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AS03-Adjuvanted H5N1 Avian Influenza Vaccine Modulates Early Innate Immune Signatures in Human Peripheral Blood Mononuclear Cells.
Howard, LM, Goll, JB, Jensen, TL, Hoek, KL, Prasad, N, Gelber, CE, Levy, SE, Joyce, S, Link, AJ, Creech, CB, et al
The Journal of infectious diseases. 2019;(11):1786-1798
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Abstract
BACKGROUND Adjuvant System 03 (AS03) markedly enhances responses to influenza A/H5N1 vaccines, but the mechanisms of this enhancement are incompletely understood. METHODS Using ribonucleic acid sequencing on peripheral blood mononuclear cells (PBMCs) from AS03-adjuvanted and unadjuvanted inactivated H5N1 vaccine recipients, we identified differentially expressed genes, enriched pathways, and genes that correlated with serologic responses. We compared bulk PBMC findings with our previously published assessments of flow-sorted immune cell types. RESULTS AS03-adjuvanted vaccine induced the strongest differential signals on day 1 postvaccination, activating multiple innate immune pathways including interferon and JAK-STAT signaling, Fcγ receptor (FcγR)-mediated phagocytosis, and antigen processing and presentation. Changes in signal transduction and immunoglobulin genes predicted peak hemagglutinin inhibition (HAI) titers. Compared with individual immune cell types, activated PBMC genes and pathways were most similar to innate immune cells. However, several pathways were unique to PBMCs, and several pathways identified in individual cell types were absent in PBMCs. CONCLUSIONS Transcriptomic analysis of PBMCs after AS03-adjuvanted H5N1 vaccination revealed early activation of innate immune signaling, including a 5- to 8-fold upregulation of FcγR1A/1B/1C genes. Several early gene responses were correlated with HAI titer, indicating links with the adaptive immune response. Although PBMCs and cell-specific results shared key innate immune signals, unique signals were identified by both approaches.
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Comparing the effects of vitamin E tocotrienol-rich fraction supplementation and α-tocopherol supplementation on gene expression in healthy older adults.
Ghani, SMA, Goon, JA, Azman, NHEN, Zakaria, SNA, Hamid, Z, Ngah, WZW
Clinics (Sao Paulo, Brazil). 2019;:e688
Abstract
OBJECTIVES This study aims to compare the differential gene expression resulting from tocotrienol-rich fraction and α-tocopherol supplementation in healthy older adults. METHODS A total of 71 eligible subjects aged 50 to 55 years from Gombak and Kuala Lumpur, Malaysia, were divided into three groups and supplemented with placebo (n=23), α-tocopherol (n=24) or tocotrienol-rich fraction (n=24). Blood samples were collected at baseline and at 3 and 6 months of supplementation for microarray analysis. RESULTS The number of genes altered by α-tocopherol was higher after 6 months (1,410) than after 3 months (273) of supplementation. α-Tocopherol altered the expression of more genes in males (952) than in females (731). Similarly, tocotrienol-rich fraction modulated the expression of more genes after 6 months (1,084) than after 3 months (596) and affected more genes in males (899) than in females (781). α-Tocopherol supplementation modulated pathways involving the response to stress and stimuli, the immune response, the response to hypoxia and bacteria, the metabolism of toxins and xenobiotics, mitosis, and synaptic transmission as well as activated the mitogen-activated protein kinase and complement pathways after 6 months. However, tocotrienol-rich fraction supplementation affected pathways such as the signal transduction, apoptosis, nuclear factor kappa B kinase, cascade extracellular signal-regulated kinase-1 and extracellular signal-regulated kinase-2, immune response, response to drug, cell adhesion, multicellular organismal development and G protein signaling pathways. CONCLUSION Supplementation with either α-tocopherol or tocotrienol-rich fraction affected the immune and drug response and the cell adhesion and signal transduction pathways but modulated other pathways differently after 6 months of supplementation, with sex-specific responses.
