CpG Improves Influenza Vaccine Efficacy in Young Adult but Not Aged Mice.
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ABSTRACT:
SUBMITTER: Ramirez A
PROVIDER: S-EPMC4774967 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Despite the advancements in vaccination research and practices, influenza viruses remain a global health concern. Inducing a robust immune response by vaccination is especially challenging in the elderly, the immunocompromised, and persons with chronic illnesses. Polysaccharides derived from food may act as a safe and readily accessible means to boost the immune system during vaccination. In this study, we investigated whether crude polysaccharides derived from carrot pomace (CPP) could stimulate innate immune cell function and promote influenza vaccine immunogenicity. In bone marrow-derived dendritic cells (BMDCs), CPP increased the fraction of CD11c+MHCII+ cells and the expression of co-stimulatory molecules CD40 and CD80, indicative of enhanced maturation and activation. Functionally, CPP-treated BMDCs promoted inflammatory cytokine production in splenic lymphocytes. In a mouse model of immunosuppression induced by cyclophosphamide, animals given CPP before and after an influenza vaccine challenge showed increased frequencies of dendritic cells and natural killer cells in the spleen, in addition to the recovery of vaccine-specific antibody titers. Moreover, innate myeloid cells in CPP-fed mice showed evidence of phenotypic modification via markedly enhanced interleukin(IL)-12 and interferon(IFN)-γ production in response to lipopolysaccharide(LPS) stimulation ex vivo. Our findings suggest that the administration of carrot pomace polysaccharides can significantly enhance the efficacy of influenza vaccination.
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Project description:Influenza vaccines are less effective in older people than younger people. This impaired ability to protect older people from influenza viral lung infection has important implications as older people suffer a higher morbidity and mortality from influenza viral lung infection than younger people. Therefore, the development of novel effective vaccines that induce protection from influenza viral infections in older people are urgently needed. We had previously shown that direct linking the TLR5 activator, flagellin, to viral peptides induces effective immunity to viral antigens in young mice and people, respectively. In this study, we tested the efficacy of this vaccine platform with the hemagglutinin peptide of the influenza A strain virus (vaccine denoted as STF2.HA1-2) in protecting aged mice from subsequent influenza viral lung infection. We found that a 3.0 μg dose of the vaccine was effective in reducing mortality and increasing clinical well-being during influenza viral lung infection in aged mice. However, this effect was inferior to the response induced in young mice. Defects in the adaptive immune system but not the innate immune system were associated with this reduced effectiveness of the vaccine with aging. Our results indicate that the STF2.HA1-2 vaccine is effective in protecting aged hosts from influenza lung infection, although defects in the adaptive immune system with aging may limit the effectiveness of this vaccine in older people.
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Project description:Biological sex affects adaptive immune responses, which could impact influenza infection and vaccine efficacy. Infection of mice with 2009 H1N1 induced antibody responses, CD4+ T cell and CD8+ T cell memory responses that were greater in females than males; both sexes, however, were equally protected against secondary challenge with an H1N1 drift variant virus. To test whether greater antibody in females is sufficient for protection against influenza, males and females were immunized with an inactivated H1N1 vaccine that induced predominantly antibody-mediated immunity. Following vaccination, females had greater antibody responses and protection against challenge with an H1N1 drift variant virus than males. Antibody derived from vaccinated females was better at protecting both naïve males and females than antibody from males, and this protection was associated with increased antibody specificity and avidity to the H1N1 virus. The expression of Tlr7 was greater in B cells from vaccinated females than males and was associated with reduced DNA methylation in the Tlr7 promoter region, higher neutralizing antibody, class switch recombination, and antibody avidity in females. Deletion of Tlr7 reduced sex differences in vaccine-induced antibody responses and protection following challenge and had a greater impact on responses in females than males. Taken together, these data illustrate that greater TLR7 activation and antibody production in females improves the efficacy of vaccination against influenza.
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Project description:Respiratory syncytial virus (RSV) is recognized as an important cause of lower and upper respiratory tract infections in older adults, and a successful vaccine would substantially lower morbidity and mortality in this age group. Recently, two vaccine candidates based on soluble purified glycoprotein F (RSV F), either alone or adjuvanted with glucopyranosyl lipid A formulated in a stable emulsion (GLA-SE), failed to reach their primary endpoints in clinical efficacy studies, despite demonstrating the desired immunogenicity profile and efficacy in young rodent models. Here, one of the RSV F vaccine candidates (post-fusion conformation, RSV post-F), and a stabilized pre-fusion form of RSV F (RSV pre-F, DS-Cav1) were evaluated in aged BALB/c mice. Humoral and cellular immunogenicity elicited after immunization of naïve, aged mice was generally lower compared to young animals. In aged mice, RSV post-F vaccination without adjuvant poorly protected the respiratory tract from virus replication, and addition of GLA-SE only improved protection in the lungs, but not in nasal turbinates. RSV pre-F induced higher neutralizing antibody titers compared to RSV post-F (as previously reported) but interestingly, RSV F-specific CD8 T cell responses were lower compared to RSV post-F responses regardless of age. The vaccines were also tested in RSV seropositive aged mice, in which both antigen forms similarly boosted neutralizing antibody titers, although GLA-SE addition boosted neutralizing activity only in RSV pre-F immunized animals. Cell-mediated immune responses in the aged mice were only slightly boosted and well below levels induced in seronegative young mice. Taken together, the findings suggest that the vaccine candidates were not able to induce a strong anti-RSV immune response in recipient mice with an aged immune system, in agreement with recent human clinical trial results. Therefore, the aged mouse model could be a useful tool to evaluate improved vaccine candidates, targeted to prevent RSV disease in older adults.
