ORCID Profile
0000-0002-1580-5245
Current Organisations
Vaxine (Australia)
,
Flinders University School of Medicine
,
Flinders Medical Centre
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Structural Biology (incl. Macromolecular Modelling) | Characterisation of Biological Macromolecules | Organic Chemistry | Biological And Medical Chemistry | Biochemistry and Cell Biology | Chemical Engineering Design | Macromolecular and Materials Chemistry | Organic Green Chemistry | Powder and Particle Technology | Characterisation Of Macromolecules | Physical Chemistry (Incl. Structural) | Other Instrumental Methods | Chemical Engineering | Pharmaceutical Sciences | Medical Biotechnology not elsewhere classified | Structural Chemistry and Spectroscopy | Receptors and Membrane Biology | Nanomaterials | Industrial Chemistry | Medical Biotechnology | Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies) | Bioprocessing, Bioproduction and Bioproducts |
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Biological Sciences | Inorganic Industrial Chemicals | Human Biological Preventatives (e.g. Vaccines) | Organic Industrial Chemicals (excl. Resins, Rubber and Plastics) | Expanding Knowledge in Technology | Management of Solid Waste from Plant Production | Human Pharmaceutical Treatments (e.g. Antibiotics) | Veterinary Pharmaceutical Treatments (e.g. Antibiotics) | Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in Engineering | Expanding Knowledge in the Agricultural and Veterinary Sciences | Prevention—biologicals (e.g. vaccines)
Related Links
Publications
Identification of Key β Cell Gene Signaling Pathways Involved in Type 1 Diabetes
Publisher: Wiley
Date: 12-2004
Abstract: In type 1 diabetes, beta cells die through a process of immune-mediated apoptosis. To better understand this process, it has been accepted practice to study beta cell or islet apoptosis in vitro in response to a range of immune stimuli, such as interferon gamma, interleukin-1, nitric oxide or free radicals. In particular, much use has been made of immortalized beta cell lines for such studies, although it is not clear to what extent the behavior of these cell lines might mimic the behavior of normal beta cells in vivo, or freshly isolated beta cells ex vivo. To address this question we compared the gene expression of freshly isolated NOD islets in the presence or absence of insulitis, with previously published data examining either islet or beta cell gene or protein expression in a range of different species and contexts. There was a high correlation between beta cell genes found be to be expressed by mouse and rat islets, by either gene expression or proteomic analysis. There was also a surprisingly high correlation between beta cell genes found be to be expressed by islets exposed to insulitis in vivo and islets stimulated with IFN-gamma and IL-1beta in vitro, suggesting that these two cytokines as produced by the islet infiltrate are important for priming beta cells in vivo. There was a much lower correlation when gene expression was compared between fresh beta cells and beta cell lines, consistent with the view that beta cell lines are very poorly representative of real beta cells. Hence, any results obtained using beta cell lines should be interpreted with great caution when extrapolating to the behavior of real beta cells.
The polysaccharide inulin is characterized by an extensive series of periodic isoforms with varying biological actions
Publisher: Oxford University Press (OUP)
Date: 12-07-2013
The Power of an Integrated Informatic and Molecular Approach to Type 1 Diabetes Research
Publisher: Wiley
Date: 12-2004
Abstract: Recent years have witnessed an explosive growth in available biological data. This includes a tremendous quantity of sequence data (e.g., biological structures, genetic and physical maps, pathways) generated by genome and transcriptome projects focused on humans, mice, and a multitude of other species. Diabetes research stands to greatly benefit from this data, which is distributed across public and private databases and the scientific literature. The increasing quantity and complexity of this biological data necessitates use of novel bioinformatics strategies for its efficient retrieval, analysis, and interpretation. Bioinformatic capability is becoming increasingly indispensable for fast and comprehensive analysis of biological data by diabetes researchers. There is great potential for diabetes scientists and clinicians to take advantage of recent bioinformatics and knowledge discovery developments to radically transform and advance this field of research. This paper will review advances in the field of bioinformatics relevant to diabetes research and preview a new specialty diabetes database, Diabetaeta, that we are creating to serve as a central bioinformatic portal for type 1 diabetes research, as well as serving as a public repository for beta cell gene and protein expression data.
Evidence from twins for acquired cellular immune hyperactivity in type 1 diabetes
Publisher: Wiley
Date: 08-2002
DOI: 10.1046/J.1365-2567.2002.01449.X
Abstract: Type 1 diabetes has been associated with an increased frequency of activated T cells and T-cell hyperactivity to non-specific and disease-specific stimuli including the islet autoantigen glutamic acid decarboxylase 65 (GAD). To address whether T-cell hyperactivity is genetic or acquired we measured whole blood cytokines in vitro in response to GAD or tetanus in 18 identical twin pairs, nine discordant for type 1 diabetes. In addition, the activity of 2', 5' oligoadenylate synthetase (OAS) in blood mononuclear cells was measured as a marker of viral infection. Interleukin-2 (IL-2) basally and IL-2 and interferon-gamma (IFN-gamma) in response to GAD, were detected more frequently and at higher levels in diabetic compared to non-diabetic twins. IL-10 was not different between groups. OAS activity was increased in diabetic compared to non-diabetic twins and showed a correlation with basal IL-2 and GAD-stimulated IFN-gamma and IL-10. These findings suggest that T-cell hyperactivity in type 1 diabetes is an acquired trait and could reflect persisting virus expression.
Improved influenza viral vector based Brucella abortus vaccine induces robust B and T-cell responses and protection against Brucella melitensis infection in pregnant sheep and goats
Publisher: Public Library of Science (PLoS)
Date: 12-10-2017
An Epitope-based Malaria Vaccine Targeting the Junctional Domain of Circumsporozoite Protein
Publisher: Cold Spring Harbor Laboratory
Date: 07-08-2020
DOI: 10.1101/2020.08.07.241802
Abstract: A malaria vaccine that elicits long-lasting protection and is suitable for use in endemic areas remains urgently needed. Here, we assessed the immunogenicity and prophylactic efficacy of a vaccine targeting a recently described epitope on the major surface antigen on Plasmodium falciparum sporozoites, circumsporozoite protein (CSP). Using a virus-like particle (VLP)-based vaccine platform technology, we developed a vaccine that targets the junctional region between the N-terminal and central repeat domains of CSP. This region is recognized by monoclonal antibodies, including mAb CIS43, that have been shown to potently prevent liver invasion in animal models. We show that CIS43 VLPs elicit high titer and long-lived anti-CSP antibody responses in mice and non-human primates. Immunization with CIS43 VLPs confers partial protection from malaria infection in a mouse model, and both immunogenicity and protection were enhanced when mice were immunized with CIS43 VLPs in combination with adjuvants including delta inulin polysaccharide particles and TLR9 agonists. Passive transfer of serum from immunized macaques also inhibited parasite liver invasion in the mouse infection model. Our findings demonstrate that a Qß VLP-based vaccine targeting the CIS43 epitope combined with various adjuvants is highly immunogenic in mice and macaques, elicits long-lasting anti-CSP antibodies, and inhibits parasite infection in a mouse model. Thus, the CIS43 VLP vaccine is a promising pre-erythrocytic malaria vaccine candidate.
Doxorubicin-Loaded Delta Inulin Conjugates for Controlled and Targeted Drug Delivery: Development, Characterization, and In Vitro Evaluation
Publisher: MDPI AG
Date: 06-11-2019
DOI: 10.3390/PHARMACEUTICS11110581
Abstract: Delta inulin, also known as microparticulate inulin (MPI), was modified by covalently attaching doxorubicin to its nanostructured surface for use as a targeted drug delivery vehicle. MPI is readily endocytosed by monocytes, macrophages, and dendritic cells and in this study, we sought to utilize this property to develop a system to target anti-cancer drugs to lymphoid organs. We investigated, therefore, whether MPI could be used as a vehicle to deliver doxorubicin selectively, thereby reducing the toxicity of this antibiotic anthracycline drug. Doxorubicin was covalently attached to the surface of MPI using an acid–labile linkage to enable pH-controlled release. The MPI-doxorubicin conjugate was characterized using FTIR and SEM, confirming covalent attachment and indicating doxorubicin coupling had no obvious impact on the physical nanostructure, integrity, and cellular uptake of the MPI particles. To simulate the stability of the MPI-doxorubicin in vivo, it was stored in artificial lysosomal fluid (ALF, pH 4.5). Although the MPI-doxorubicin particles were still visible after 165 days in ALF, 53% of glycosidic bonds in the inulin particles were hydrolyzed within 12 days in ALF, reflected by the release of free glucose into solution. By contrast, the fructosidic bonds were much more stable. Drug release studies of the MPI-doxorubicin in vitro, demonstrated a successful pH-dependent controlled release effect. Confocal laser scanning microscopy studies and flow cytometric analysis confirmed that when incubated with live cells, MPI-doxorubicin was efficiently internalized by immune cells. An assay of cell metabolic activity demonstrated that the MPI carrier alone had no toxic effects on RAW 264.7 murine monocyte/macrophage-like cells, but exhibited anti-cancer effects against HCT116 human colon cancer cells. MPI-doxorubicin had a greater anti-cancer cell effect than free doxorubicin, particularly when at lower concentrations, suggesting a drug-sparing effect. This study establishes that MPI can be successfully modified with doxorubicin for chemotherapeutic drug delivery.
World Vaccine Congress Asia 2011 June 20-24, 2011, Singapore
Publisher: Portico
Date: 2011
Influence of Oxidation Degree on the Physicochemical Properties of Oxidized Inulin
Publisher: MDPI AG
Date: 05-2020
Abstract: This paper reports the oxidation of inulin using varying ratios of sodium periodate and the characterization of the inulin polyaldehyde. The physicochemical properties of the inulin polyaldehyde (oxidized inulin) were characterized using different techniques including 1D NMR spectroscopy, 13C Nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), differential scanning calorimetric (DSC), ultraviolet-visible spectroscopy (UV), and scanning electron microscopy (SEM). The aldehyde peak was not very visible in the FTIR, because the aldehyde functional group exists in a masked form (hemiacetal). The thermal stability of the oxidized inulin decreased with the increasing oxidation degree. The smooth spherical shape of raw inulin was destructed due to the oxidation, as confirmed by the SEM result. The 1HNMR results show some new peaks from 4.8 to 5.0 as well as around 5.63 ppm. However, no aldehyde peak was found around 9.7 ppm. This can be attributed to the hemiacetal. The reaction of oxidized inulin with tert-butyl carbazate produced a carbazone conjugate. There was clear evidence of decreased peak intensity for the proton belonging to the hemiacetal group. This clearly shows that not all of the hemiacetal group can be reverted by carbazate. In conclusion, this work provides vital information as regards changes in the physicochemical properties of the oxidized inulin, which has direct implications when considering the further utilization of this biomaterial.