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Effects of dietary RRR α-tocopherol vs all-racemic α-tocopherol on health outcomes.
Ranard, KM, Erdman, JW
Nutrition reviews. 2018;(3):141-153
Abstract
Of the 8 vitamin E analogues, RRR α-tocopherol likely has the greatest effect on health outcomes. Two sources of α-tocopherol, naturally sourced RRR α-tocopherol and synthetic all-racemic α-tocopherol, are commonly consumed from foods and dietary supplements in the United States. A 2016 US Food and Drug Administration ruling substantially changed the RRR to all-racemic α-tocopherol ratio of biopotency from 1.36:1 to 2:1 for food-labeling purposes, but the correct ratio is still under debate in the literature. Few studies have directly compared the 2 α-tocopherol sources, and existing studies do not compare the efficacy of either source for preventing or treating disease in humans. To help close this gap, this review evaluates studies that investigated the effects of either RRR α-tocopherol or all-racemic α-tocopherol on health outcomes, and compares the overall findings. α-Tocopherol has been used to prevent and/or treat cancer and diseases of the central nervous system, the immune system, and the cardiovascular system, so these diseases are the focus of the review. No firm conclusions about the relative effects of the α-tocopherol sources on health outcomes can be made. Changes to α-tocopherol-relevant policies have proceeded without adequate scientific support. Additional research is needed to assemble the pieces of the α-tocopherol puzzle and to determine the RRR to all-racemic α-tocopherol ratio of biopotency for health outcomes.
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Nasal mucosa healing after endoscopic sinus surgery in chronic rhinosinusitis of elderly patients: role of topic alpha-tocopherol acetate.
Testa, D, Marcuccio, G, Panin, G, Bianco, A, Tafuri, D, Thyrion, FZ, Nunziata, M, Piombino, P, Guerra, G, Motta, G
Aging clinical and experimental research. 2017;(Suppl 1):191-195
Abstract
BACKGROUND Chronic rhinosinusitis (CRS) in European country ranges in elderly patients from 4.5 to 12% of population and has a significant effect on quality of life. In these patients, rhinosinusitis is linked to immune functions changes with age and to mucosal paraphysiological alterations such as crusting formations with atrophic epithelium, variations of nasal airflow and modifications of the mucociliary clearance. Failure of medical treatments leads to surgery in patients with persistent symptoms and radiographic signs of CRS. The choice of appropriate post-surgical topic treatments is important for healing time and for preventing mucosal complications such as synechiae, crusting formation and atrophy with secondary bacterial and fungal infections. AIMS Defining the effects of topic alpha-tocopherol acetate administration on nasal mucosa healing after endoscopic sinus surgery in CRS of elderly patients. METHODS In this study were included 32 patients, mean age 68.6, who underwent FESS because affected by CRS not responsive to medical treatments. After surgical treatment, we distinguish two groups basing on local nasal therapy. RESULTS We investigated, in the postoperative time, the role of alpha-tocopherol acetate compared to gomenol oil. Follow-up was performed at 7-15 days and 1-3 months after surgery. We evaluated mucosal restoration using Rhinoscopy Sum Score and quality of life using Nasal Six Items Symptom Questionnaire. We observed a faster healing time and less recurrence of complications in patients who underwent topic treatment with alpha-tocopherol acetate. DISCUSSION In our research, we observed that alpha-tocopherol acetate has no contraindications and side effects. CONCLUSIONS Our study showed the effectiveness of alpha-tocopherol acetate topic treatment in elderly patients affected by CRS after FESS, in improving and speeding up the process of restoring the sinonasal mucosa, compared to another topic medication.