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Project description:Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging associated frailty may preclude physical activity. AMP-activated protein kinase (AMPK) is a transcriptional regulator important for muscle physiology. In the present study we investigated effects of AMPK agonist 5-aminoimidazole-4-carboxamide riboside (AICAR) on memory and motor function in young (2-month-old), aged (23-month-old) C57Bl/6 mice, and transgenic mice with muscle-specific mutated AMPK alpha-subunit (AMPK-DN). Mice were injected with AICAR (500 mg/kg) for 3 to 14 days and tested in the Morris water maze, rotarod and open field. Improved water maze performance and motor function was observed, albeit at longer duration of administration, in aged (14 days AICAR) than young (3 days AICAR) mice. In the AMPKDN mice, the compound did not enhance behavior, providing support for a muscle mediated mechanism. In addition, microarray analysis of muscle and hippocampal tissue derived from aged mice treated with AICAR revealed changes in gene expression in both tissues, which correlated with behavioral effects in a dose-dependent manner. Pronounced up-regulation of mitochondrial genes in muscle was observed. In the hippocampus genes relevant to neuronal development and plasticity were enriched. Altogether, endurance related factors may mediate both muscle and brain health in aging, and could play a role in new therapeutic interventions. Key words: Skeletal Muscle, Brain, Exercise, AMPK, Learning and Memory, Morris water maze 23-month old female C57BL/6J mice (Jackson Laboratory, Bar Harbor, ME) were housed under standard conditions, 3 mice per cage, with food and water ad libitum. Mice were injected intraperitoneally with 5-Aminoimidazole-4-carboxamide-1-a-D-ribofuranoside (AICAR, Toronto Research Chemicals Inc., Canada) dissolved in saline, 500 mg/kg/day for 3 (ACR3), 7 (ACR7) or 14 (ACR14) days or saline vehicle, for 3 (CTR) days. Thirty-three days after the final injection animals were deeply anesthetized with isofluorane and perfused transcardially with 0.9% NaCl solution. The gastrocnemius muscle and Hippocampus were quickly removed, frozen on dry ice and stored at M-bM-^HM-^R80 M-BM-0C for RNA isolation and microarray analysis.
2014-01-17 | E-GEOD-50873 | biostudies-arrayexpress
Project description:Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging-associated frailty can preclude physical activity. In young sedentary animals, pharmacological activation of AMP-activated protein kinase (AMPK), a transcriptional regulator important for muscle physiology, enhanced spatial memory function, and endurance. In the present study we investigated effects of AMPK agonist 5-aminoimidazole-4-carboxamide riboside (AICAR) on memory and motor function in young (5- to 7-wk-old) and aged (23-mo-old) female C57Bl/6 mice, and in young (4- to 6-wk-old) transgenic mice with muscle-specific mutated AMPK ?2-subunit (AMPK-DN). Mice were injected with AICAR (500 mg/kg) for 3-14 d. Two weeks thereafter animals were tested in the Morris water maze, rotarod, and open field. Improved water maze performance and motor function were observed, albeit at longer duration of administration, in aged (14-d AICAR) than in young (3-d AICAR) mice. In the AMPK-DN mice, the compound did not enhance behavior, providing support for a muscle-mediated mechanism. In addition, microarray analysis of muscle and hippocampal tissue derived from aged mice treated with AICAR revealed changes in gene expression in both tissues, which correlated with behavioral effects in a dose-dependent manner. Pronounced up-regulation of mitochondrial genes in muscle was observed. In the hippocampus, genes relevant to neuronal development and plasticity were enriched. Altogether, endurance-related factors may mediate both muscle and brain health in aging, and could play a role in new therapeutic interventions.
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Project description:Enterotoxin-based adjuvants including cholera toxin and heat-labile toxin (LT) are powerful manipulators of mucosal immunity; however, past clinical trials identified unacceptable neurological toxicity when LT or mutant AB5 adjuvant proteins were added to intranasal vaccines. Here, we examined the isolated enzymatic A1 domain of LT (LTA1) for intranasal safety and efficacy in combination with influenza (flu) vaccination. LTA1-treated mice exhibited no neurotoxicity, as measured by olfactory system testing and H&E staining of nasal tissue in contrast with cholera toxin. In vaccination studies, intranasal LTA1 enhanced immune responses to inactivated virus antigen and subsequent protection against H1N1 flu challenge in mice (8-week or 24-months). In addition, lung H1N1 viral titers post-challenge correlated to serum antibody responses; however, enhanced protection was also observed in μMT mice lacking B-cells while activation and recruitment of CD4 T-cells into the lung was apparent. Thus, we report that LTA1 protein is a novel, safe and effective enterotoxin adjuvant that improves protection of an intranasal flu vaccination by a mechanism that does not appear to require B-cells.