Relative Adipose Tissue Failure in Alström Syndrome Drives Obesity-Induced Insulin Resistance
Publisher: American Diabetes Association
Date: 29-09-2020
DOI: 10.2337/DB20-0647
Abstract: Obesity is a major risk factor for insulin resistance (IR) and its attendant complications. The pathogenic mechanisms linking them remain poorly understood, partly due to a lack of intermediary monogenic human phenotypes. Here, we report on a monogenic form of IR-prone obesity, Alström syndrome (ALMS). Twenty-three subjects with monogenic or polygenic obesity underwent hyperinsulinemic-euglycemic cl ing with concomitant adipose tissue (AT) microdialysis and an in-depth analysis of subcutaneous AT histology. We have shown a relative AT failure in a monogenic obese cohort, a finding supported by observations in a novel conditional mouse model (Almsflin/flin) and ALMS1-silenced human primary adipocytes, whereas selective reactivation of ALMS1 gene in AT of an ALMS conditional knockdown mouse model (Almsflin/flin Adipo-Cre+/−) restores systemic insulin sensitivity and glucose tolerance. Hence, we show for the first time the relative AT failure in human obese cohorts to be a major determinant of accelerated IR without evidence of lipodystrophy. These new insights into adipocyte-driven IR may assist development of AT-targeted therapeutic strategies for diabetes.
DNA prime/protein boost vaccination elicits robust humoral response in rhesus macaques using oligomeric simian immunodeficiency virus envelope and Advax delta inulin adjuvant
Publisher: Microbiology Society
Date: 08-2017
DOI: 10.1099/JGV.0.000863
P11-21. Induction of persistent mucosal humoral and cellular responses following immunization of mice with HIV-1 envelope protein in inulin-derived adjuvants
Publisher: Springer Science and Business Media LLC
Date: 10-2009
Immunogenicity and safety of Advax™, a novel polysaccharide adjuvant based on delta inulin, when formulated with hepatitis B surface antigen: A randomized controlled Phase 1 study
Publisher: Elsevier BV
Date: 11-2014
Toll-like receptor-7/8 agonist kill Leishmania amazonensis by acting as pro-oxidant and pro-inflammatory agent
Publisher: Oxford University Press (OUP)
Date: 03-05-2021
DOI: 10.1093/JPP/RGAB063
Abstract: Evaluation of the anti-Leishmanial activity of imidazoquinoline-based TLR7/8 agonists. TLR7/8-active imidazoquinolines (2 and 3) were synthesized and assessed for activity against Leishmania amazonensis-intracellular amastigotes using mouse peritoneal macrophages. The production of reactive oxygen species (ROS), nitric oxide (NO) and cytokines was determined in infected and non-infected macrophages. The imidazoquinolines, 2 and 3, were primarily agonists of TLR7 with compound 3 also showing modest TLR8 activity. Docking studies showed them to occupy the same binding pocket on TLR7 and 8 as the known agonists, imiquimod and resiquimod. Compounds 2 and 3 inhibited the growth of L. amazonensis-intracellular amastigotes with the most potent compound (3, IC50 = 5.93 µM) having an IC50 value close to miltefosine (IC50 = 4.05 µM), a known anti-Leishmanial drug. Compound 3 induced macrophages to produce ROS, NO and inflammatory cytokines that likely explain the anti-Leishmanial effects. This study shows that activating TLR7 using compounds 2 or 3 induces anti-Leishmanial activity associated with induction of free radicals and inflammatory cytokines able to kill the parasites. While 2 and 3 had a very narrow cytotoxicity window for macrophages, this identifies the possibility to further develop this chemical scaffold to less cytotoxic TLR7/8 agonist for potential use as anti-Leishmanial drug.
SARS-CoV-2 seroprevalence among Vancouver public school staff in British Columbia, Canada: A cross-sectional study
Publisher: BMJ
Date: 04-2022
DOI: 10.1136/BMJOPEN-2021-057846
Abstract: Few studies reported COVID-19 cases in schools during the 2020/21 academic year in a setting of uninterrupted in-person schooling. The main objective was to determine the SARS-CoV-2 seroprevalence among school staff in Vancouver public schools. Cumulative incident COVID-19 cases among all students and school staff based on public health data, with an embedded cross-sectional serosurvey among a school staff s le that was compared to period, age, sex and geographical location-weighted data from blood donors. Vancouver School District (British Columbia, Canada) from kindergarten to grade 12. Active school staff enrolled from 3 February to 23 April 2021 with serology testing from 10 February to 15 May 2021. SARS-CoV-2 seroprevalence among school staff, based on spike (S)-based (unvaccinated staff) or N-based serology testing (vaccinated staff). Public health data showed the cumulative incidence of COVID-19 among students attending in-person was 9.8 per 1000 students (n=47 280), and 13 per 1000 among school staff (n=7071). In a representative s le of 1689 school staff, 78.2% had classroom responsibilities, and spent a median of 17.6 hours in class per week (IQR: 5.0–25 hours). Although 21.5% (363/1686) of surveyed staff self-reported close contact with a COVID-19 case outside of their household (16.5% contacts were school-based), 5 cases likely acquired the infection at school based on viral testing. Sensitivity/Specificity-adjusted seroprevalence in 1556/1689 staff (92.1%) was 2.3% (95% CI: 1.6% to 3.2%), comparable to a sex, age, date and residency area-weighted seroprevalence of 2.6% (95% CI: 2.2% to 3.1%) among 5417 blood donors. Seroprevalence among staff was comparable to a reference group of blood donors from the same community. These data show that in-person schooling could be safely maintained during the 2020/21 school year with mitigation measures, in a large school district in Vancouver, Canada.
Mitochondrial haplogroups are not associated with diabetic retinopathy in a large Australian and British Caucasian sample
Publisher: Springer Science and Business Media LLC
Date: 24-01-2019
DOI: 10.1038/S41598-018-37388-8
Abstract: Mitochondrial haplogroups H1, H2 and UK have previously been reported to be associated with proliferative diabetic retinopathy (PDR) in Caucasian patients with diabetes. We aimed to replicate this finding with a larger s le and expand the analysis to include different severities of DR, and diabetic macular edema (DME). Caucasian participants (n = 2935) with either type 1 or type 2 diabetes from the Australian Registry of Advanced Diabetic Retinopathy were enrolled in this study. Twenty-two mitochondrial single nucleotide polymorphisms were genotyped by MassArray and haplogroups reconstructed using Haplogrep. Chi square tests and logistic regressions were used to test associations between haplogroup and DR phenotypes including any DR, non-proliferative DR (NPDR), proliferative DR (PDR) and DME. After stratifying the s les in type 1 and type 2 diabetes groups, and adjusting for sex, age, diabetes duration, concurrent HbA1c and hypertension, neither haplogroups H1, H2, UK, K or JT were associated with any DR, NPDR, PDR or DME.
Determining the optimal SARS-CoV-2 mRNA vaccine dosing interval for maximum immunogenicity
Publisher: Cold Spring Harbor Laboratory
Date: 04-03-2022
DOI: 10.1101/2022.03.01.482592
Abstract: Emerging evidence indicates that longer SARS-CoV-2 vaccine dosing intervals results in an enhanced immune response. However, the optimal vaccine dosing interval for achieving maximum immunogenicity is unclear. This study included s les from adult paramedics in Canada who received two doses of either BNT162b2 or mRNA-1273 vaccines and provided blood s les 6 months (170 to 190 days) after the first vaccine dose. The main exposure variable was vaccine dosing interval (days), categorized as “ short ” (first quartile), “ moderate ” (second quartile), “ long ” (third quartile), and “ longest” interval (fourth quartile). The primary outcome was total spike antibody concentrations, measured using the Elecsys SARS-CoV-2 total antibody assay. Secondary outcomes included: spike and RBD IgG antibody concentrations, and inhibition of angiotensin-converting enzyme 2 (ACE-2) binding to wild-type spike protein and several different Delta variant spike proteins. We fit a multiple log-linear regression model to investigate the association between vaccine dosing intervals and the antibody concentrations. A total of 564 adult paramedics (mean age 40 years, SD=10) were included. Compared to “short interval” (≤30 days), higher dosing interval quartiles ( moderate : 31-38 days long : 39-73 days and longest : ≥74 days) were all associated with increased Elescys spike total antibody concentration. Compared to the short interval, “ long ” and “ longest ” interval quartiles were associated with higher spike and RBD IgG antibody concentrations. Similarly, increasing dosing intervals increased inhibition of ACE-2 binding to viral spike protein, regardless of the vaccine type. Increased mRNA vaccine dosing intervals longer than 30 days result in higher levels of circulating antibodies and viral neutralization when assessed at 6 months.
Pharmaceutical and preclinical evaluation of Advax adjuvant as a dose-sparing strategy for ant venom immunotherapy
Publisher: Elsevier BV
Date: 08-2019
Danazol in the treatment of a systemic lupus erythematosus (SLE)‐like illness associated with deficiency of the fourth component of complement
Publisher: Wiley
Date: 04-1997
DOI: 10.1111/J.1445-5994.1997.TB00941.X
Abstract: Breast cancer is one of the most common malignancies in women and the leading cause of cancer mortality. Hypercholesterolemia and obesity are potential risk factors for the incidence of breast cancer, and their detection can enhance cancer prevention. In this paper, we discuss the current state of investigations on the importance of lipoproteins, such as low denisity lipoproteins (LDL) and high density lipoproteins (HDL), and cholesterol transporters in the progression of breast cancer, and the therapeutic strategies to reduce breast cancer mortality. Although some research has been unsuccessful at uncovering links between the roles of lipoproteins and breast cancer risk, major scientific trials have found a straight link between LDL levels and incidence of breast cancer, and an inverse link was found between HDL and breast cancer development. Cholesterol and its transporters were shown to have significant importance in the development of breast cancer in studies on breast cancer cell lines and experimental mice models. Instead of cholesterol, 27-hydroxycholesterol, which is a cholesterol metabolite, is thought to promote propagation and metastasis of estrogen receptor-positive breast cancer cell lines. Alteration of lipoproteins via oxidation and HDL glycation are thought to activate many pathways associated with inflammation, thereby promoting cellular proliferation and migration, leading to metastasis while suppressing apoptosis. Medications that lower cholesterol levels and apolipoprotein A-I mimics have appeared to be possible therapeutic agents for preventing excessive cholesterol's role in promoting the development of breast cancer.
