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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.).