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Project description:Influenza virus infections pose a significant threat to global health. Vaccination is the main countermeasure against influenza virus spread, however, the effectiveness of vaccines is variable. Current seasonal influenza virus vaccines mostly rely on the immunodominant hemagglutinin (HA) glycoprotein on the viral surface, which usually leads to a narrow and strain-specific immune response. The HA undergoes constant antigenic drift, which can lead to a dramatic loss in vaccine effectiveness, requiring the annual reformulation and readministration of influenza virus vaccines. Recently, it has been demonstrated that the subdominant glycoprotein, neuraminidase (NA), is an attractive target for vaccine development. Here, we tested a newly developed recombinant influenza virus N1 neuraminidase vaccine candidate, named N1-MPP, adjuvanted with CpG 1018, a TLR9 agonist. Additionally, N2-MPP and B-NA-MPP vaccine constructs have been generated to cover the range of influenza viruses that are seasonally circulating in humans. These constructs have been characterized in vitro and in vivo regarding their functionality and protective potential. Furthermore, a trivalent NA-MPP mix was tested. No antigenic competition between the individual NA constructs was detected. By adjuvating the recombinant protein constructs with CpG 1018 it was possible to induce a strong and robust immune response against the NA, which provided full protection against morbidity and mortality after high lethal challenges in vivo. This study provides important insights for the development of a broadly protective NA-based influenza virus vaccine candidate.
| S-EPMC9305062 | biostudies-literature
Project description:Background: Influenza causes significant morbidity and mortality; the pandemic in 2009-2010 was a reminder of the potential for novel strains and antigenic changes. Studies have shown that vitamin D deficiency may be associated with poor vaccine immunogenicity, therefore we sought to determine if there was a correlation between 25-hydroxyvitamin D [25(OH)D] and influenza vaccine response.Methods: A retrospective observational study was conducted among young, healthy military members to evaluate the association between total 25(OH)D levels with post influenza vaccination antibody titers and healthcare encounters during the 2009-10 influenza season. Univariate analyses were performed to evaluate whether 25(OH)D levels are associated with baseline characteristics and post-vaccination antibody responses. Multivariable logistic regression models were utilized to determine the associations between antibody responses and 25(OH)D levels adjusting for possible confounders.Results: A total of 437 subjects were studied. Most participants were young adults (91% were 18-39 years of age), 50% were male, and 56% resided in the southern U.S. Overall, 152 (34.8%) were vitamin D deficient, 167 (38.2%) insufficient, and 118 (27.0%) with normal 25(OH)D levels. There were no demographic differences by 25(OH)D category. Only 224 (51.3%) demonstrated a seroprotective anti-influenza post-vaccination titer, which did not vary by categorical 25(OH)D levels [vitamin D deficient vs. normal: OR 1.10 (0.68-1.78) and insufficient vs. normal: OR 1.25 (0.78-2.01)] or continuous vitamin D levels [OR 0.98 (0.84-1.15)]. There were also no associations with increased influenza like illnesses, respiratory diagnoses and healthcare encounters between the vitamin D groups.Conclusion: Vitamin D insufficiency and deficiency were highly prevalent despite evaluating a young, healthy adult population. There were no significant associations between 25(OH)D levels and post-vaccination antibody titers to influenza vaccine. Further studies are required to discover strategies to improve vaccine efficacy as well as to determine the role of 25(OH)D in vaccine immunity.
| S-EPMC5806853 | biostudies-literature
Project description:Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging associated frailty may preclude physical activity. AMP-activated protein kinase (AMPK) is a transcriptional regulator important for muscle physiology. In the present study we investigated effects of AMPK agonist 5-aminoimidazole-4-carboxamide riboside (AICAR) on memory and motor function in young (2-month-old), aged (23-month-old) C57Bl/6 mice, and transgenic mice with muscle-specific mutated AMPK alpha-subunit (AMPK-DN). Mice were injected with AICAR (500 mg/kg) for 3 to 14 days and tested in the Morris water maze, rotarod and open field. Improved water maze performance and motor function was observed, albeit at longer duration of administration, in aged (14 days AICAR) than young (3 days AICAR) mice. In the AMPKDN mice, the compound did not enhance behavior, providing support for a muscle mediated mechanism. In addition, microarray analysis of muscle and hippocampal tissue derived from aged mice treated with AICAR revealed changes in gene expression in both tissues, which correlated with behavioral effects in a dose-dependent manner. Pronounced up-regulation of mitochondrial genes in muscle was observed. In the hippocampus genes relevant to neuronal development and plasticity were enriched. Altogether, endurance related factors may mediate both muscle and brain health in aging, and could play a role in new therapeutic interventions. Key words: Skeletal Muscle, Brain, Exercise, AMPK, Learning and Memory, Morris water maze
2014-01-17 | GSE50873 | GEO