Sugar-Based Immune Adjuvants for Use in Recombinant, Viral Vector, DNA and Other Styles of Vaccines
Publisher: Springer Vienna
Date: 2014
An epitope-based malaria vaccine targeting the junctional region of circumsporozoite protein
Publisher: Springer Science and Business Media LLC
Date: 21-01-2021
DOI: 10.1038/S41541-020-00274-4
Abstract: A malaria vaccine that elicits long-lasting protection and is suitable for use in endemic areas remains urgently needed. Here, we assessed the immunogenicity and prophylactic efficacy of a vaccine targeting a recently described epitope on the major surface antigen on Plasmodium falciparum sporozoites, circumsporozoite protein (CSP). Using a virus-like particle (VLP)-based vaccine platform technology, we developed a vaccine that targets the junctional region between the N-terminal and central repeat regions of CSP. This region is recognized by monoclonal antibodies, including mAb CIS43, that have been shown to potently prevent liver invasion in animal models. We show that CIS43 VLPs elicit high-titer and long-lived anti-CSP antibody responses in mice and is immunogenic in non-human primates. In mice, vaccine immunogenicity was enhanced by using mixed adjuvant formulations. Immunization with CIS43 VLPs conferred partial protection from malaria infection in a mouse model, and passive transfer of serum from immunized macaques also inhibited parasite liver invasion in the mouse infection model. Our findings demonstrate that a Qβ VLP-based vaccine targeting the CIS43 epitope combined with various adjuvants is highly immunogenic in mice and macaques, elicits long-lasting anti-CSP antibodies, and inhibits parasite infection in a mouse model. Thus, the CIS43 VLP vaccine is a promising pre-erythrocytic malaria vaccine candidate.
Allergen databases
Publisher: Wiley
Date: 17-10-2003
DOI: 10.1034/J.1398-9995.2003.00248.X
Abstract: Allergies represent a significant medical and industrial problem. Molecular and clinical data on allergens are growing exponentially and in this article we have reviewed nine specialized allergen databases and identified data sources related to protein allergens contained in general purpose molecular databases. An analysis of allergens contained in public databases indicates a high level of redundancy of entries and a relatively low coverage of allergens by in idual databases. From this analysis we identify current database needs for allergy research and, in particular, highlight the need for a centralized reference allergen database.
Computational methods for prediction of T-cell epitopes—a framework for modelling, testing, and applications
Publisher: Elsevier BV
Date: 12-2004
DOI: 10.1016/J.YMETH.2004.06.006
Abstract: Computational models complement laboratory experimentation for efficient identification of MHC-binding peptides and T-cell epitopes. Methods for prediction of MHC-binding peptides include binding motifs, quantitative matrices, artificial neural networks, hidden Markov models, and molecular modelling. Models derived by these methods have been successfully used for prediction of T-cell epitopes in cancer, autoimmunity, infectious disease, and allergy. For maximum benefit, the use of computer models must be treated as experiments analogous to standard laboratory procedures and performed according to strict standards. This requires careful selection of data for model building, and adequate testing and validation. A range of web-based databases and MHC-binding prediction programs are available. Although some available prediction programs for particular MHC alleles have reasonable accuracy, there is no guarantee that all models produce good quality predictions. In this article, we present and discuss a framework for modelling, testing, and applications of computational methods used in predictions of T-cell epitopes.
Virtual models of the HLA class I antigen processing pathway
Publisher: Elsevier BV
Date: 12-2004
DOI: 10.1016/J.YMETH.2004.06.005
Abstract: Antigen recognition by cytotoxic CD8 T cells is dependent upon a number of critical steps in MHC class I antigen processing including proteosomal cleavage, TAP transport into the endoplasmic reticulum, and MHC class I binding. Based on extensive experimental data relating to each of these steps there is now the capacity to model in idual antigen processing steps with a high degree of accuracy. This paper demonstrates the potential to bring together models of in idual antigen processing steps, for ex le proteosome cleavage, TAP transport, and MHC binding, to build highly informative models of functional pathways. In particular, we demonstrate how an artificial neural network model of TAP transport was used to mine a HLA-binding database so as to identify HLA-binding peptides transported by TAP. This integrated model of antigen processing provided the unique insight that HLA class I alleles apparently constitute two separate classes: those that are TAP-efficient for peptide loading (HLA-B27, -A3, and -A24) and those that are TAP-inefficient (HLA-A2, -B7, and -B8). Hence, using this integrated model we were able to generate novel hypotheses regarding antigen processing, and these hypotheses are now capable of being tested experimentally. This model confirms the feasibility of constructing a virtual immune system, whereby each additional step in antigen processing is incorporated into a single modular model. Accurate models of antigen processing have implications for the study of basic immunology as well as for the design of peptide-based vaccines and other immunotherapies.
The paradoxical association between immunodeficiency and autoimmunity: Comment on he article by Atkinson
Publisher: Wiley
Date: 1996
Inulin crystal initiation via a glucose-fructose cross-link of adjacent polymer chains: Atomic force microscopy and static molecular modelling
Publisher: Elsevier BV
Date: 03-2015
Panblok-H1+advax H1N1/2009pdm vaccine: Insights into rapid development of a delta inulin adjuvanted recombinant pandemic influenza vaccine.
Publisher: Informa UK Limited
Date: 16-03-2017
BBIQ, a pure TLR7 agonist, is an effective influenza vaccine adjuvant
Publisher: Informa UK Limited
Date: 16-04-2020
Bioinformatics for study of autoimmunity
Publisher: Informa UK Limited
Date: 2006
DOI: 10.1080/08916930601062437
Abstract: Recent years have witnessed an explosive growth in available biological data pertaining to autoimmunity research. This includes a tremendous quantity of sequence data (biological structures, genetic and physical maps, pathways, etc.) generated by genome and proteome projects plus extensive clinical and epidemiological data. Autoimmunity research stands to greatly benefit from this data so long as appropriate strategies are available to enable full access to and utilization of this data. The quantity and complexity of this biological data necessitates use of advanced bioinformatics strategies for its efficient retrieval, analysis and interpretation. Major progress has been made in development of specialized tools for storage, analysis and modeling of immunological data, and this has led to development of a whole new field know as immunoinformatics. With advances in novel high-throughput immunology technologies immunoinformatics is transforming understanding of how the immune system functions. This paper reviews advances in the field of immunoinformatics pertinent to autoimmunity research including databases, tools in genomics and proteomics, tools for study of B- and T-cell epitopes, integrative approaches, and web servers.
Calcium Signaling As a Therapeutic Target for Liver Steatosis
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.TEM.2019.02.005
Abstract: Hepatic steatosis, the first step in nonalcoholic fatty liver disease (NAFLD), can arise from various pathophysiological conditions. While lipid metabolism in the liver is normally balanced such that there is no excessive lipid accumulation, when this homeostasis is disrupted lipid droplets (LDs) accumulate in hepatocytes resulting in cellular toxicity. The mechanisms underlying this accumulation and the subsequent hepatocellular damage are multifactorial and poorly understood, with the result that there are no currently approved treatments for NAFLD. Impaired calcium signaling has recently been identified as a cause of increased endoplasmic reticulum (ER) stress contributing to hepatic lipid accumulation. This review highlights new findings on the role of impaired Ca
An Advax-CpG adjuvanted recombinant H5 hemagglutinin vaccine protects mice against lethal influenza infection
Publisher: Elsevier BV
Date: 09-2023
Prefusion RSV F Immunization Elicits Th2-Mediated Lung Pathology in Mice When Formulated With a Th2 (but Not a Th1/Th2-Balanced) Adjuvant Despite Complete Viral Protection
Publisher: Frontiers Media SA
Date: 29-07-2020
Diabetic retinopathy is associated with elevated serum asymmetric and symmetric dimethylarginines
Publisher: American Diabetes Association
Date: 12-08-2009
DOI: 10.2337/DC09-0816
Abstract: Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and l-arginine directly influence nitric oxide production. Our objective was to test whether serum ADMA, SDMA, or l-arginine levels correlate with diabetic retinopathy subtype or severity. A total of 162 subjects with type 1 diabetes and 343 with type 2 diabetes, of whom 329 subjects had no diabetic retinopathy, 27 had nonproliferative diabetic retinopathy (NPDR), 101 had proliferative diabetic retinopathy (PDR), and 107 had clinically significant macular edema (CSME), were recruited. Blinding diabetic retinopathy was defined as severe NPDR, PDR, or CSME. Serum ADMA, SDMA, and l-arginine concentrations were determined by mass spectroscopy. In multivariate analysis, blinding diabetic retinopathy, PDR, and nephropathy were associated with significantly increased serum levels of ADMA (P & 0.001), SDMA (P & 0.001), and l-arginine (P = 0.001). Elevated ADMA (P & 0.001) and SDMA (P & 0.001) were also significantly associated with CSME. Severe forms of diabetic retinopathy are associated with elevated serum ADMA, SDMA, and l-arginine. Further investigation is required to determine whether these findings are of clinical relevance.
Severe Acute Respiratory Syndrome-Associated Coronavirus Vaccines Formulated with Delta Inulin Adjuvants Provide Enhanced Protection while Ameliorating Lung Eosinophilic Immunopathology
Publisher: American Society for Microbiology
Date: 15-03-2015
DOI: 10.1128/JVI.02980-14
Abstract: Although the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) epidemic was controlled by nonvaccine measures, coronaviruses remain a major threat to human health. The design of optimal coronavirus vaccines therefore remains a priority. Such vaccines present major challenges: coronavirus immunity often wanes rapidly, in iduals needing to be protected include the elderly, and vaccines may exacerbate rather than prevent coronavirus lung immunopathology. To address these issues, we compared in a murine model a range of recombinant spike protein or inactivated whole-virus vaccine candidates alone or adjuvanted with either alum, CpG, or Advax, a new delta inulin-based polysaccharide adjuvant. While all vaccines protected against lethal infection, addition of adjuvant significantly increased serum neutralizing-antibody titers and reduced lung virus titers on day 3 postchallenge. Whereas unadjuvanted or alum-formulated vaccines were associated with significantly increased lung eosinophilic immunopathology on day 6 postchallenge, this was not seen in mice immunized with vaccines formulated with delta inulin adjuvant. Protection against eosinophilic immunopathology by vaccines containing delta inulin adjuvants correlated better with enhanced T-cell gamma interferon (IFN-γ) recall responses rather than reduced interleukin-4 (IL-4) responses, suggesting that immunopathology predominantly reflects an inadequate vaccine-induced Th1 response. This study highlights the critical importance for development of effective and safe coronavirus vaccines of selection of adjuvants based on the ability to induce durable IFN-γ responses. IMPORTANCE Coronaviruses such as SARS-CoV and Middle East respiratory syndrome-associated coronavirus (MERS-CoV) cause high case fatality rates and remain major human public health threats, creating a need for effective vaccines. While coronavirus antigens that induce protective neutralizing antibodies have been identified, coronavirus vaccines present a unique problem in that immunized in iduals when infected by virus can develop lung eosinophilic pathology, a problem that is further exacerbated by the formulation of SARS-CoV vaccines with alum adjuvants. This study shows that formulation of SARS-CoV spike protein or inactivated whole-virus vaccines with novel delta inulin-based polysaccharide adjuvants enhances neutralizing-antibody titers and protection against clinical disease but at the same time also protects against development of lung eosinophilic immunopathology. It also shows that immunity achieved with delta inulin adjuvants is long-lived, thereby overcoming the natural tendency for rapidly waning coronavirus immunity. Thus, delta inulin adjuvants may offer a unique ability to develop safer and more effective coronavirus vaccines.
