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Alum Adjuvant Enhances Protection against Respiratory Syncytial Virus but Exacerbates Pulmonary Inflammation by Modulating Multiple Innate and Adaptive Immune Cells.

Kim KH, Lee YT, Hwang HS, Kwon YM, Jung YJ, Lee Y, Lee JS, Lee YN, Park S, Kang SM - PLoS ONE (2015)

Bottom Line: Alum adjuvant significantly improved protection as evidenced by effective viral clearance compared to unadjuvanted FI-RSV.Alum adjuvant in the FI-RSV-A was found to be mainly responsible for inducing high levels of RSV-specific IFN-γ-IL4+, IFN-γ-TNF-α+ CD4+ T cells, and proinflammatory cytokines IL-6 and IL-4 as well as B220+ plasmacytoid and CD4+ dendritic cells, and inhibiting the induction of IFN-γ+CD8 T cells.This study suggests that alum adjuvant in FI-RSV vaccines increases immunogenicity and viral clearance but also induces atypical T helper CD4+ T cells and multiple inflammatory dendritic cell subsets responsible for vaccine-enhanced severe RSV disease.

View Article: PubMed Central - PubMed

Affiliation: Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, United States of America.

ABSTRACT
Respiratory syncytial virus (RSV) is well-known for inducing vaccine-enhanced respiratory disease after vaccination of young children with formalin-inactivated RSV (FI-RSV) in alum formulation. Here, we investigated alum adjuvant effects on protection and disease after FI-RSV immunization with or without alum in comparison with live RSV reinfections. Despite viral clearance, live RSV reinfections caused weight loss and substantial pulmonary inflammation probably due to high levels of RSV specific IFN-γ+IL4-, IFN-γ-TNF-α+, IFN-γ+TNF-α- effector CD4 and CD8 T cells. Alum adjuvant significantly improved protection as evidenced by effective viral clearance compared to unadjuvanted FI-RSV. However, in contrast to unadjuvanted FI-RSV, alum-adjuvanted FI-RSV (FI-RSV-A) induced severe vaccine-enhanced RSV disease including weight loss, eosinophilia, and lung histopathology. Alum adjuvant in the FI-RSV-A was found to be mainly responsible for inducing high levels of RSV-specific IFN-γ-IL4+, IFN-γ-TNF-α+ CD4+ T cells, and proinflammatory cytokines IL-6 and IL-4 as well as B220+ plasmacytoid and CD4+ dendritic cells, and inhibiting the induction of IFN-γ+CD8 T cells. This study suggests that alum adjuvant in FI-RSV vaccines increases immunogenicity and viral clearance but also induces atypical T helper CD4+ T cells and multiple inflammatory dendritic cell subsets responsible for vaccine-enhanced severe RSV disease.

No MeSH data available.


Related in: MedlinePlus

Effects of a low dose alum adjuvant in FI-RSV on body weight, protection, lung inflammation and effector cells.A low dose of alum (5 μg) adjuvant effects was compared with FI-RSV-A (with 20 μg alum) after FI-RSV vaccination and RSV challenge of mice (n = 5). (A) Body weight changes. (B) RSV lung viral titers. (C) Pulmonary inflammation scores. (D) PAS positive mucus production (%). (E) IFN-γ secreting lung cell spots. (F) IL-4 secreting lung cell spots. Cytokine secreting cell spots were determined after stimulation with CD8 T cell epitope F92-106 peptide or CD4 T cell epitope G183-195. Results are presented as mean ± SEM. Statistical analysis were analyzed by two-way ANOVA in GraphPad Prism; *** p<0.001, ** p<0.01. ND: Not detected.
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pone.0139916.g006: Effects of a low dose alum adjuvant in FI-RSV on body weight, protection, lung inflammation and effector cells.A low dose of alum (5 μg) adjuvant effects was compared with FI-RSV-A (with 20 μg alum) after FI-RSV vaccination and RSV challenge of mice (n = 5). (A) Body weight changes. (B) RSV lung viral titers. (C) Pulmonary inflammation scores. (D) PAS positive mucus production (%). (E) IFN-γ secreting lung cell spots. (F) IL-4 secreting lung cell spots. Cytokine secreting cell spots were determined after stimulation with CD8 T cell epitope F92-106 peptide or CD4 T cell epitope G183-195. Results are presented as mean ± SEM. Statistical analysis were analyzed by two-way ANOVA in GraphPad Prism; *** p<0.001, ** p<0.01. ND: Not detected.

