 2009 viruses induced by seasonal influenza a h3n2 virus is mediated by virus specific t cells
Journal of General Virology, 2011Co-Authors: Marine L B Hillaire, Rogier Bodewes, Joost H C M Kreijtz, Martina M Geelhoedmieras, Ron A M Fouchier, Albert D M E Osterhaus, S E Van Trierum, Thijs Kuiken, Nella J Nieuwkoop, Guus F RimmelzwaanAbstract:Influenza A (H1N1) viruses of swine origin were introduced into the human population in 2009 and caused a pandemic. The disease burden in the elderly was relatively low, which was attributed to the presence of cross-reacting serum antibodies in this age group, which were raised against seasonal influenza A (H1N1) viruses that circulated before 1957. It has also been described how infection with Heterosubtypic influenza viruses can induce some degree of protection against infection by a novel strain of influenza virus. Here, we assess the extent of protective Immunity against infection with the 2009 influenza A (H1N1) pandemic influenza virus that is afforded by infection with a seasonal influenza A (H3N2) virus in mice. Mice that experienced a primary A (H3N2) influenza virus infection displayed reduced weight loss after challenge infection and cleared the 2009 influenza A (H1N1) virus infection more rapidly. To elucidate the correlates of protection of this Heterosubtypic Immunity to pandemic H1N1 virus infection, adoptive transfer experiments were carried out by using selected post-infection lymphocyte populations. Virus-specific CD8+ T-cells in concert with CD4+ T-cells were responsible for the observed protection. These findings may not only provide an explanation for epidemiological differences in the incidence of severe pandemic H1N1 infections, they also indicate that the induction of cross-reactive virus-specific CD8+ and CD4+ T-cell responses may be a suitable approach for the development of universal influenza vaccines.
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vaccination against seasonal influenza a h3n2 virus reduces the induction of Heterosubtypic Immunity against influenza a h5n1 virus infection in ferrets
Journal of Virology, 2011Co-Authors: Rogier Bodewes, Joost H C M Kreijtz, Martina M Geelhoedmieras, Ron A M Fouchier, Albert D M E Osterhaus, G Van Amerongen, R J Verburgh, S E Van Trierum, Thijs Kuiken, Guus F RimmelzwaanAbstract:Infection with seasonal influenza viruses induces a certain extent of protective Immunity against potentially pandemic viruses of novel subtypes, also known as Heterosubtypic Immunity. Here we demonstrate that infection with a recent influenza A/H3N2 virus strain induces robust protection in ferrets against infection with a highly pathogenic avian influenza virus of the H5N1 subtype. Prior H3N2 virus infection reduced H5N1 virus replication in the upper respiratory tract, as well as clinical signs, mortality, and histopathological changes associated with virus replication in the brain. This protective Immunity correlated with the induction of T cells that cross-reacted with H5N1 viral antigen. We also demonstrated that prior vaccination against influenza A/H3N2 virus reduced the induction of Heterosubtypic Immunity otherwise induced by infection with the influenza A/H3N2 virus. The implications of these findings are discussed in the context of vaccination strategies and vaccine development aiming at the induction of Immunity to pandemic influenza.
