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Anke Huckriede - One of the best experts on this subject based on the ideXlab platform.
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Effect of viral membrane fusion activity on antibody induction by influenza H5N1 whole Inactivated Virus Vaccine
Vaccine, 2012Co-Authors: Felix Geeraedts, Wouter Ter Veer, Jan Wilschut, Anke Huckriede, Aalzen De HaanAbstract:Whole Inactivated Virus (WIV) influenza Vaccines are more immunogenic in unprimed individuals than split-Virus or subunit Vaccines. In mice, this superior immunogenicity has been linked to the recognition of the viral ssRNA by endosomal TLR7 receptors in immune cells, leading to IFNα production and Th1-type antibody responses. Recent data suggest that viral membrane fusion in target cell endosomes is necessary for TLR7-mediated IFNα induction. If so, Virus inactivation procedures that compromise the fusion activity of WIV Vaccines, like formaldehyde (FA) treatment, could potentially harm Vaccine efficacy. Therefore, we measured the effect of fusion inactivation of H5N1 WIV on TLR7 activation in vitro, and on antibody isotype responses in vivo. Fusion inactivation of WIV reduced, but did not block, TLR7-dependent IFNα induction in murine dendritic cells in vitro. In vivo, fusion-inactive WIV was as potent as fusion-active WIV in inducing total H5N1-specific serum IgG and IgG2c subtype antibodies in unprimed mice. Both Vaccines induced only small amounts of IgG1. However, FA treatment of WIV did reduce the capacity of the Vaccine to induce hemagglutination-inhibiting (HI) antibodies. This possibly relates to modification of epitopes that are targets for HI antibodies rather than to loss of fusion activity. Antibody affinity maturation was not negatively affected by fusion inactivation. In conclusion, fusion activity of H5N1 WIV does not play a major role in Th1-type antibody induction. Yet, to preserve the full immunogenicity of WIV, or possibly also other Inactivated influenza Vaccines, harsh treatment with formaldehyde should be avoided.
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Induction of Heterosubtypic Cross-Protection against Influenza by a Whole Inactivated Virus Vaccine : The Role of Viral Membrane Fusion Activity
PloS one, 2012Co-Authors: Natalija Budimir, Jan Wilschut, Anke Huckriede, Tjarko Meijerhof, Louis Boon, Emma Gostick, David Price, Aalzen De HaanAbstract:Background The 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 Findings In 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/Significance The 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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Development of a dried influenza whole Inactivated Virus Vaccine for pulmonary immunization
Vaccine, 2011Co-Authors: Sandrine A. L. Audouy, Henderik W. Frijlink, Jan Wilschut, Wouter L. J. Hinrichs, Gieta Van Der Schaaf, Anke HuckriedeAbstract:Stabilization and ease of administration are two ways to substantially improve the use of current Vaccines. In the present study an influenza whole Inactivated Virus (WIV) Vaccine was freeze-dried or spray-freeze dried in the presence of inulin as a cryoprotectant. Only spray-freeze drying rendered powders compatible with administration to the lungs by insufflation. Pulmonary administration of the powder Vaccine obtained by this method to BALB/c mice led to a transient influx of neutrophils and a concomitant decrease in the number of macrophages as did administration of liquid Vaccine. Inflammatory reactions to both Vaccines were mild and short-lived. Immunization studies showed that the immunogenic properties of WIV Vaccine were not affected by drying. Pulmonary administration of the powder WIV Vaccine induced a systemic immune response of the same magnitude as liquid Vaccine while mucosal IgA responses were higher for powder WIV. In a challenge study where immunized mice were exposed to a lethal dose of live Virus, two pulmonary doses of either liquid or powder WIV Vaccine were equally effective as a single intramuscular injection of subunit Vaccine in terms of reduction of the viral load in the lungs. To conclude, in the models employed for these studies the use of a dry powder WIV Vaccine for pulmonary immunization was shown to be safe and efficient.