Mentions: After staining lung sections with periodic acid-schiff (PAS), PAS positive area was analyzed to determine mucus production (Fig 5B and 5F). In contrast to the FI-RSV-A group that showed high PAS staining area, the FI-RSV group did not exhibit PAS positive area before or after challenge indicating no detectable mucus production (Fig 5B and 5F, Fig A panels A-D in S1 File). Furthermore, highest levels of pulmonary inflammation, mucus production, eosinophils, and eotaxin were well correlated with the presence of alum in FI-RSV before (Fig 5G) or after challenge (Fig 5A, 5B and 5H–5J). Whereas, FI-RSV immune mice did not induce siglecF+CD11b+ eosinophils (Fig 5G–5I) as determined by flow cytometry analysis before or after challenge and eotaxin chemokine in lungs (Fig 5J). Interestingly, live RSV reinfections induced more eosinophils in the airway fluids compared to FI-RSV immunization (live RSV vs. FI-RSV, Fig 5I). Next, we determined the effects of a lower dose of alum in FI-RSV vaccines on inducing protection and disease (Fig 6). Interestingly, a low dose alum (FI-RSV-A 5μg) immune mice displayed less weight loss and suppressed mucus production as well as cleared lung viral loads (Fig 6A, 6B and 6D). However, pulmonary inflammation scores were only slightly lower in the low alum-FI-RSV group without a statistical difference (Fig 6C). Therefore, these results suggest that inactivation of RSV may not be the major factor in inducing vaccine-enhanced RSV disease and that alum adjuvant in FI-RSV vaccine formulations appears to be largely responsible for inducing host immune responses of severe lung inflammation through the mucus production and eosinophilia upon RSV infection.


Alum Adjuvant Enhances Protection against Respiratory Syncytial Virus but Exacerbates Pulmonary Inflammation by Modulating Multiple Innate and Adaptive Immune Cells.

Kim KH, Lee YT, Hwang HS, Kwon YM, Jung YJ, Lee Y, Lee JS, Lee YN, Park S, Kang SM - PLoS ONE (2015)

Effects of a low dose alum adjuvant in FI-RSV on body weight, protection, lung inflammation and effector cells.A low dose of alum (5 μg) adjuvant effects was compared with FI-RSV-A (with 20 μg alum) after FI-RSV vaccination and RSV challenge of mice (n = 5). (A) Body weight changes. (B) RSV lung viral titers. (C) Pulmonary inflammation scores. (D) PAS positive mucus production (%). (E) IFN-γ secreting lung cell spots. (F) IL-4 secreting lung cell spots. Cytokine secreting cell spots were determined after stimulation with CD8 T cell epitope F92-106 peptide or CD4 T cell epitope G183-195. Results are presented as mean ± SEM. Statistical analysis were analyzed by two-way ANOVA in GraphPad Prism; *** p<0.001, ** p<0.01. ND: Not detected.
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getmorefigures.php?uid=PMC4607166&req=5