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Long-Term Persistence of Cell-Mediated and Humoral Responses to A(H1N1)pdm09 Influenza Virus Vaccines and the Role of the AS03 Adjuvant System in Adults during Two Randomized Controlled Trials.
van der Most, RG, Clément, F, Willekens, J, Dewé, W, Walravens, K, Vaughn, DW, Leroux-Roels, G
Clinical and vaccine immunology : CVI. 2017;(6)
Abstract
We investigated the role of AS03A (here AS03), an α-tocopherol oil-in-water emulsion-based adjuvant system, on the long-term persistence of humoral and cell-mediated immune responses to A(H1N1)pdm09 influenza vaccines. In two studies, a total of 261 healthy adults (≤60 years old) were randomized to receive two doses of AS03-adjuvanted vaccine containing 3.75 μg of hemagglutinin (HA) or nonadjuvanted vaccine containing 15 μg of hemagglutinin (in study A) or 3.75 μg of hemagglutinin (in study B) 21 days apart. Hemagglutination inhibition (HI) antibody, memory B-cell, and CD4+/CD8+ T-cell responses were characterized up to 1 year following dose 1. We also assessed the effects of age and seasonal influenza vaccination history. AS03-adjuvanted (3.75 μg HA) vaccine and nonadjuvanted vaccine at 15 μg but not at 3.75 μg HA elicited HI antibody responses persisting at levels that continued to meet European licensure criteria through month 12. At month 12, the geometric mean titer for AS03-adjuvanted vaccine was similar to that for nonadjuvanted (15-μg) vaccine in study A (1:86 and 1:88, respectively) and higher than that for nonadjuvanted (3.75-μg) vaccine in study B (1:77 and 1:35, respectively). A(H1N1)pdm09-specific CD4+ T-cell and B-cell responses were stronger in AS03-adjuvanted groups and persisted only in these groups for 12 months at levels exceeding prevaccination frequencies. Advancing age and a seasonal vaccination history tended to reduce HI antibody and memory B-cell responses and, albeit less consistently, CD4+ T-cell responses. Thus, AS03 seemed to enhance the persistence of humoral and cell-mediated responses to A(H1N1)pdm09 vaccine, allowing for antigen sparing and mitigating potential negative effects of age and previous seasonal vaccination. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00968539 and NCT00989287.).
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Immunogenicity and Safety of an AS03-Adjuvanted H7N9 Pandemic Influenza Vaccine in a Randomized Trial in Healthy Adults.
Madan, A, Segall, N, Ferguson, M, Frenette, L, Kroll, R, Friel, D, Soni, J, Li, P, Innis, BL, Schuind, A
The Journal of infectious diseases. 2016;(11):1717-1727
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BACKGROUND Almost 700 cases of human infection with avian influenza A/H7N9 have been reported since 2013. Pandemic preparedness strategies include H7N9 vaccine development. METHODS We evaluated an inactivated H7N9 vaccine in an observer-blind study in healthy adults aged 18-64 years. Participants (420) were randomized to receive 1 of 4 AS03-adjuvanted vaccines (low or medium dose of hemagglutinin with AS03A or AS03B), one nonadjuvanted vaccine, or placebo. The coprimary immunogenicity objective determined whether adjuvanted vaccines elicited an immune response against the vaccine-homologous virus, 21 days after the second vaccine dose per US and European licensure criteria in the per-protocol cohort (n = 389). RESULTS All adjuvanted vaccines met regulatory acceptance criteria. In groups receiving adjuvanted formulations, seroconversion rates were ≥85.7%, seroprotection rates ≥91.1%, and geometric mean titers ≥92.9% versus 23.2%, 28.6%, and 17.2 for the nonadjuvanted vaccine. The AS03 adjuvant enhanced immune response at antigen-sparing doses. Injection site pain occurred more frequently with adjuvanted vaccines (in ≤98.3% of vaccinees) than with the nonadjuvanted vaccine (40.7%) or placebo (20.0%). None of the 20 serious adverse events reported were related to vaccination. CONCLUSIONS Two doses of AS03-adjuvanted H7N9 vaccine were well tolerated and induced a robust antibody response at antigen-sparing doses in healthy adults. CLINICAL TRIALS REGISTRATION NCT01999842.