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vaccination with whole inactivated virus vaccine affects the induction of Heterosubtypic Immunity against influenza virus a h5n1 and immunodominance of virus specific cd8 t cell responses in mice
Journal of General Virology, 2010Co-Authors: Rogier Bodewes, Joost H C M Kreijtz, Marine L B Hillaire, Martina M Geelhoedmieras, Ron A M Fouchier, Albert D M E Osterhaus, Guus F RimmelzwaanAbstract:It was recently shown that the use of an experimental subunit vaccine protected mice against infection with a human A/H3N2 influenza virus, but consequently affected the induction of Heterosubtypic Immunity to a highly pathogenic A/H5N1 influenza virus, which was otherwise induced by the A/H3N2 infection. As whole inactivated virus (WIV) vaccines are widely used to protect against seasonal influenza and also contain inner viral proteins such as the nucleoprotein (NP), the potential of a WIV vaccine to induce protective Immunity against infection was tested with a homologous A/H3N2 (A/Hong Kong/2/68) and a Heterosubtypic A/H5N1 influenza virus (A/Indonesia/5/05). As expected, the vaccine afforded protection against infection with the A/H3N2 virus only. In addition, it was demonstrated that the use of WIV vaccine for protection against A/H3N2 infection affected the induction of Heterosubtypic Immunity that was otherwise afforded by A/H3N2 influenza virus infection. The reduction in protective Immunity correlated with changes in the immunodominance patterns of the CD8+ T-cell responses directed to the epitopes located in the acid polymerase subunit of the viral RNA polymerase (PA224–233) and the NP (NP366–374). In unvaccinated mice that experienced infection with the A/H3N2 influenza virus, the magnitude of the CD8+ T-cell response to both peptides was similar on secondary infection with A/H5N1 influenza virus. In contrast, prior vaccination with WIV affected the immunodominance pattern and skewed the response after infection with influenza virus A/Indonesia/5/05 towards a dominant NP366–374-specific response. These findings may have implications for vaccination strategies aimed at the induction of protective Immunity to seasonal and/or pandemic influenza.
Albert D M E Osterhaus - One of the best experts on this subject based on the ideXlab platform.
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Heterosubtypic Immunity to Influenza A Virus Infections in Mallards May Explain Existence of Multiple Virus
2016Co-Authors: Ron A M Fouchier, Albert D M E OsterhausAbstract:Wild birds, particularly duck species, are the main reservoir of influenza A virus (IAV) in nature. However, knowledge of IAV infection dynamics in the wild bird reservoir, and the development of immune responses, are essentially absent. Importantly, a detailed understanding of how subtype diversity is generated and maintained is lacking. To address this, 18,679 samples from 7728 Mallard ducks captured between 2002 and 2009 at a single stopover site in Sweden were screened for IAV infections, and the resulting 1081 virus isolates were analyzed for patterns of Immunity. We found support for development of homosubtypic hemagglutinin (HA) Immunity during the peak of IAV infections in the fall. Moreover, re-infections with the same HA subtype and related prevalent HA subtypes were uncommon, suggesting the development of natural homosubtypic and Heterosubtypic Immunity (p-value = 0.02). Heterosubtypic Immunity followed phylogenetic relatedness of HA subtypes, both at the level of HA clades (p-value = 0.04) and the level of HA groups (p-value = 0.05). In contrast, infection patterns did not support specific Immunity for neuraminidase (NA) subtypes. For the H1 and H3 Clades, Heterosubtypic Immunity showed a clear temporal pattern and we estimated within-clade Immunity to last at least 30 days. The strength and duration of Heterosubtypic Immunity has important implications for transmission dynamics of IAV in th
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Heterosubtypic Immunity to influenza a virus infections in mallards may explain existence of multiple virus subtypes
PLOS Pathogens, 2013Co-Authors: Neus Latorremargalef, Ron A M Fouchier, Albert D M E Osterhaus, Vladimir Grosbois, John Wahlgren, Vincent J Munster, Conny Tolf, Bjorn R Olsen, Jonas WaldenstromAbstract:Wild birds, particularly duck species, are the main reservoir of influenza A virus (IAV) in nature. However, knowledge of IAV infection dynamics in the wild bird reservoir, and the development of immune responses, are essentially absent. Importantly, a detailed understanding of how subtype diversity is generated and maintained is lacking. To address this, 18,679 samples from 7728 Mallard ducks captured between 2002 and 2009 at a single stopover site in Sweden were screened for IAV infections, and the resulting 1081 virus isolates were analyzed for patterns of Immunity. We found support for development of homosubtypic hemagglutinin (HA) Immunity during the peak of IAV infections in the fall. Moreover, re-infections with the same HA subtype and related prevalent HA subtypes were uncommon, suggesting the development of natural homosubtypic and Heterosubtypic Immunity (p-value = 0.02). Heterosubtypic Immunity followed phylogenetic relatedness of HA subtypes, both at the level of HA clades (p-value = 0.04) and the level of HA groups (p-value = 0.05). In contrast, infection patterns did not support specific Immunity for neuraminidase (NA) subtypes. For the H1 and H3 Clades, Heterosubtypic Immunity showed a clear temporal pattern and we estimated within-clade Immunity to last at least 30 days. The strength and duration of Heterosubtypic Immunity has important implications for transmission dynamics of IAV in the natural reservoir, where immune escape and disruptive selection may increase HA antigenic variation and explain IAV subtype diversity.