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Preservation of the immunogenicity of dry-powder influenza H5N1 whole Inactivated Virus Vaccine at elevated storage temperatures.
The AAPS journal, 2010Co-Authors: Felix Geeraedts, Vinay Saluja, Wouter Ter Veer, Jean-pierre Amorij, Henderik W. Frijlink, Jan Wilschut, Wouter L. J. Hinrichs, Anke HuckriedeAbstract:Stockpiling of pre-pandemic influenza Vaccines guarantees immediate Vaccine availability to counteract an emerging pandemic. Generally, influenza Vaccines need to be stored and handled refrigerated to prevent thermal degradation of the antigenic component. Requirement of a cold-chain, however, complicates stockpiling and the logistics of Vaccine distribution. We, therefore, investigated the effect of elevated storage temperatures on the immunogenicity of a pre-pandemic influenza A H5N1 whole Inactivated Virus Vaccine. Either suspended in liquid or kept as a freeze-dried powder, Vaccines could be stored for 1 year at ambient temperature (20°C) with minimal loss of immunogenicity in mice. Elevation of the storage temperature to 40°C, however, resulted in a significant loss of immunogenic potency within 3 months if Vaccines were stored in liquid suspension. In sharp contrast, freeze-dried powder formulations were stable at 40°C for at least 3 months. The presence of inulin or trehalose sugar excipients during freeze-drying of the Vaccine proved to be critical to maintain its immunogenic potency during storage, and to preserve the characteristic Th1-type response to whole Inactivated Virus Vaccine. These results indicate that whole Inactivated Virus Vaccines may be stored and handled at room temperature in moderate climate zones for over a year with minimal decline and, if converted to dry-powder, even in hot climate zones for at least 3 months. The increased stability of dry-powder Vaccine at 40°C may also point to an extended shelf-life when stored at 4°C. Use of the more stable dry-powder formulation could simplify stockpiling and thereby facilitating successful pandemic intervention.
Aalzen De Haan - One of the best experts on this subject based on the ideXlab platform.
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Effect of viral membrane fusion activity on antibody induction by influenza H5N1 whole Inactivated Virus Vaccine
Vaccine, 2012Co-Authors: Felix Geeraedts, Wouter Ter Veer, Jan Wilschut, Anke Huckriede, Aalzen De HaanAbstract:Whole Inactivated Virus (WIV) influenza Vaccines are more immunogenic in unprimed individuals than split-Virus or subunit Vaccines. In mice, this superior immunogenicity has been linked to the recognition of the viral ssRNA by endosomal TLR7 receptors in immune cells, leading to IFNα production and Th1-type antibody responses. Recent data suggest that viral membrane fusion in target cell endosomes is necessary for TLR7-mediated IFNα induction. If so, Virus inactivation procedures that compromise the fusion activity of WIV Vaccines, like formaldehyde (FA) treatment, could potentially harm Vaccine efficacy. Therefore, we measured the effect of fusion inactivation of H5N1 WIV on TLR7 activation in vitro, and on antibody isotype responses in vivo. Fusion inactivation of WIV reduced, but did not block, TLR7-dependent IFNα induction in murine dendritic cells in vitro. In vivo, fusion-inactive WIV was as potent as fusion-active WIV in inducing total H5N1-specific serum IgG and IgG2c subtype antibodies in unprimed mice. Both Vaccines induced only small amounts of IgG1. However, FA treatment of WIV did reduce the capacity of the Vaccine to induce hemagglutination-inhibiting (HI) antibodies. This possibly relates to modification of epitopes that are targets for HI antibodies rather than to loss of fusion activity. Antibody affinity maturation was not negatively affected by fusion inactivation. In conclusion, fusion activity of H5N1 WIV does not play a major role in Th1-type antibody induction. Yet, to preserve the full immunogenicity of WIV, or possibly also other Inactivated influenza Vaccines, harsh treatment with formaldehyde should be avoided.