Chiral Self-Assembly of Designed Amphiphiles: Influences on Aggregate Morphology
Publisher: American Chemical Society (ACS)
Date: 30-07-2013
DOI: 10.1021/LA401987Y
Abstract: A series of novel hiphiles were designed for self-assembly into chiral morphologies, the hiphiles consisting of a glutamic acid (Glu) headgroup connected through an 11-carbon alkoxy chain to a diphenyldiazenyl (Azo) group and terminated with a variable length alkyl chain (R-Azo-11-Glu, where R denotes the number of carbons in the distal chain). TEM imaging of hiphile aggregates self-assembled from heated, methanolic, aqueous solution showed that chiral order, expressed as twisted ribbons, helical ribbons, and helically based nanotubes, increased progressively up to a distal chain length containing eight carbons, and then decreased with further increases in distal chain length. TEM and CD showed that the chiral aggregations of single enantiomers were influenced by the molecular chirality of the headgroup. However, the assembly of D,L-10-Azo-11-Glu into nanotubes demonstrated that chiral symmetry breaking effected by the azo group was also relevant to the chiral organization of the hiphiles. The chiral order of aggregate morphologies was additionally affected by the temperature and solvent composition of assembly in a manner correlated to the mechanism driving assembly i.e., D,L-10-Azo-11-Glu was sensitive to the temperature of assembly but less so to solvent composition, while L-14-Azo-11-Glu was sensitive to solvent composition and not to temperature. FTIR and UV-vis spectroscopic investigations into the organization of the head and azo groups, in chiral and achiral structures, illustrated that a balance of the influences of the hydrophilic and hydrophobic components on self-assembly was required for the optimization of the chiral organization of the self-assembled structures.
An Advax-Adjuvanted Inactivated Cell-Culture Derived Japanese Encephalitis Vaccine Induces Broadly Neutralising Anti-Flavivirus Antibodies, Robust Cellular Immunity and Provides Single Dose Protection
Publisher: MDPI AG
Date: 23-10-2021
Abstract: ccJE+Advax is an inactivated cell culture Japanese encephalitis (JE) vaccine formulated with Advax, a novel polysaccharide adjuvant based on delta inulin. This vaccine has previously shown promise in murine and equine studies and the current study sought to better understand its mechanism of action and assess the feasibility of single dose vaccine protection. Mice immunised with ccJE+Advax had higher serum neutralisation titres than those immunised with ccJE alone or with alum adjuvant. ccJE+Advax induced extraordinarily broad cross-neutralising antibodies against multiple flaviviruses including West Nile virus (WNV), Murray Valley encephalitis virus (MVEV), St Louis encephalitis virus (SLEV) and Dengue virus-1 and -2 (DENV-1 and -2). Notably, the DENV-2 cross-neutralising antibodies from ccJE+Advax immunised mice uniquely had no DENV-2 antibody-dependent infection enhancement (ADIE) activity, in contrast to high ADIE activity seen with DENV-1 cross-reactive antibodies induced by mbJE or ccJE alone or with alum adjuvant. JEV-stimulated splenocytes from ccJE+Advax immunised mice showed increased IL-17 and IFN-γ production, consistent with a mixed Th1 and Th17 response, whereas ccJE-alum was associated with production of mainly Th2 cytokines. In a mouse lethal challenge study against highly virulent JaTH160 JEV strain, ccJE+Advax conferred complete protection in a two-dose schedule with 50 ng of vaccine antigen and near complete protection after a single 200 ng dose of vaccine antigen. There is an ongoing lack of human vaccines against particular flaviviruses, including WNV, SLEV and MVEV. Given its ability to provide single-dose JEV protection and induce broadly neutralising antibodies devoid of ADIE activity, ccJE+Advax vaccine could be useful in situations where rapid protection is desirable, e.g., during a local outbreak or for use in travellers or armies requiring rapid deployment to JEV endemic regions.
Upper mantle P‐wave velocity structure from PASSCAL teleseismic transects across Idaho, Wyoming and Colorado
Publisher: American Geophysical Union (AGU)
Date: 04-2004
DOI: 10.1029/2004GL019476
Delta inulin: a novel, immunologically active, stable packing structure comprising -D-[2 -> 1] poly(fructo-furanosyl) -D-glucose polymers
Publisher: Oxford University Press (OUP)
Date: 07-12-2010
Prediction of novel mouse TLR9 agonists using a random forest approach
Publisher: Springer Science and Business Media LLC
Date: 12-2019
DOI: 10.1186/S12860-019-0241-0
Abstract: Toll-like receptor 9 is a key innate immune receptor involved in detecting infectious diseases and cancer. TLR9 activates the innate immune system following the recognition of single-stranded DNA oligonucleotides (ODN) containing unmethylated cytosine-guanine (CpG) motifs. Due to the considerable number of rotatable bonds in ODNs, high-throughput in silico screening for potential TLR9 activity via traditional structure-based virtual screening approaches of CpG ODNs is challenging. In the current study, we present a machine learning based method for predicting novel mouse TLR9 (mTLR9) agonists based on features including count and position of motifs, the distance between the motifs and graphically derived features such as the radius of gyration and moment of Inertia. We employed an in-house experimentally validated dataset of 396 single-stranded synthetic ODNs, to compare the results of five machine learning algorithms. Since the dataset was highly imbalanced, we used an ensemble learning approach based on repeated random down-s ling. Using in-house experimental TLR9 activity data we found that random forest algorithm outperformed other algorithms for our dataset for TLR9 activity prediction. Therefore, we developed a cross-validated ensemble classifier of 20 random forest models. The average Matthews correlation coefficient and balanced accuracy of our ensemble classifier in test s les was 0.61 and 80.0%, respectively, with the maximum balanced accuracy and Matthews correlation coefficient of 87.0% and 0.75, respectively. We confirmed common sequence motifs including ‘CC’, ‘GG’,‘AG’, ‘CCCG’ and ‘CGGC’ were overrepresented in mTLR9 agonists. Predictions on 6000 randomly generated ODNs were ranked and the top 100 ODNs were synthesized and experimentally tested for activity in a mTLR9 reporter cell assay, with 91 of the 100 selected ODNs showing high activity, confirming the accuracy of the model in predicting mTLR9 activity. We combined repeated random down-s ling with random forest to overcome the class imbalance problem and achieved promising results. Overall, we showed that the random forest algorithm outperformed other machine learning algorithms including support vector machines, shrinkage discriminant analysis, gradient boosting machine and neural networks. Due to its predictive performance and simplicity, the random forest technique is a useful method for prediction of mTLR9 ODN agonists.
Symptomatic and Asymptomatic Transmission of SARS-CoV-2 in K-12 Schools, British Columbia, Canada April to June 2021
Publisher: American Society for Microbiology
Date: 31-08-2022
DOI: 10.1128/SPECTRUM.00622-22
Abstract: There is concern that schools may be a setting where asymptomatic infections might result in significant “silent” transmission of SARS-CoV-2, particularly after the emergence of more transmissible variants of concern. After the programmatic implementation of a strategy of asymptomatic testing of close COVID-19 contacts as part of contact tracing in the school setting, the majority of the secondary cases were still found to have occurred in home or social contacts.
Alström syndrome: insights into the pathogenesis of metabolic disorders
Publisher: Springer Science and Business Media LLC
Date: 07-12-2010
Abstract: Genetic causes of obesity include the ciliopathies Alström syndrome and Bardet-Biedl syndrome. In these disorders, mutations cause dysfunction of the primary cilium, an organelle involved in intracellular and intercellular sensing and signaling. Alström syndrome is an autosomal-recessive disorder caused solely by mutations in ALMS1. By contrast, Bardet-Biedl syndrome is caused by mutations in at least 14 genes involved in primary cilium function. Despite equivalent levels of obesity, patients with Alström syndrome are more likely than those with Bardet-Biedl syndrome to develop childhood type 2 diabetes mellitus (T2DM), suggesting that ALMS1 might have a specific role in β-cell function and/or peripheral insulin signaling pathways. How mutations in genes that encode proteins involved in primary cilium function lead to the clinical phenotypes of these syndromes is being revealed by work in mutant mouse models. With the aid of these models, insights are being obtained into the pathogenic mechanisms that underlie obesity, insulin resistance and T2DM. Research into ciliopathies, including Alström syndrome and Bardet-Biedl syndrome, should lead not only to improved treatments for in iduals with these genetic disorders, but also to improved understanding of the cellular pathways involved in other common causes of obesity and T2DM.
HLA Class II-associated polymorphism of interferon-γ production implications for HLA-disease association
Publisher: Elsevier BV
Date: 03-1997
DOI: 10.1016/S0198-8859(96)00271-6
Abstract: The structural spike (S) protein from the SARS-CoV-2 β-coronavirus is shown to make different pre- and post-fusion conformations within its homotrimer unit. To support the ongoing novel vaccine design and development strategies, we report the structure-based design approach to develop self-derived S peptides. A dataset of crucial regions from the S protein were transformed into linear motifs that could act as the blockers or stabilizers for the S protein homotrimer unit. Among these distinct S peptides, the pep02 (537-QQFGRDIAD-545) and pep07 (821-RDLICAQKFNGLTVLPPLLTDE-842) were found making stable folded binding with the S protein (550-750 and 950-1050 regions). Upon inserting SARS-CoV-2 S variants in the peptide destabilized the complexed S protein structure, resulting an allosteric effect in different functional regions of the protein. Particularly, the molecular dynamics revealed that A544D mutation in the pep02 peptide induced instability for the complexed S protein, whereas the N943K variant from pep09 exhibited an opposite behavior. An increased protein-peptide binding affinity and the stable structural folding were observed in mutated systems, compared to that of the wild type systems. The presence of mutation has induced an "up" active conformation of the spike (RBD) domain, responsible for interacting the host cell receptor. Among the lower affinity peptide datasets (e.g., pep01), the S1 and S2 subunit in the protein formed an "open" conformation, whereas with higher affinity peptides (e.g., pep07) these domains gained a "closed" conformation. These findings propose that our designed self-derived S peptides could replace a single S protein monomer, blocking the homotrimer formation or inducing stability.
Pushing the frontiers of T-cell vaccines: accurate measurement of human T-cell responses.