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infection of the upper respiratory tract with seasonal influenza a h3n2 virus induces protective Immunity in ferrets against infection with a h1n1 pdm09 virus after intranasal but not intratracheal inoculation
Journal of Virology, 2013Co-Authors: Rogier Bodewes, Joost H C M Kreijtz, Marine L B Hillaire, Ron A M Fouchier, G Van Amerongen, Thijs Kuiken, Nella J Nieuwkoop, Stella Vogelzangvan E Trierum, Peter Van Run, Albert D M E OsterhausAbstract:The clinical symptoms caused by infection with influenza A virus vary widely and depend on the strain causing the infection, the dose and route of inoculation, and the presence of preexisting Immunity. In most cases, seasonal influenza A viruses cause relatively mild upper respiratory tract disease, while sometimes patients develop an acute severe pneumonia. Heterosubtypic Immunity induced by previous infections with influenza A viruses may dampen the development of clinical symptoms caused by infection with influenza A viruses of another subtype, as is the case during influenza pandemics. Here we show that ferrets acquire protective Immunity after infection of the upper respiratory tract with a seasonal influenza A(H3N2) virus against subsequent infection with influenza A(H1N1)pdm09 virus inoculated by the intranasal route. However, protective Heterosubtypic Immunity was afforded locally, since the prior infection with the A(H3N2) virus did not provide protection against the development of pneumonia induced after intratracheal inoculation with the A(H1N1)pdm09 virus. Interestingly, some of these animals developed more severe disease than that observed in naive control animals. These findings are of interest in light of the development of so-called universal influenza vaccines that aim at the induction of cross-reactive T cell responses.
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annual influenza vaccination affects the development of Heterosubtypic Immunity
Vaccine, 2012Co-Authors: Rogier Bodewes, Joost H C M Kreijtz, Martina M Geelhoedmieras, Ron A M Fouchier, Albert D M E Osterhaus, Pieter L A Fraaij, Guus F RimmelzwaanAbstract:Annual vaccination of healthy children >6 months of age against seasonal influenza has been recommended by public health authorities of some countries. However, currently used seasonal vaccines provide only limited protection against (potentially) pandemic influenza viruses. Furthermore, we recently hypothesized that annual vaccination may hamper the development of cross-reactive Immunity against influenza A viruses of novel subtypes, that would otherwise be induced by natural infection. Here we summarize our findings in animal models in which we demonstrated that vaccination against influenza A/H3N2 virus reduced the induction of Heterosubtypic Immunity against highly pathogenic avian influenza A/H5N1 virus, otherwise induced by a prior infection with influenza A/H3N2 virus. The reduction of Heterosubtypic Immunity correlated with reduced virus-specific CD8+ T cell responses. An additional study was performed in humans, in which we collected peripheral blood mononuclear cells from annually vaccinated children with cystic fibrosis (CF) and age-matched unvaccinated healthy control children to study the virus-specific T cell response. An age-related increase of the virus-specific CD8+ T cell response was observed in unvaccinated children that was absent in vaccinated children with CF. These findings highlight the importance of the development of vaccines that provide protection against influenza A viruses of all subtypes.