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Induction of Heterosubtypic Cross-Protection against Influenza by a Whole Inactivated Virus Vaccine : The Role of Viral Membrane Fusion Activity
PloS one, 2012Co-Authors: Natalija Budimir, Jan Wilschut, Anke Huckriede, Tjarko Meijerhof, Louis Boon, Emma Gostick, David Price, Aalzen De HaanAbstract:Background The 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 Findings In 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/Significance The 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.
Jan Wilschut - One of the best experts on this subject based on the ideXlab platform.
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Effect of viral membrane fusion activity on antibody induction by influenza H5N1 whole Inactivated Virus Vaccine
Vaccine, 2012Co-Authors: Felix Geeraedts, Wouter Ter Veer, Jan Wilschut, Anke Huckriede, Aalzen De HaanAbstract:Whole Inactivated Virus (WIV) influenza Vaccines are more immunogenic in unprimed individuals than split-Virus or subunit Vaccines. In mice, this superior immunogenicity has been linked to the recognition of the viral ssRNA by endosomal TLR7 receptors in immune cells, leading to IFNα production and Th1-type antibody responses. Recent data suggest that viral membrane fusion in target cell endosomes is necessary for TLR7-mediated IFNα induction. If so, Virus inactivation procedures that compromise the fusion activity of WIV Vaccines, like formaldehyde (FA) treatment, could potentially harm Vaccine efficacy. Therefore, we measured the effect of fusion inactivation of H5N1 WIV on TLR7 activation in vitro, and on antibody isotype responses in vivo. Fusion inactivation of WIV reduced, but did not block, TLR7-dependent IFNα induction in murine dendritic cells in vitro. In vivo, fusion-inactive WIV was as potent as fusion-active WIV in inducing total H5N1-specific serum IgG and IgG2c subtype antibodies in unprimed mice. Both Vaccines induced only small amounts of IgG1. However, FA treatment of WIV did reduce the capacity of the Vaccine to induce hemagglutination-inhibiting (HI) antibodies. This possibly relates to modification of epitopes that are targets for HI antibodies rather than to loss of fusion activity. Antibody affinity maturation was not negatively affected by fusion inactivation. In conclusion, fusion activity of H5N1 WIV does not play a major role in Th1-type antibody induction. Yet, to preserve the full immunogenicity of WIV, or possibly also other Inactivated influenza Vaccines, harsh treatment with formaldehyde should be avoided.
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Induction of Heterosubtypic Cross-Protection against Influenza by a Whole Inactivated Virus Vaccine : The Role of Viral Membrane Fusion Activity
PloS one, 2012Co-Authors: Natalija Budimir, Jan Wilschut, Anke Huckriede, Tjarko Meijerhof, Louis Boon, Emma Gostick, David Price, Aalzen De HaanAbstract:Background The 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 Findings In 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/Significance The 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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Development of a dried influenza whole Inactivated Virus Vaccine for pulmonary immunization
Vaccine, 2011Co-Authors: Sandrine A. L. Audouy, Henderik W. Frijlink, Jan Wilschut, Wouter L. J. Hinrichs, Gieta Van Der Schaaf, Anke HuckriedeAbstract:Stabilization and ease of administration are two ways to substantially improve the use of current Vaccines. In the present study an influenza whole Inactivated Virus (WIV) Vaccine was freeze-dried or spray-freeze dried in the presence of inulin as a cryoprotectant. Only spray-freeze drying rendered powders compatible with administration to the lungs by insufflation. Pulmonary administration of the powder Vaccine obtained by this method to BALB/c mice led to a transient influx of neutrophils and a concomitant decrease in the number of macrophages as did administration of liquid Vaccine. Inflammatory reactions to both Vaccines were mild and short-lived. Immunization studies showed that the immunogenic properties of WIV Vaccine were not affected by drying. Pulmonary administration of the powder WIV Vaccine induced a systemic immune response of the same magnitude as liquid Vaccine while mucosal IgA responses were higher for powder WIV. In a challenge study where immunized mice were exposed to a lethal dose of live Virus, two pulmonary doses of either liquid or powder WIV Vaccine were equally effective as a single intramuscular injection of subunit Vaccine in terms of reduction of the viral load in the lungs. To conclude, in the models employed for these studies the use of a dry powder WIV Vaccine for pulmonary immunization was shown to be safe and efficient.