Publisher: Informa UK Limited
Date: 12-2012
DOI: 10.1586/ERV.12.125
A fresh perspective from immunologists and vaccine researchers: Active vaccination strategies to prevent and reverse Alzheimer's disease
Publisher: Wiley
Date: 17-07-2015
SARS-CoV-2 seroprevalence among Vancouver public school staff in British Columbia, Canada
Publisher: Cold Spring Harbor Laboratory
Date: 18-06-2021
DOI: 10.1101/2021.06.16.21258861
Abstract: Contact-tracing studies suggest minimal secondary transmission in schools. However, there are limited school data accounting for asymptomatic cases, particularly late in the 2020/21 school year, and in the context of uninterrupted in-person schooling and widespread community transmission. To determine the SARS-CoV-2 seroprevalence in a s le of school staff, compared to the community, and to COVID-19 rates among all students and staff within the same school population. Incident COVID-19 cases among students and school staff using public health data, with an embedded cross-sectional serosurvey among school staff s led from February 10 to May 15, 2021, comparing to age, sex and geographic location-matched blood donors s led in January 2021. Vancouver School District (British Columbia, Canada) from kindergarten to grade 12. Active s chool staff enrolled from February 3 to April 23, 2021. SARS-CoV-2 antibodies in a s le of school staff using spike (S)-based testing (unvaccinated staff) or N-based serology testing (vaccinated staff). The incidence of COVID-19 cases among students attending in-person was 9.8 per 1,000 students during the 2020/21 school year (N = 47,280 students), and among staff was 13 per 1,000 since the beginning of the pandemic (N = 7,071 active school staff). In total, 1,689 school staff (64% elementary, 28% secondary, 8.3% school board staff or multiple grades) completed the questionnaire, 78.2% had classroom responsibilities, and spent a median of 17.6 hours in class per week [IQR: 5.0 – 25 hours]. Although 21.5% (363/1,686) reported close contact with a COVID-19 case, only 1.4% (24/1688) of the school staff reported having had a positive viral nucleic acid test. Of this group, five believed they acquired the infection at school. The adjusted seroprevalence in staff who gave blood (1,556/1,689, 92.1%) was 2.3% [95%CI: 1.6 – 3.2%] compared to 2.3% [95%CI: 1.7 – 3.0%] in blood donors. Despite high reported COVID-19 cases among students and staff, and frequent within-school exposures, we found no detectable increase in seroprevalence among school staff above the community seroprevalence. These findings corroborate claims that, with appropriate mitigation strategies, in-person schooling is not associated with significantly increased risk for school staff. What was the prevalence of COVID-19 infections in school staff who maintained in-person schooling during the 2020/21 school year in Vancouver, British Columbia, and how does it compare to the risk of COVID-19 infection in the community. As of March 4, 2021, the incidence of COVID-19 cases among school staff was 13 per 1,000 (N = 7,071 school staff) since the beginning of the pandemic. In a cross-sectional seroprevalence analysis from February 10 to May 15, 2021, the adjusted seroprevalence among a s le of school staff (N = 1,556) was 2.3% [95%CI: 1.6 – 3.2%], compared to 2.3% [95%CI: 1.7 – 3.0%] in 1:2 age, sex and geographical location (by postal code)-matched reference group of blood donors. We found no detectable increase in seroprevalence among school staff above the community seroprevalence. These findings corroborate claims that, with appropriate mitigation strategies in place, in-person schooling is not associated with significantly higher risk for school staff.
Delta inulin-based adjuvants promote the generation of polyfunctional CD4+ T cell responses and protection against Mycobacterium tuberculosis infection
Publisher: Springer Science and Business Media LLC
Date: 17-08-2017
DOI: 10.1038/S41598-017-09119-Y
Abstract: There is an urgent need for the rational design of safe and effective vaccines to protect against chronic bacterial pathogens such as Mycobacterium tuberculosis . Advax™ is a novel adjuvant based on delta inulin microparticles that enhances immunity with a minimal inflammatory profile and has entered human trials to protect against viral pathogens. In this report we determined if Advax displays broad applicability against important human pathogens by assessing protective immunity against infection with M. tuberculosis . The fusion protein CysVac2, comprising the M. tuberculosis antigens Ag85B (Rv1886c) and CysD (Rv1285) formulated with Advax provided significant protection in the lungs of M. tuberculosis -infected mice. Protection was associated with the generation of CysVac2-specific multifunctional CD4 + T cells (IFN-γ + TNF + IL-2 + ). Addition to Advax of the TLR9 agonist, CpG oligonucleotide (Advax CpG ), improved both the immunogenicity and protective efficacy of CysVac2. Immunisation with CysVac2/Advax CpG resulted in heightened release of the chemoattractants, CXCL1, CCL3, and TNF, and rapid influx of monocytes and neutrophils to the site of vaccination, with pronounced early priming of CysVac2 - specific CD4 + T cells. As delta inulin adjuvants have shown an excellent safety and tolerability profile in humans, CysVac2/Advax CpG is a strong candidate for further preclinical evaluation for progression to human trials.
Pulmonary Hypertension in Chronic Lung Diseases and/or Hypoxia
Publisher: InTech
Date: 17-07-2013
DOI: 10.5772/55681
A MultiTEP platform-based epitope vaccine targeting the phosphatase activating domain (PAD) of tau: therapeutic efficacy in PS19 mice
Publisher: Springer Science and Business Media LLC
Date: 29-10-2019
DOI: 10.1038/S41598-019-51809-2
Abstract: Pathological tau correlates well with cognitive impairments in Alzheimer’s disease (AD) patients and therefore represents a promising target for immunotherapy. Targeting an appropriate B cell epitope in pathological tau could in theory produce an effective reduction of pathology without disrupting the function of normal native tau. Recent data demonstrate that the N-terminal region of tau (aa 2-18), termed the “phosphatase activation domain (PAD)”, is hidden within native Tau in a ‘paperclip’-like conformation. Conversely, PAD is exposed in pathological tau and plays an essential role in the inhibition of fast axonal transport and tau polymerization. Thus, we hypothesized that anti-tau2-18 antibodies may safely and specifically reduce pathological tau and prevent further aggregation, which in turn would neutralize tau toxicity. Therefore, we evaluated the immunogenicity and therapeutic efficacy of our MultiTEP platform-based vaccine targeting tau2-18 formulated with Advax CpG adjuvant (AV-1980R/A) in PS19 tau transgenic mice. The AV-1980R/A induced extremely high antibody responses and the resulting sera recognized neurofibrillary tangles and plaque-associated dystrophic neurites in AD brain sections. In addition, under non-denaturing conditions AV-1980R/A sera preferentially recognized AD-associated tau. Importantly, vaccination also prevented age-related motor and cognitive deficits in PS19 mice and significantly reduced insoluble total and phosphorylated tau species. Taken together, these findings suggest that predominantly targeting misfolded tau with AV-1980R/A could represent an effective strategy for AD immunotherapy.
Comparative Safety of Vaccine Adjuvants: A Summary of Current Evidence and Future Needs
Publisher: Springer Science and Business Media LLC
Date: 08-10-2015
Co-Administration of Adjuvanted Recombinant Ov-103 and Ov-RAL-2 Vaccines Confer Protection against Natural Challenge in A Bovine Onchocerca ochengi Infection Model of Human Onchocerciasis
Publisher: MDPI AG
Date: 27-05-2022
Abstract: Onchocerciasis (river blindness), caused by the filarial nematode Onchocerca volvulus, is a neglected tropical disease mainly of sub-Saharan Africa. Worldwide, an estimated 20.9 million in iduals live with infection and a further 205 million are at risk of disease. Current control methods rely on mass drug administration of ivermectin to kill microfilariae and inhibit female worm fecundity. The identification and development of efficacious vaccines as complementary preventive tools to support ongoing elimination efforts are therefore an important objective of onchocerciasis research. We evaluated the protective effects of co-administering leading O. volvulus-derived recombinant vaccine candidates (Ov-103 and Ov-RAL-2) with subsequent natural exposure to the closely related cattle parasite Onchocerca ochengi. Over a 24-month exposure period, vaccinated calves (n = 11) were shown to acquire infection and microfilaridermia at a significantly lower rate compared to unvaccinated control animals (n = 10). Furthermore, adult female worm burdens were negatively correlated with anti-Ov-103 and Ov-RAL-2 IgG1 and IgG2 responses. Peptide arrays identified several Ov-103 and Ov-RAL-2-specific epitopes homologous to those identified as human B-cell and helper T-cell epitope candidates and by naturally-infected human subjects in previous studies. Overall, this study demonstrates co-administration of Ov-103 and Ov-RAL-2 with Montanide™ ISA 206 VG is highly immunogenic in cattle, conferring partial protection against natural challenge with O. ochengi. The strong, antigen-specific IgG1 and IgG2 responses associated with vaccine-induced protection are highly suggestive of a mixed Th1/Th2 associated antibody responses. Collectively, this evidence suggests vaccine formulations for human onchocerciasis should aim to elicit similarly balanced Th1/Th2 immune responses.
AFCo1, a meningococcal B-derived cochleate adjuvant, strongly enhances antibody and T-cell immunity against Plasmodium falciparum merozoite surface protein 4 and 5.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2009
Development of a SARS Coronavirus Vaccine from Recombinant Spike Protein Plus Delta Inulin Adjuvant
Publisher: Springer New York
Date: 2016
Proteomic analysis of influenza haemagglutinin-specific antibodies following vaccination reveals convergent immunoglobulin variable region signatures
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.VACCINE.2017.08.053
Abstract: Analysis of the anti-haemagglutinin serum antibody proteome from six H1N1pdm09 influenza A vaccinated subjects demonstrated restricted IgG1 heavy chain species encoded by IGHV5-51 and IGHV3-7 gene families in 2 subjects and either IGHV5-51 or IGHV3-7 in 4 in iduals. All subjects exhibited a dominant IGKV3-20 light chain, however 5 subjects also exhibited IGKV3-11 and IGKV4-1 families. Sequences were closely aligned with the matched germline sequence, with few shared mutations. This study illustrates the feasibility of using a proteomic approach to determine the expressed V region signatures of serum antibodies induced by vaccination.
Systematic genome‐wide approach to positional candidate cloning for identification of novel human disease genes
Publisher: Wiley
Date: 03-2208
Sequence variation in DDAH1 and DDAH2 genes is strongly and additively associated with serum ADMA concentrations in individuals with type 2 diabetes
Publisher: Public Library of Science (PLoS)
Date: 03-2010
Vaccine adjuvants: In search of new paradigms
Publisher: Informa UK Limited
Date: 07-2013
Observation of the keto tautomer of d-fructose in D2O using 1H NMR spectroscopy
Publisher: Elsevier BV
Date: 2012
Vaccine adjuvant safety: the elephant in the room.