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Phase II, randomized, open, controlled study of AS03-adjuvanted H5N1 pre-pandemic influenza vaccine in children aged 3 to 9 years: follow-up of safety and immunogenicity persistence at 24 months post-vaccination.
Díez-Domingo, J, Baldó, JM, Planelles-Catarino, MV, Garcés-Sánchez, M, Ubeda, I, Jubert-Rosich, A, Marès, J, Garcia-Corbeira, P, Moris, P, Teko, M, et al
Influenza and other respiratory viruses. 2015;(2):68-77
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BACKGROUND An AS03-adjuvanted H5N1 influenza vaccine elicited broad and persistent immune responses with an acceptable safety profile up to 6 months following the first vaccination in children aged 3-9 years. METHODS In this follow-up of the Phase II study, we report immunogenicity persistence and safety at 24 months post-vaccination in children aged 3-9 years. The randomized, open-label study assessed two doses of H5N1 A/Vietnam/1194/2004 influenza vaccine (1·9 μg or 3·75 μg hemagglutinin antigen) formulated with AS03A or AS03B (11·89 mg or 5·93 mg tocopherol, respectively). Control groups received seasonal trivalent influenza vaccine. Safety was assessed prospectively and included potential immune-mediated diseases (pIMDs). Immunogenicity was assessed by hemagglutination-inhibition assay 12 and 24 months after vaccination; cross-reactivity and cell-mediated responses were also assessed. (NCT00502593). RESULTS The safety population included 405 children. Over 24 months, five events fulfilled the criteria for pIMDs, of which four occurred in H5N1 vaccine recipients, including uveitis (n = 1) and autoimmune hepatitis (n = 1), which were considered to be vaccine-related. Overall, safety profiles of the vaccines were clinically acceptable. Humoral immune responses at 12 and 24 months were reduced versus those observed after the second dose of vaccine, although still within the range of those observed after the first dose. Persistence of cell-mediated immunity was strong, and CD4(+) T cells with a TH 1 profile were observed. CONCLUSIONS Two doses of an AS03-adjuvanted H5N1 influenza vaccine in children showed low but persistent humoral immune responses and a strong persistence of cell-mediated immunity, with clinically acceptable safety profiles up to 24 months following first vaccination.
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Single dose vaccination of the ASO3-adjuvanted A(H1N1)pdm09 monovalent vaccine in health care workers elicits homologous and cross-reactive cellular and humoral responses to H1N1 strains.
Lartey, S, Pathirana, RD, Zhou, F, Jul-Larsen, Å, Montomoli, E, Wood, J, Cox, RJ
Human vaccines & immunotherapeutics. 2015;(7):1654-62
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Healthcare workers (HCW) were prioritized for vaccination during the 2009 influenza A(H1N1)pdm09 pandemic. We conducted a clinical trial in October 2009 where 237 HCWs were immunized with a AS03-adjuvanted A(H1N1)pdm09 monovalent vaccine. In the current study, we analyzed the homologous and cross-reactive H1N1 humoral responses using prototype vaccine strains dating back to 1977 by the haemagglutinin inhibition (HI), single radial hemolysis SRH), antibody secreting cell (ASC) and memory B cell (MBC) assays. The cellular responses were assessed by interferon-γ (IFN-γ) ELISPOT and by intracellular staining (ICS) for the Th1 cytokines IFN-γ, interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α). All assays were performed using blood samples obtained prior to (day 0) and 7, 14 and 21 d post-pandemic vaccination, except for ASC (day 7) and ICS (days 0 and 21). Vaccination elicited rapid HI, SRH and ASC responses against A(H1N1)pdm09 which cross reacted with seasonal H1N1 strains. MBC responses were detected against the homologous and seasonal H1N1 strains before vaccination and were boosted 2 weeks post-vaccination. An increase in cellular responses as determined by IFN-γ ELISPOT and ICS were observed 1-3 weeks after vaccination. Collectively, our data show that the AS03-adjuvanted A(H1N1)pdm09 vaccine induced rapid cellular and humoral responses against the vaccine strain and the response cross-reacted against prototype H1N1 strains dating back to 1977.