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Preservation of the immunogenicity of dry-powder influenza H5N1 whole Inactivated Virus Vaccine at elevated storage temperatures.
The AAPS journal, 2010Co-Authors: Felix Geeraedts, Vinay Saluja, Wouter Ter Veer, Jean-pierre Amorij, Henderik W. Frijlink, Jan Wilschut, Wouter L. J. Hinrichs, Anke HuckriedeAbstract:Stockpiling of pre-pandemic influenza Vaccines guarantees immediate Vaccine availability to counteract an emerging pandemic. Generally, influenza Vaccines need to be stored and handled refrigerated to prevent thermal degradation of the antigenic component. Requirement of a cold-chain, however, complicates stockpiling and the logistics of Vaccine distribution. We, therefore, investigated the effect of elevated storage temperatures on the immunogenicity of a pre-pandemic influenza A H5N1 whole Inactivated Virus Vaccine. Either suspended in liquid or kept as a freeze-dried powder, Vaccines could be stored for 1 year at ambient temperature (20°C) with minimal loss of immunogenicity in mice. Elevation of the storage temperature to 40°C, however, resulted in a significant loss of immunogenic potency within 3 months if Vaccines were stored in liquid suspension. In sharp contrast, freeze-dried powder formulations were stable at 40°C for at least 3 months. The presence of inulin or trehalose sugar excipients during freeze-drying of the Vaccine proved to be critical to maintain its immunogenic potency during storage, and to preserve the characteristic Th1-type response to whole Inactivated Virus Vaccine. These results indicate that whole Inactivated Virus Vaccines may be stored and handled at room temperature in moderate climate zones for over a year with minimal decline and, if converted to dry-powder, even in hot climate zones for at least 3 months. The increased stability of dry-powder Vaccine at 40°C may also point to an extended shelf-life when stored at 4°C. Use of the more stable dry-powder formulation could simplify stockpiling and thereby facilitating successful pandemic intervention.
Adriano Boasso - One of the best experts on this subject based on the ideXlab platform.
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alloantigen based aids Vaccine revisiting a rightfully discarded promising strategy
F1000 Medicine Reports, 2011Co-Authors: Gene M Shearer, Adriano BoassoAbstract:This report revisits the accidental discovery that protection against simian immunodeficiency Virus (SIV) infection in the early successful experimental AIDS Vaccine studies in Rhesus macaques was due to antibodies directed against human leukocyte antigens (HLAs). The Inactivated Virus Vaccine approach was discarded because protection was due to the host's immune reaction against the HLA acquired by SIV from the human cell lines in which it was grown, rather than against antigenic determinants of SIV itself. Subsequent studies have revealed that immune recognition of HLA on uninfected leukocytes also induces other factors that inhibit infection by both SIV and the human immunodeficiency Virus. Pro and con aspects of immunization against HLA as a potential AIDS Vaccine strategy are discussed.
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Alloantigen-based AIDS Vaccine: revisiting a "rightfully" discarded promising strategy Gene M. Shearer
2011Co-Authors: Adriano Boasso, Gene M ShearerAbstract:This report revisits the accidental discovery that protection against simian immunodeficiency Virus (SIV) infection in the early successful experimental AIDS Vaccine studies in Rhesus macaques was due to antibodies directed against human leukocyte antigens (HLAs). The Inactivated Virus Vaccine approach was discarded because protection was due to the host’s immune reaction against the HLA acquired by SIV from the human cell lines in which it was grown, rather than against antigenic determinants of SIV itself. Subsequent studies have revealed that immune recognition of HLA on uninfected leukocytes also induces other factors that inhibit infection by both SIV and the human immunodeficiency Virus. Pro and con aspects of immunization against HLA as a potential AIDS Vaccine strategy are discussed.