Publisher: Informa UK Limited
Date: 07-2013
Enhanced Immunogenicity of Inactivated Dengue Vaccines by Novel Polysaccharide-Based Adjuvants in Mice
Publisher: MDPI AG
Date: 16-05-2022
DOI: 10.3390/MICROORGANISMS10051034
Abstract: Dengue fever, caused by any of four dengue viruses (DENV1-4), is a major global burden. Currently, there is no effective vaccine that prevents infection in dengue naïve populations. We tested the ability of two novel adjuvants (Advax-PEI and Advax-2), using aluminum hydroxide (alum) as control, to enhance the immunogenicity of formalin- or psoralen-inactivated (PIV or PsIV) DENV2 vaccines in mice. Mice were vaccinated on days 0 and 30, and serum s les were collected on days 30, 60, 90, and 101. Neutralizing antibodies were determined by microneutralization (MN) assays, and the geometric mean 50% MN (MN50) titers were calculated. For the PIV groups, after one dose MN50 titers were higher in the novel adjuvant groups compared to the alum control, while MN50 titers were comparable between the adjuvant groups after the second dose. For the PsIV groups, both novel adjuvants induced higher MN50 titers than the alum control after the second dose. Spleen cells were collected on days 45 and 101 for enzyme-linked immunospot (ELISPOT) for IFNγ and IL4. Both PIV and PsIV groups elicited different degrees of IFNγ and IL4 responses. Overall, Advax-2 gave the best responses just ahead of Advax-PEI. Given Advax-2’s extensive human experience in other vaccine applications, it will be pursued for further development.
Induction of mucosal and systemic antibody and T-cell responses following prime-boost immunization with novel adjuvanted human immunodeficiency virus-1-vaccine formulations
Publisher: Microbiology Society
Date: 15-12-2010
4-Hydroxydocosahexaenoic acid, a potent peroxisome proliferator-activated receptor γ agonist alleviates the symptoms of DSS-induced colitis
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.BBRC.2007.12.188
Abstract: (5E,7Z,10Z,13Z,16Z,19Z)-4-Hydroxy-5,7,10,13,16,19-docosahexaenoic acid (4-OHDHA) is a potential agonist of peroxisome proliferator-activated receptor-gamma (PPARgamma) and antidiabetic agent as has been previously reported. As PPARgamma agonists may also have anti-inflammatory functions, in this study, we investigated whether 4-OHDHA has an inhibitory effect on expression of inflammatory genes in vitro and whether 4-OHDHA could relieve the symptoms of dextran sodium sulfate (DSS)-induced colitis in a murine model of inflammatory bowel disease. 4-OHDHA inhibited production of nitric oxide and expression of a subset of inflammatory genes including inducible nitric oxide synthase (Nos2/iNOS) and interleukin 6 (Il6) by lipopolysaccharide (LPS)-activated macrophages. In addition, 4-OHDHA-treated mice when compared to control mice not receiving treatment recovered better from the weight loss caused by DSS-induced colitis. Changes in disease activity index (DAI) of 4-OHDHA-treated mice were also more favorable than for control mice and were comparable with mice treated with a typical anti-inflammatory-drug, 5-aminosalichylic acid (5-ASA). These results suggest that 4-OHDHA has potentially clinically useful anti-inflammatory effects mediated by suppression of inflammatory gene expression.
Th1 and Th2: swinging to a hormonal rhythm
Publisher: Elsevier BV
Date: 12-1995
Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice
Publisher: Springer Science and Business Media LLC
Date: 12-2019
DOI: 10.1186/S13195-019-0556-2
Abstract: Alzheimer disease (AD) is characterized by the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline. Current therapeutic approaches have primarily aimed to reduce pathological aggregates of either Aβ or tau, yet phase 3 clinical trials of these approaches have thus far failed to delay disease progression in humans. Strong preclinical evidence indicates that these two abnormally aggregated proteins interact synergistically to drive downstream neurodegeneration. Therefore, combinatorial therapies that concurrently target both Aβ and tau might be needed for effective disease modification. A combinatorial vaccination approach was designed to concurrently target both Aβ and tau pathologies. Tau22/5xFAD (T5x) bigenic mice that develop both pathological Aβ and tau aggregates were injected intramuscularly with a mixture of two MultiTEP epitope vaccines: AV-1959R and AV-1980R, targeting Aβ and tau, respectively, and formulated in Advax CpG , a potent polysaccharide adjuvant. Antibody responses of vaccinated animals were measured by ELISA, and neuropathological changes were determined in brain homogenates of vaccinated and control mice using ELISA and Meso Scale Discovery (MSD) multiplex assays. T5x mice immunized with a mixture of Aβ- and tau-targeting vaccines generated high Aβ- and tau-specific antibody titers that recognized senile plaques and neurofibrillary tangles/neuropil threads in human AD brain sections. Production of these antibodies in turn led to significant reductions in the levels of soluble and insoluble total tau, and hyperphosphorylated tau as well as insoluble Aβ 42 , within the brains of bigenic T5x mice. AV-1959R and AV-1980R formulated with Advax CpG adjuvant are immunogenic and therapeutically potent vaccines that in combination can effectively reduce both of the hallmark pathologies of AD in bigenic mice. Taken together, these findings warrant further development of this vaccine technology for ultimate testing in human AD.
Response of Serum Macrophage Migration Inhibitory Factor Levels to Stimulation or Suppression of the Hypothalamo-Pituitary-Adrenal Axis in Normal Subjects and Patients with Cushing's Disease
Publisher: The Endocrine Society
Date: 04-2002
DOI: 10.1210/JC.87.4.1834
Advax delta inulin adjuvant overcomes immune immaturity in neonatal mice thereby allowing single–dose influenza vaccine protection
Publisher: Elsevier BV
Date: 09-2015
Review of polysaccharide particle-based functional drug delivery
Publisher: Elsevier BV
Date: 10-2019
Enhanced pulmonary immunization with aerosolized inactivated influenza vaccine containing delta inulin adjuvant
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.EJPS.2014.10.008
Abstract: Vaccination is the primary intervention to contain influenza virus spread during seasonal and pandemic outbreaks. Pulmonary vaccination is gaining increasing attention for its ability to induce both local mucosal and systemic immune responses without the need for invasive injections. However, pulmonary administration of whole inactivated influenza virus (WIV) vaccine induces a Th2 dominant systemic immune response while a more balanced Th1/Th2 vaccine response may be preferred and only induces modest nasal immunity. This study evaluated immunity elicited by pulmonary versus intramuscular (i.m.) delivery of WIV, and tested whether the immune response could be improved by co-administration of delta (δ)-inulin, a novel carbohydrate-based particulate adjuvant. After pulmonary administration both unadjuvanted and δ-inulin adjuvanted WIV induced a potent systemic immune response, inducing higher serum anti-influenza IgG titers and nasal IgA titers than i.m. administration. Moreover, the addition of δ-inulin induced a more balanced Th1/Th2 response and induced higher nasal IgA titers versus pulmonary WIV alone. Pulmonary WIV alone or with δ-inulin induced hemagglutination inhibition (HI) titers>40, titers which are considered protective against influenza virus. In conclusion, in this study we have shown that δ-inulin adjuvanted WIV induces a better immune response after pulmonary administration than vaccine alone.
Immunogenicity of MultiTEP platform technology-based Tau vaccine in non-human primates
Publisher: Springer Science and Business Media LLC
Date: 12-10-2022
DOI: 10.1038/S41541-022-00544-3
Abstract: Pathological forms of Tau protein are directly associated with neurodegeneration and correlate with Alzheimer’s Disease (AD) symptoms, progression, and severity. Previously, using various mouse models of Tauopathies and AD, we have demonstrated the immunogenicity and efficacy of the MultiTEP-based adjuvanted vaccine targeting the phosphatase activating domain (PAD) of Tau, AV-1980R/A. Here, we analyzed its immunogenicity in non-human primates (NHP), the closest phylogenic relatives to humans with a similar immune system, to initiate the transition of this vaccine into clinical trials. We have demonstrated that AV-1980R/A is highly immunogenic in these NHPs, activating a broad but unique to each monkey repertoire of MultiTEP-specific T helper (Th) cells that, in turn, activate B cells specific to PAD. The resulting anti-PAD IgG antibodies recognize pathological Tau tangles and Tau-positive neuritis in AD case brain sections with no staining in control non-AD cases. These published data and efficacy results support the AV-1980R/A vaccine progression to first-in-human clinical trials.
Type 1 Diabetes: Immunology and Genetics
Publisher: Elsevier
Date: 2006
Systems Immunology, Vaccine Adjuvant
Publisher: Springer New York
Date: 2013
Active immunization with tau epitope in a mouse model of tauopathy induced strong antibody response together with improvement in short memory and pSer396-tau pathology
Publisher: Elsevier BV
Date: 02-2020
Vaccine therapies for the prevention of type 1 diabetes mellitus.
Publisher: Springer Science and Business Media LLC
Date: 2003
DOI: 10.2165/00148581-200305090-00001
Abstract: Type 1 diabetes mellitus results from immune-mediated destruction of pancreatic beta-cells, leading to loss of insulin production. Strategies to prevent or reverse diabetes development include beta-cell protection, regeneration, or replacement. Recent advances in our understanding of the autoimmune process leading to diabetes has generated interest in the potential use of immunomodulatory agents that may collectively be termed vaccines, to prevent type 1 diabetes. Vaccines may work in various ways, including changing the immune response from a destructive (e.g. Th1) to a more benign (e.g. Th2) response, inducing antigen-specific regulatory T cells, deleting autoreactive T cells, or preventing immune cell interaction. To date, most diabetes vaccine development has been in animal models, with relatively few human trials having been completed. A major finding of animal models such as the non-obese diabetic (NOD) mouse is that they are extremely sensitive to diabetes protection, such that many interventions that protect mice are not successful in humans. This is particularly evident for human insulin tolerance studies, including the Diabetes Prevention Trial-1, where no human protection was seen from insulin despite positive NOD results. Further challenges are posed by the need to translate protective vaccine doses in mice to effective human doses. Despite such problems, some promising human vaccine data are beginning to emerge. Recent pilot studies have suggested a beneficial effect in recent-onset human type 1 diabetes from administration of nondepleting anti-CD3 antibodies or a peptide from heat shock protein 60. Given past experience, however, large multicenter, double-blind, controlled confirmatory studies are clearly required and longer term toxicity issues of drugs such as anti-CD3 need to be addressed.Diabetes vaccine development would benefit greatly from the development of reliable surrogate markers of immunoregulation. These would allow faster and more efficient screening of vaccine candidates, and would also assist in the translation of vaccine doses from animal to human studies. Unfortunately, research funding bodies desperate to find a cure are embarking on expensive clinical trials without first addressing important underlying issues such as animal-human dose translation and possible mechanisms of action. No doubt this is due to pressure from their constituency to rapidly find a cure, but unfortunately this approach may slow rather than speed the development of an effective vaccine cure. However, despite the significant hurdles that remain, vaccines remain one of the most promising strategies to prevent type 1 diabetes, with major advantages including convenience, safety, and long-lasting protection.