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Long-term immunogenicity of two doses of 2009 A/H1N1v vaccine with and without AS03(A) adjuvant in HIV-1-infected adults.
Durier, C, Desaint, C, Lucht, F, Girard, PM, Lévy, Y, May, T, Michelet, C, Rami, A, Roman, F, Delfraissy, JF, et al
AIDS (London, England). 2013;(1):87-93
Abstract
OBJECTIVE In immunocompromised patients, alternative schedules more immunogenic than the standard influenza vaccine regimen are necessary to enhance and prolong vaccine efficacy. We previously reported that the AS03A-adjuvanted 2009 A/H1N1v vaccine yielded a higher short-term immune response than the nonadjuvanted one in HIV-1-infected adults. This study reports the long-term persistence of the immune response. DESIGN AND METHODS In a prospective, multicenter, randomized, patient-blinded trial, two doses of AS03A-adjuvanted H1N1v vaccine containing 3.75 μg haemagglutinin (n = 155; group A) or nonadjuvanted H1N1v vaccine containing 15 μg haemagglutinin (n = 151; group B), were administered 21 days apart. Haemagglutination inhibition and neutralizing antibodies were assessed 6 and 12 months after vaccination. RESULTS In group A and B, the seroprotection rates were 83.7 and 59.4% at month 6, and 70.4 and 49.3 at month 12, respectively. In a multivariate analysis, persistence of seroprotection 12 months after vaccination was negatively associated with current smoking (odds ratio = 0.6, P = 0.03) and positively related with the AS03A-adjuvanted H1N1v vaccine (odds ratio = 2.7, P = 0.0002). CONCLUSION In HIV-1-infected adults, two doses of adjuvanted influenza vaccine induce long-term persistence of immune response up to 1 year after vaccination.
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Randomized, placebo-controlled pilot trial of the effects of alpha-tocopherol supplementation on levels of autoantibodies against 5-hydroxymethyl-2-deoxyuridine in melanoma patients.
Mahabir, S, Frenkel, K, Brady, MS, Coit, D, Leibes, L, Karkoszka, J, Berwick, M
Melanoma research. 2004;(1):49-56
Abstract
We conducted a randomized, placebo-controlled pilot trial to assess whether supplementation of 1000 mg/day alpha-tocopherol for 3 months offered protection against DNA base damage in melanoma outpatients (n=46). Plasma autoantibodies (aAbs) against 5-hydroxymethyl-2-deoxyuridine (HMdU) were measured as an immune marker of DNA base damage. After 3 months of supplementation (final level), plasma levels of alpha-tocopherol increased significantly (P<0.0005) in the alpha-tocopherol compared with the placebo treatment group. Supplementation with alpha-tocopherol also resulted in a significant (P=0.04) decrease in plasma gamma-tocopherol levels among males. Overall, we did not find any significant differences in the plasma anti-HMdU aAb levels between the two treatment groups. However, when the patients were stratified by the clinical characteristics of the melanoma, we found that alpha-tocopherol supplementation resulted in a borderline significant (P=0.06) 48% decrease in plasma anti-HMdU aAb levels in patients with less aggressive melanomas (Breslow thickness ≤1 mm) only. Within-group analysis showed that women had significantly (P<0.05) higher baseline levels of anti-HMdU aAbs compared with men in each treatment group. However, the final levels of anti-HMdU aAbs were significantly (P<0.05) higher in women in the alpha-tocopherol supplemented group only. Although reliable conclusions cannot be drawn from this pilot study, which is limited by the small sample size, the results suggest that short-term alpha-tocopherol supplementation may offer some protection against less aggressive melanomas. Further studies using much larger sample sizes are required to confirm this finding.