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cross protective Immunity against influenza ph1n1 2009 viruses induced by seasonal influenza a h3n2 virus is mediated by virus specific t cells
Journal of General Virology, 2011Co-Authors: Marine L B Hillaire, Rogier Bodewes, Joost H C M Kreijtz, Martina M Geelhoedmieras, Ron A M Fouchier, Albert D M E Osterhaus, S E Van Trierum, Thijs Kuiken, Nella J Nieuwkoop, Guus F RimmelzwaanAbstract:Influenza A (H1N1) viruses of swine origin were introduced into the human population in 2009 and caused a pandemic. The disease burden in the elderly was relatively low, which was attributed to the presence of cross-reacting serum antibodies in this age group, which were raised against seasonal influenza A (H1N1) viruses that circulated before 1957. It has also been described how infection with Heterosubtypic influenza viruses can induce some degree of protection against infection by a novel strain of influenza virus. Here, we assess the extent of protective Immunity against infection with the 2009 influenza A (H1N1) pandemic influenza virus that is afforded by infection with a seasonal influenza A (H3N2) virus in mice. Mice that experienced a primary A (H3N2) influenza virus infection displayed reduced weight loss after challenge infection and cleared the 2009 influenza A (H1N1) virus infection more rapidly. To elucidate the correlates of protection of this Heterosubtypic Immunity to pandemic H1N1 virus infection, adoptive transfer experiments were carried out by using selected post-infection lymphocyte populations. Virus-specific CD8+ T-cells in concert with CD4+ T-cells were responsible for the observed protection. These findings may not only provide an explanation for epidemiological differences in the incidence of severe pandemic H1N1 infections, they also indicate that the induction of cross-reactive virus-specific CD8+ and CD4+ T-cell responses may be a suitable approach for the development of universal influenza vaccines.
Ron A M Fouchier - One of the best experts on this subject based on the ideXlab platform.
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Heterosubtypic Immunity to Influenza A Virus Infections in Mallards May Explain Existence of Multiple Virus
2016Co-Authors: Ron A M Fouchier, Albert D M E OsterhausAbstract:Wild birds, particularly duck species, are the main reservoir of influenza A virus (IAV) in nature. However, knowledge of IAV infection dynamics in the wild bird reservoir, and the development of immune responses, are essentially absent. Importantly, a detailed understanding of how subtype diversity is generated and maintained is lacking. To address this, 18,679 samples from 7728 Mallard ducks captured between 2002 and 2009 at a single stopover site in Sweden were screened for IAV infections, and the resulting 1081 virus isolates were analyzed for patterns of Immunity. We found support for development of homosubtypic hemagglutinin (HA) Immunity during the peak of IAV infections in the fall. Moreover, re-infections with the same HA subtype and related prevalent HA subtypes were uncommon, suggesting the development of natural homosubtypic and Heterosubtypic Immunity (p-value = 0.02). Heterosubtypic Immunity followed phylogenetic relatedness of HA subtypes, both at the level of HA clades (p-value = 0.04) and the level of HA groups (p-value = 0.05). In contrast, infection patterns did not support specific Immunity for neuraminidase (NA) subtypes. For the H1 and H3 Clades, Heterosubtypic Immunity showed a clear temporal pattern and we estimated within-clade Immunity to last at least 30 days. The strength and duration of Heterosubtypic Immunity has important implications for transmission dynamics of IAV in th
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Increased protein degradation improves influenza virus nucleoprotein-specific CD8⁺ T cell activation in vitro but not in C57BL/6 mice
'American Society for Microbiology', 2016Co-Authors: Altenburg, Arwen F, Ron A M Fouchier, Van De Sandt, Carolien E, Van Trierum, Stella E, Heidi Lm ,de Gruyter, Van Run, Peter Rwa, Roose Kenny, Saelens Xavier, Volz Asisa, Sutter GerdAbstract:Due to antigenic drift of influenza viruses, seasonal influenza vaccines need to be updated annually. These vaccines are based on predictions of strains likely to circulate in the next season. However, vaccine efficacy is greatly reduced in the case of a mismatch between circulating and vaccine strains. Furthermore, novel antigenically distinct influenza viruses are introduced into the human population from animal reservoirs occasionally and may cause pandemic outbreaks. To dampen the impact of seasonal and pandemic influenza, vaccines that