An adjuvanted subunit SARS-CoV-2 spike protein vaccine provides protection against Covid-19 infection and transmission
Publisher: Springer Science and Business Media LLC
Date: 23-02-2022
DOI: 10.1038/S41541-022-00450-8
Abstract: Recombinant protein approaches offer major promise for safe and effective vaccine prevention of SARS-CoV-2 infection. We developed a recombinant spike protein vaccine (called NARUVAX-C19) and characterized its ability when formulated with a nanoemulsion adjuvant to induce anti-spike antibody and T-cell responses and provide protection including against viral transmission in rodent. In mice, NARUVAX-C19 vaccine administered intramuscularly twice at 21-day interval elicited balanced Th1/Th2 humoral and T-cell responses with high titers of neutralizing antibodies against wild-type (D614G) and delta (B.1.617.2) variants. In Syrian hamsters, NARUVAX-C19 provided complete protection against wild-type (D614G) infection and prevented its transmission to naïve animals ( n = 2/group) placed in the same cage as challenged animals ( n = 6/group). The results contrasted with only weak protection seen with a monomeric spike receptor-binding domain (RBD) vaccine even when formulated with the same adjuvant. These encouraging results warrant the ongoing development of this COVID-19 vaccine candidate.
Common Sequence Variation in the VEGFC Gene Is Associated with Diabetic Retinopathy and Diabetic Macular Edema
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.OPHTHA.2015.05.004
Abstract: To investigate associations between single nucleotide polymorphisms (SNPs) in the VEGFC gene and the development of diabetic retinopathy (DR) in white patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Cross-sectional, case control study. White patients with T1DM or T2DM (n = 2899) were recruited from ophthalmology and endocrine clinics in Australia and the United Kingdom. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be receiving oral hypoglycemic treatment or insulin. Participants were categorized according to their worst-ever DR grading, as having "no DR" (no history of nonproliferative DR [NPDR], proliferative DR [PDR], or diabetic macular edema [DME]) or "any DR" (further subclassified as NPDR or PDR, without or with DME). Clinical characteristics, glycemic control (hemoglobin A1c [HbA1c]), and presence of diabetic complications were determined at recruitment. Genotyping was performed for 13 VEGFC tag SNPs. Odds ratios (ORs) were determined for associations with DR of VEGFC tag SNPs, in idually and within haplotypes. Logistic regression was used to adjust for clinical covariates, including DM type, age, sex, DM duration, hypertension, nephropathy, HbA1c, and smoking. Participants with DM but "no DR" (n = 980) were compared with 1919 participants with DM and "any DR." Three VEGFC SNPs were associated with DR after logistic regression: rs17697419 (P = 0.001 OR, 0.67 confidence interval [CI], 0.52-0.85), rs17697515 (P = 0.001 OR, 0.62 CI, 0.47-0.81), and rs2333526 (P = 0.005 OR, 0.69 CI, 0.54-0.90). rs17697515 Was also specifically associated with DME in those with T2DM (P = 0.004 OR, 0.53 CI, 0.35-0.82). Haplotype analysis revealed 2 significantly associated haplotypes, both protective against DR development. Significant associations were found between VEGFC tag SNPs (in idually and within haplotypes) and the presence of any DR or DME in white participants with T1DM and T2DM.
Autoimmune Diabetes in the NOD Mouse: An Essential Role of Fas‐FasL Signaling in β Cell Apoptosis
Publisher: Wiley
Date: 11-2003
Abstract: Despite evidence that both Fas and FasL can be expressed in pancreatic islets, there has been considerable controversy regarding the potential role of Fas signaling in autoimmune beta cell death. Using the HIPFasL model, we have been able to demonstrate that, in the presence of an inflammatory infiltrate, FasL-expressing beta cells are exquisitely sensitive to Fas-mediated apoptosis and that this can be blocked by preventing FasL-Fas interaction. This points to a highly important role of Fas-FasL interaction in autoimmune beta cell death.
In silico structural homology modelling and docking for assessment of pandemic potential of a novel H7N9 influenza virus and its ability to be neutralized by existing anti-hemagglutinin antibodies.
Publisher: Public Library of Science (PLoS)
Date: 21-07-2014
Gamma ray sterilization of delta inulin adjuvant particles (Advax™) makes minor, partly reversible structural changes without affecting adjuvant activity
Publisher: Elsevier BV
Date: 2014
Towards a unified model of neuroendocrine–immune interaction
Publisher: Wiley
Date: 08-2001
DOI: 10.1046/J.1440-1711.2001.01029.X
Abstract: Although the neuroendocrine system has immunomodulating potential, studies examining the relationship between stress, immunity and infection have, until recently, largely been the preserve of behavioural psychologists. Over the last decade, however, immunologists have begun to increasingly appreciate that neuroendocrine-immune interactions hold the key to understanding the complex behaviour of the immune system in vivo. The nervous, endocrine and immune systems communicate bidirectionally via shared messenger molecules variously called neurotransmitters, cytokines or hormones. Their classification as neurotransmitters, cytokines or hormones is more serendipity than a true reflection of their sphere of influence. Rather than these systems being discrete entities we would propose that they constitute, in reality, a single higher-order entity. This paper reviews current knowledge of neuroendocrine-immune interaction and uses the ex le of T-cell subset differentiation to show the previously under-appreciated importance of neuroendocrine influences in the regulation of immune function and, in particular, Th1/Th2 balance and diurnal variation there of.
Efficient discovery of immune response targets by cyclical refinement of QSAR models of peptide binding
Publisher: Elsevier BV
Date: 10-2001
DOI: 10.1016/S1093-3263(00)00099-1
Abstract: Peptides that induce and recall T-cell responses are called T-cell epitopes. T-cell epitopes may be useful in a subunit vaccine against malaria. Computer models that simulate peptide binding to MHC are useful for selecting candidate T-cell epitopes since they minimize the number of experiments required for their identification. We applied a combination of computational and immunological strategies to select candidate T-cell epitopes. A total of 86 experimental binding assays were performed in three rounds of identification of HLA-A11 binding peptides from the six preerythrocytic malaria antigens. Thirty-six peptides were experimentally confirmed as binders. We show that the cyclical refinement of the ANN models results in a significant improvement of the efficiency of identifying potential T-cell epitopes.
Association between erythropoietin gene polymorphisms and diabetic retinopathy
Publisher: American Medical Association (AMA)
Date: 2010
DOI: 10.1001/ARCHOPHTHALMOL.2009.355
Abstract: To determine whether sequence variation in the erythropoietin gene (EPO) is associated with the development of diabetic retinopathy (DR). This was a multicenter study based on 518 subjects with long-standing diabetes mellitus (DM), 173 with type 1 DM (T1DM) and 345 with type 2 DM (T2DM). Study groups consisted of 233 control subjects with no DR, 155 subjects with nonproliferative DR, 126 with proliferative DR, and 90 with clinically significant macular edema. Subjects with end-stage renal disease were excluded. DNA extracted from blood of each subject was genotyped for 3 EPO single-nucleotide polymorphisms (SNPs). All 3 SNPs in EPO were associated with overall DR status in the combined T1DM and T2DM and T2DM alone groups (CC genotype of rs507392, P < .008 GG genotype of rs1617640, P < .008 and CC genotype of rs551238, P < .008) in the multivariate analysis. The GCC haplotype was also associated with overall DR status in the combined DM and T2DM alone groups (P = .008) by multivariate analysis. All SNPs and the GCC haplotype were also associated with proliferative DR and clinically significant macular edema in the combined DM and T2DM alone groups. No associations were found with T1DM alone. Sequence variation in EPO is associated with the risk of DR independent of duration of DM, degree of glycemic control, and nephropathy. Identifying EPO genetic markers for high risk of developing DR could lead to the possibility of developing novel treatments or preventive therapies.
Evaluation of observed and unobserved self-collection of saline gargle samples for the detection of SARS-CoV-2 in outpatients
Publisher: Elsevier BV
Date: 02-2022
Passive inhalation of dry powder influenza vaccine formulations completely protects chickens against H5N1 lethal viral challenge
Publisher: Elsevier BV
Date: 12-2018
An Advax-CpG55.2™ adjuvanted recombinant spike protein vaccine protects cynomolgus macaques from a homologous SARS-CoV-2 virus challenge
Publisher: Elsevier BV
Date: 07-2023
Molecular Adjuvants for DNA Vaccines
Publisher: MDPI AG
Date: 2017
Structural evolution of toll-like receptor 7/8 agonists from imidazoquinolines to imidazoles
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1MD00031D
Abstract: TLR7/8 agonists are emerging as promising vaccine adjuvant candidates. An evolution of imidazole based TLR7/8 agonist from imidazoquinoline based scaffold is delineated along with the elaboration of detailed structure activity relationship (SAR) in each chemotype.
A gold glyco-nanoparticle carrying a listeriolysin O peptide and formulated with Advax™ delta inulin adjuvant induces robust T-cell protection against listeria infection
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.VACCINE.2015.01.062
Abstract: In the search for an effective vaccine against the human pathogen, Listeria monocytogenes (Listeria), gold glyconanoparticles (GNP) loaded with a listeriolysin O peptide LLO91-99 (GNP-LLO) were used to immunise mice, initially using a dendritic cell (DC) vaccine approach, but subsequently using a standard parenteral immunisation approach. To enhance vaccine immunogenicity a novel polysaccharide adjuvant based on delta inulin (Advax™) was also co-formulated with the GNP vaccine. Confirming previous results, DC loaded in vitro with GNP-LLO provided better protection against listeriosis than DC loaded in vitro using free LLO peptide. The immunogenicity of GNP-LLO loaded DC vaccines was further increased by addition of Advax™ adjuvant. However, as DC vaccines are expensive and impracticable for prophylactic use, we next asked whether the same GNP-LLO antigen could be used to directly target DC in vivo. Immunisation of mice with GNP-LLO plus Advax™ adjuvant induced LLO-specific T-cell immunity and protection against Listeria challenge. Protection correlated with an increased frequency of splenic CD4(+) and CD8(+) T cells, NK cells and CD8α(+) DC, and Th1 cytokine production (IL-12, IFN-γ, TNF-α, and MCP-1), post-challenge. Enhanced T-cell epitope recruitment post-challenge was seen in the groups that received Advax™ adjuvant. Immunisation with GNP-LLO91-99 plus Advax™ adjuvant provided equally robust Listeria protection as the best DC vaccine strategy but without the complexity and cost, making this a highly promising strategy for development of a prophylactic vaccine against listeriosis.