Felix Geeraedts - One of the best experts on this subject based on the ideXlab platform.
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Effect of viral membrane fusion activity on antibody induction by influenza H5N1 whole Inactivated Virus Vaccine
Vaccine, 2012Co-Authors: Felix Geeraedts, Wouter Ter Veer, Jan Wilschut, Anke Huckriede, Aalzen De HaanAbstract:Whole Inactivated Virus (WIV) influenza Vaccines are more immunogenic in unprimed individuals than split-Virus or subunit Vaccines. In mice, this superior immunogenicity has been linked to the recognition of the viral ssRNA by endosomal TLR7 receptors in immune cells, leading to IFNα production and Th1-type antibody responses. Recent data suggest that viral membrane fusion in target cell endosomes is necessary for TLR7-mediated IFNα induction. If so, Virus inactivation procedures that compromise the fusion activity of WIV Vaccines, like formaldehyde (FA) treatment, could potentially harm Vaccine efficacy. Therefore, we measured the effect of fusion inactivation of H5N1 WIV on TLR7 activation in vitro, and on antibody isotype responses in vivo. Fusion inactivation of WIV reduced, but did not block, TLR7-dependent IFNα induction in murine dendritic cells in vitro. In vivo, fusion-inactive WIV was as potent as fusion-active WIV in inducing total H5N1-specific serum IgG and IgG2c subtype antibodies in unprimed mice. Both Vaccines induced only small amounts of IgG1. However, FA treatment of WIV did reduce the capacity of the Vaccine to induce hemagglutination-inhibiting (HI) antibodies. This possibly relates to modification of epitopes that are targets for HI antibodies rather than to loss of fusion activity. Antibody affinity maturation was not negatively affected by fusion inactivation. In conclusion, fusion activity of H5N1 WIV does not play a major role in Th1-type antibody induction. Yet, to preserve the full immunogenicity of WIV, or possibly also other Inactivated influenza Vaccines, harsh treatment with formaldehyde should be avoided.
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Preservation of the immunogenicity of dry-powder influenza H5N1 whole Inactivated Virus Vaccine at elevated storage temperatures.
The AAPS journal, 2010Co-Authors: Felix Geeraedts, Vinay Saluja, Wouter Ter Veer, Jean-pierre Amorij, Henderik W. Frijlink, Jan Wilschut, Wouter L. J. Hinrichs, Anke HuckriedeAbstract:Stockpiling of pre-pandemic influenza Vaccines guarantees immediate Vaccine availability to counteract an emerging pandemic. Generally, influenza Vaccines need to be stored and handled refrigerated to prevent thermal degradation of the antigenic component. Requirement of a cold-chain, however, complicates stockpiling and the logistics of Vaccine distribution. We, therefore, investigated the effect of elevated storage temperatures on the immunogenicity of a pre-pandemic influenza A H5N1 whole Inactivated Virus Vaccine. Either suspended in liquid or kept as a freeze-dried powder, Vaccines could be stored for 1 year at ambient temperature (20°C) with minimal loss of immunogenicity in mice. Elevation of the storage temperature to 40°C, however, resulted in a significant loss of immunogenic potency within 3 months if Vaccines were stored in liquid suspension. In sharp contrast, freeze-dried powder formulations were stable at 40°C for at least 3 months. The presence of inulin or trehalose sugar excipients during freeze-drying of the Vaccine proved to be critical to maintain its immunogenic potency during storage, and to preserve the characteristic Th1-type response to whole Inactivated Virus Vaccine. These results indicate that whole Inactivated Virus Vaccines may be stored and handled at room temperature in moderate climate zones for over a year with minimal decline and, if converted to dry-powder, even in hot climate zones for at least 3 months. The increased stability of dry-powder Vaccine at 40°C may also point to an extended shelf-life when stored at 4°C. Use of the more stable dry-powder formulation could simplify stockpiling and thereby facilitating successful pandemic intervention.