induce broadly protective and long-lasting Immunity are preferred. Because influenza virusspecific CD8(+) T cells are directed mainly against relatively conserved internal proteins, like nucleoprotein (NP), they are highly cross-reactive and afford protection against infection with antigenically distinct influenza virus strains, so-called Heterosubtypic Immunity. Here, we used modified vaccinia virus Ankara (MVA) as a vaccine vector for the induction of influenza virus NP-specific CD8(+) T cells. To optimize the induction of CD8(+) T cell responses, we made several modifications to NP, aiming at retaining the protein in the cytosol or targeting it to the proteasome. We hypothesized that these strategies would increase antigen processing and presentation and thus improve the induction of CD8 (+) T cell responses. We showed that NP with increased degradation rates improved CD8(+) T cell activation in vitro if the amount of antigen was limited or if CD8 (+) T cells were of low functional avidity. However, after immunization of C57BL/6 mice, no differences were detected between modified NP and wild-type NP (NPwt), since NPwt already induced optimal CD8(+) T cell responses. IMPORTANCE : Due to the continuous antigenic drift of seasonal influenza viruses and the threat of a novel pandemic, there is a great need for the development of novel influenza vaccines that offer broadly protective Immunity against multiple subtypes. CD8(+) T cells can provide Immunity against multiple subtypes of influenza viruses by the recognition of relatively conserved internal antigens. In this study, we aimed at optimizing the CD8(+) T cell response to influenza A virus by making modifications to influenza A virus nucleoprotein (NP) expressed from the modified vaccinia virus Ankara (MVA) vaccine vector. These modifications resulted in increased antigen degradation, thereby producing elevated levels of peptides that can be presented on major histocompatibility complex (MHC) class I molecules to CD8(+) T cells. Although we were unable to increase the NP-specific immune response in the mouse strain used, this approach may have benefits for vaccine development using less-immunogenic proteins
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Heterosubtypic Immunity to h7n9 influenza virus in isogenic guinea pigs after infection with pandemic h1n1 virus
Vaccine, 2015Co-Authors: Lidewij Wiersma, Joost H C M Kreijtz, Ron A M Fouchier, G Van Amerongen, Stella Vogelzangvan E Trierum, Peter Van Run, Mechtild Ladwig, Stefanie Banneke, Hubert Schaefer, Thijs KuikenAbstract:Heterosubtypic Immunity is defined as immune-mediated (partial) protection against an influenza virus induced by an influenza virus of another subtype to which the host has not previously been exposed. This cross-protective effect has not yet been demonstrated to the newly emerging avian influenza A viruses of the H7N9 subtype. Here, we assessed the induction of protective Immunity to these viruses by infection with A(H1N1)pdm09 virus in a newly developed guinea pig model. To this end, ten female 12-16 week old strain 2 guinea pigs were inoculated intratracheally with either A(H1N1)pdm09 influenza virus or PBS (unprimed controls) followed 4 weeks later with an A/H7N9 influenza virus challenge. Nasal swabs were taken daily and animals from both groups were sacrificed on days 2 and 7 post inoculation (p.i.) with A/H7N9 virus and full necropsies were performed. Nasal virus excretion persisted until day 7 in unprimed control animals, whereas only two out of seven H1N1pdm09-primed animals excreted virus via the nose. Infectious virus was recovered from nasal turbinates, trachea and lung of all animals at day 2 p.i., but titers were lower for H1N1pdm09-primed animals, especially in the nasal turbinates. By day 7 p.i., relatively high virus titers were found in the nasal turbinates of all unprimed control animals but infectious virus was isolated from the nose of only one of four H1N1pdm09-primed animals. Animals of both groups developed inflammation of variable severity in the entire respiratory tract. Viral antigen positive cells were demonstrated in the nasal epithelium of both groups at day 2. The bronchi(oli) and alveoli of unprimed animals showed a moderate to strong positive signal at day 2, whereas H1N1pdm09-primed animals showed only minimal positivity. By day 7, only viral antigen positive cells were found after H7N9 virus infection in the nasal turbinates and the lungs of unprimed controls. Thus infection with H1N1pdm09 virus induced partially protective Heterosubtypic Immunity to H7N9 virus in (isogenic) guinea pigs that could not be attributed to cross-reactive virus neutralizing antibodies.