pone.0139916.g006: Effects of a low dose alum adjuvant in FI-RSV on body weight, protection, lung inflammation and effector cells.A low dose of alum (5 μg) adjuvant effects was compared with FI-RSV-A (with 20 μg alum) after FI-RSV vaccination and RSV challenge of mice (n = 5). (A) Body weight changes. (B) RSV lung viral titers. (C) Pulmonary inflammation scores. (D) PAS positive mucus production (%). (E) IFN-γ secreting lung cell spots. (F) IL-4 secreting lung cell spots. Cytokine secreting cell spots were determined after stimulation with CD8 T cell epitope F92-106 peptide or CD4 T cell epitope G183-195. Results are presented as mean ± SEM. Statistical analysis were analyzed by two-way ANOVA in GraphPad Prism; *** p<0.001, ** p<0.01. ND: Not detected.
Mentions: After staining lung sections with periodic acid-schiff (PAS), PAS positive area was analyzed to determine mucus production (Fig 5B and 5F). In contrast to the FI-RSV-A group that showed high PAS staining area, the FI-RSV group did not exhibit PAS positive area before or after challenge indicating no detectable mucus production (Fig 5B and 5F, Fig A panels A-D in S1 File). Furthermore, highest levels of pulmonary inflammation, mucus production, eosinophils, and eotaxin were well correlated with the presence of alum in FI-RSV before (Fig 5G) or after challenge (Fig 5A, 5B and 5H–5J). Whereas, FI-RSV immune mice did not induce siglecF+CD11b+ eosinophils (Fig 5G–5I) as determined by flow cytometry analysis before or after challenge and eotaxin chemokine in lungs (Fig 5J). Interestingly, live RSV reinfections induced more eosinophils in the airway fluids compared to FI-RSV immunization (live RSV vs. FI-RSV, Fig 5I). Next, we determined the effects of a lower dose of alum in FI-RSV vaccines on inducing protection and disease (Fig 6). Interestingly, a low dose alum (FI-RSV-A 5μg) immune mice displayed less weight loss and suppressed mucus production as well as cleared lung viral loads (Fig 6A, 6B and 6D). However, pulmonary inflammation scores were only slightly lower in the low alum-FI-RSV group without a statistical difference (Fig 6C). Therefore, these results suggest that inactivation of RSV may not be the major factor in inducing vaccine-enhanced RSV disease and that alum adjuvant in FI-RSV vaccine formulations appears to be largely responsible for inducing host immune responses of severe lung inflammation through the mucus production and eosinophilia upon RSV infection.

Bottom Line: Alum adjuvant significantly improved protection as evidenced by effective viral clearance compared to unadjuvanted FI-RSV.Alum adjuvant in the FI-RSV-A was found to be mainly responsible for inducing high levels of RSV-specific IFN-γ-IL4+, IFN-γ-TNF-α+ CD4+ T cells, and proinflammatory cytokines IL-6 and IL-4 as well as B220+ plasmacytoid and CD4+ dendritic cells, and inhibiting the induction of IFN-γ+CD8 T cells.This study suggests that alum adjuvant in FI-RSV vaccines increases immunogenicity and viral clearance but also induces atypical T helper CD4+ T cells and multiple inflammatory dendritic cell subsets responsible for vaccine-enhanced severe RSV disease.

View Article: PubMed Central - PubMed

Affiliation: Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, United States of America.

ABSTRACT
Respiratory syncytial virus (RSV) is well-known for inducing vaccine-enhanced respiratory disease after vaccination of young children with formalin-inactivated RSV (FI-RSV) in alum formulation. Here, we investigated alum adjuvant effects on protection and disease after FI-RSV immunization with or without alum in comparison with live RSV reinfections. Despite viral clearance, live RSV reinfections caused weight loss and substantial pulmonary inflammation probably due to high levels of RSV specific IFN-γ+IL4-, IFN-γ-TNF-α+, IFN-γ+TNF-α- effector CD4 and CD8 T cells. Alum adjuvant significantly improved protection as evidenced by effective viral clearance compared to unadjuvanted FI-RSV. However, in contrast to unadjuvanted FI-RSV, alum-adjuvanted FI-RSV (FI-RSV-A) induced severe vaccine-enhanced RSV disease including weight loss, eosinophilia, and lung histopathology. Alum adjuvant in the FI-RSV-A was found to be mainly responsible for inducing high levels of RSV-specific IFN-γ-IL4+, IFN-γ-TNF-α+ CD4+ T cells, and proinflammatory cytokines IL-6 and IL-4 as well as B220+ plasmacytoid and CD4+ dendritic cells, and inhibiting the induction of IFN-γ+CD8 T cells. This study suggests that alum adjuvant in FI-RSV vaccines increases immunogenicity and viral clearance but also induces atypical T helper CD4+ T cells and multiple inflammatory dendritic cell subsets responsible for vaccine-enhanced severe RSV disease.

No MeSH data available.


Related in: MedlinePlus