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Heterosubtypic Immunity to influenza a virus infections in mallards may explain existence of multiple virus subtypes
PLOS Pathogens, 2013Co-Authors: Neus Latorremargalef, Ron A M Fouchier, Albert D M E Osterhaus, Vladimir Grosbois, John Wahlgren, Vincent J Munster, Conny Tolf, Bjorn R Olsen, Jonas WaldenstromAbstract:Wild birds, particularly duck species, are the main reservoir of influenza A virus (IAV) in nature. However, knowledge of IAV infection dynamics in the wild bird reservoir, and the development of immune responses, are essentially absent. Importantly, a detailed understanding of how subtype diversity is generated and maintained is lacking. To address this, 18,679 samples from 7728 Mallard ducks captured between 2002 and 2009 at a single stopover site in Sweden were screened for IAV infections, and the resulting 1081 virus isolates were analyzed for patterns of Immunity. We found support for development of homosubtypic hemagglutinin (HA) Immunity during the peak of IAV infections in the fall. Moreover, re-infections with the same HA subtype and related prevalent HA subtypes were uncommon, suggesting the development of natural homosubtypic and Heterosubtypic Immunity (p-value = 0.02). Heterosubtypic Immunity followed phylogenetic relatedness of HA subtypes, both at the level of HA clades (p-value = 0.04) and the level of HA groups (p-value = 0.05). In contrast, infection patterns did not support specific Immunity for neuraminidase (NA) subtypes. For the H1 and H3 Clades, Heterosubtypic Immunity showed a clear temporal pattern and we estimated within-clade Immunity to last at least 30 days. The strength and duration of Heterosubtypic Immunity has important implications for transmission dynamics of IAV in the natural reservoir, where immune escape and disruptive selection may increase HA antigenic variation and explain IAV subtype diversity.
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infection of the upper respiratory tract with seasonal influenza a h3n2 virus induces protective Immunity in ferrets against infection with a h1n1 pdm09 virus after intranasal but not intratracheal inoculation
Journal of Virology, 2013Co-Authors: Rogier Bodewes, Joost H C M Kreijtz, Marine L B Hillaire, Ron A M Fouchier, G Van Amerongen, Thijs Kuiken, Nella J Nieuwkoop, Stella Vogelzangvan E Trierum, Peter Van Run, Albert D M E OsterhausAbstract:The clinical symptoms caused by infection with influenza A virus vary widely and depend on the strain causing the infection, the dose and route of inoculation, and the presence of preexisting Immunity. In most cases, seasonal influenza A viruses cause relatively mild upper respiratory tract disease, while sometimes patients develop an acute severe pneumonia. Heterosubtypic Immunity induced by previous infections with influenza A viruses may dampen the development of clinical symptoms caused by infection with influenza A viruses of another subtype, as is the case during influenza pandemics. Here we show that ferrets acquire protective Immunity after infection of the upper respiratory tract with a seasonal influenza A(H3N2) virus against subsequent infection with influenza A(H1N1)pdm09 virus inoculated by the intranasal route. However, protective Heterosubtypic Immunity was afforded locally, since the prior infection with the A(H3N2) virus did not provide protection against the development of pneumonia induced after intratracheal inoculation with the A(H1N1)pdm09 virus. Interestingly, some of these animals developed more severe disease than that observed in naive control animals. These findings are of interest in light of the development of so-called universal influenza vaccines that aim at the induction of cross-reactive T cell responses.