Inulin isoforms differ by repeated additions of one crystal unit cell
Publisher: Elsevier BV
Date: 03-2014
Immunisation of ferrets and mice with recombinant SARS-CoV-2 spike protein formulated with Advax-SM adjuvant protects against COVID-19 infection
Publisher: Elsevier BV
Date: 09-2021
Advax adjuvant formulations promote protective immunity against aerosol Mycobacterium tuberculosis in the absence of deleterious inflammation and reactogenicity
Publisher: Elsevier BV
Date: 04-2021
Strategies for active and passive pediatric RSV immunization
Publisher: SAGE Publications
Date: 2021
Abstract: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in children worldwide, with the most severe disease occurring in very young infants. Despite half a century of research there still are no licensed RSV vaccines. Difficulties in RSV vaccine development stem from a number of factors, including: (a) a very short time frame between birth and first RSV exposure (b) interfering effects of maternal antibodies and (c) differentially regulated immune responses in infants causing a marked T helper 2 (Th2) immune bias. This review seeks to provide an age-specific understanding of RSV immunity critical to the development of a successful pediatric RSV vaccine. Historical and future approaches to the prevention of infant RSV are reviewed, including passive protection using monoclonal antibodies or maternal immunization strategies versus active infant immunization using pre-fusion forms of RSV F protein antigens formulated with novel adjuvants such as Advax that avoid excess Th2 immune polarization.
Focus on Influenza vaccines
Publisher: Informa UK Limited
Date: 10-2009
DOI: 10.4161/HV.5.10.9315
Molecular mechanisms for enhanced DNA vaccine immunogenicity
Publisher: Informa UK Limited
Date: 28-12-2015
Data Extraction for Improved Prediction Outcomes in Organ Transplantation — A Hybrid Approach
Publisher: WORLD SCIENTIFIC
Date: 10-2006
Combination adjuvants enhance recombinant protein vaccine protection against fungal infection
Publisher: Cold Spring Harbor Laboratory
Date: 12-03-2021
DOI: 10.1101/2021.03.11.434977
Abstract: The development of effective vaccines against fungal infections requires the induction of protective, pathogen-specific cell mediated immune responses. Here, we asked whether combination adjuvants based on delta inulin (Advax) formulated with TLR agonists could improve vaccine protection mediated by a fungal recombinant protein, Bl-Eng2, which itself harbors an immunodominant antigen and Dectin-2 agonist/adjuvant. We found that Bl-Eng2 formulated with Advax3 containing TLR9 agonist or Advax8, containing TLR4 agonist, provided the best protection against pulmonary infection with Blastomyces dermatitidis , being more effective than Freund’s complete adjuvant or Adjuplex. Advax3 was most efficient in inducing IFN-γ and IL-17 producing antigen-specific T cells that migrated to the lung upon Blastomyces dermatitidis infection. Mechanistic studies revealed Bl-Eng2/Advax3 protection was tempered by neutralization of IL-17 and particularly IFN-γ. Likewise, greater numbers of lung-resident T cells producing IFN-γ, IL-17, or IFN-γ + and IL-17 + correlated with fewer fungi recovered from lung. Protection was maintained after depletion of CD4 + T cells, partially reduced by depletion of CD8 + T cells, and completely eliminated after depletion of both CD4 + and CD8 + T cells. We conclude that Bl-Eng2 formulated with Advax3 is promising for eliciting vaccine-induced antifungal immunity, through a previously uncharacterized mechanism involving CD8 + and also CD4 + T cells producing IFN-γ and/or IL-17. Although no licensed vaccine exists as yet against any fungal disease, these findings indicate the importance of adjuvant selection for the development of effective fungal vaccines. Fungal disease remains a challenging clinical and public health problem. Despite medical advances, invasive fungal infections have skyrocketed over the last decade and pose a mounting health threat in immune-competent and -deficient hosts with worldwide mortality rates ranking 7th, even ahead of tuberculosis. The development of safe, effective vaccines remains a major hurdle for fungi. Critical barriers to progress include the lack of defined fungal antigens and suitable adjuvants. Our research is significant in identifying adjuvant combinations that elicit optimal vaccine-induced protection when formulated with a recombinant protective antigen and uncovering the mechanistic bases of the underlaying vaccine protection, which will foster the strategic development of anti-fungal vaccines.
Vaccine-Induced Th1-Type Response Protects against Invasive Group A Streptococcus Infection in the Absence of Opsonizing Antibodies
Publisher: American Society for Microbiology
Date: 28-04-2020
Abstract: Availability of a group A Streptococcus vaccine remains an unmet public health need. Here, we tested different adjuvant formulations to improve the protective efficacy of non-M protein vaccine Combo5 in an invasive disease model. We show that novel adjuvants can dramatically shape the type of immune response developed following immunization with Combo5 and significantly improve protection. In addition, protection afforded by Combo5 is not mediated by opsonizing antibodies, believed to be the main correlate of protection against GAS infections. Overall, this report highlights the importance of adjuvant selection in raising protective immune responses against GAS invasive infection. Adjuvants that can provide a more balanced Th1/Th2-type response may be required to optimize protection of GAS vaccines, particularly those based on non-M protein antigens.
Use of Artificial Neural Networks in Improving Renal Transplantation Outcomes
Publisher: Portico
Date: 2002
Onchocerca volvulus bivalent subunit vaccine induces protective immunity in genetically diverse collaborative cross recombinant inbred intercross mice
Publisher: Springer Science and Business Media LLC
Date: 26-01-2021
DOI: 10.1038/S41541-020-00276-2
Abstract: This study tests the hypothesis that an Onchocerca volvulus vaccine, consisting of two recombinant antigens ( Ov -103 and Ov -RAL-2) formulated with the combination-adjuvant Advax-2, can induce protective immunity in genetically erse Collaborative Cross recombinant inbred intercross mice (CC-RIX). CC-RIX lines were immunized with the O. volvulus vaccine and challenged with third-stage larvae. Equal and significant reductions in parasite survival were observed in 7 of 8 CC-RIX lines. Innate protective immunity was seen in the single CC-RIX line that did not demonstrate protective adaptive immunity. Analysis of a wide array of immune factors showed that each line of mice have a unique set of immune responses to vaccination and challenge suggesting that the vaccine is polyfunctional, inducing different equally-protective sets of immune responses based on the genetic background of the immunized host. Vaccine efficacy in genetically erse mice suggests that it will also be effective in genetically complex human populations.
Impaired Ca2+ signaling due to hepatic steatosis mediates hepatic insulin resistance in Alström syndrome mice that is reversed by GLP-1 analog treatment
Publisher: American Physiological Society
Date: 07-2021
DOI: 10.1152/AJPCELL.00020.2021
Abstract: Ca 2+ signaling plays a critical role in the regulation of hepatic metabolism by hormones including insulin. Changes in cytoplasmic Ca 2+ regulate synthesis and posttranslational modification of key signaling proteins in the insulin pathways. Emerging evidence suggests that hepatocyte intracellular Ca 2+ signaling is altered in lipid-loaded liver cells isolated from obese rodent models. The mechanisms of altered Ca 2+ -insulin and insulin-Ca 2+ signaling pathways in obesity remain poorly understood. Here, we show that the kinetics of insulin-initiated intracellular (initial) Ca 2+ release from endoplasmic reticulum is significantly impaired in steatotic hepatocytes from obese Alström syndrome mice. Furthermore, exenatide, a glucagon-like peptide-1 (GLP-1) analog, reversed lipid-induced inhibition of intracellular Ca 2+ release kinetics in steatotic hepatocytes, without affecting the total content of intracellular Ca 2+ released. Exenatide reversed the lipid-induced inhibition of intracellular Ca 2+ release, at least partially, via lipid reduction in hepatocytes, which then restored hormone-regulated cytoplasmic Ca 2+ signaling and insulin sensitivity. This data provides additional evidence for the important role of Ca 2+ signaling pathways in obesity-associated impaired hepatic lipid homeostasis and insulin signaling. It also highlights a potential advantage of GLP-1 analogs when used to treat type 2 diabetes associated with hepatic steatosis.
Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia
Publisher: Massachusetts Medical Society
Date: 03-01-2019
Accelerated vaccine induction of IgM neutralising antibody enables vaccine protection against same day lethal influenza virus challenge
Publisher: Cold Spring Harbor Laboratory
Date: 18-02-2021
DOI: 10.1101/2021.02.17.431751
Abstract: Novel influenza strains to which humans have no pre-existing immunity can trigger global pandemics without warning. Current pandemic vaccines typically require two doses and up to 6 weeks to induce protective immunity. In addition, to their role in increasing vaccine-induced immune response, adjuvants may also play a part in reducing the time between immunization and vaccine protection, although this role has seldom been previously explored in literature. This study assessed the speed of protection achievable with a standard inactivated influenza vaccine when formulated with or without a novel delta-inulin adjuvant (Advax). When formulated with Advax adjuvant mice were protected even when the vaccine was administered intramuscularly contemporaneously with a lethal intranasal virus challenge. The protection was found to be B-cell dependent and transfer of day 6 immune serum from mice immunised with Advax-adjuvanted influenza vaccine conferred protection to naïve animals. This protection was shown to be mediated by vaccine induced IgM rather than IgG neutralising antibodies. The results show that influenza vaccine can be formulated to provide immediate protection following immunization with this novel concept warranting testing in human trials. In the past 100 years there have been several major influenza pandemics that resulted in significant loss of life. The time taken for in iduals to develop vaccine protection is an important factor in curbing the spread of infection and reducing pandemic mortality rates. Current influenza vaccines can take up to 5-6 weeks to generate full protection leaving front-line heath care workers and others, at risk for an extended period of time. Our novel accelerated vaccine protection approach provides effectively immediate vaccine protection against lethal virus challenge. This would assist front-line workers to continue to provide essential services and maintain critical infrastructure during pandemic. The study also highlights the often-overlooked role that antigen-specific IgM plays in virus protection and provides a novel adjuvanted strategy for enlisting IgM to provide accelerated vaccine protection.
Immunisation of ferrets and mice with recombinant SARS-CoV-2 spike protein formulated with Advax-SM adjuvant protects against COVID-19 infection
Publisher: Cold Spring Harbor Laboratory
Date: 05-07-2021
DOI: 10.1101/2021.07.03.451026
Abstract: The development of a safe and effective vaccine is a key requirement to overcoming the COVID-19 pandemic. Recombinant proteins represent the most reliable and safe vaccine approach but generally require a suitable adjuvant for robust and durable immunity. We used the SARS-CoV-2 genomic sequence and in silico structural modelling to design a recombinant spike protein vaccine (Covax-19™). A synthetic gene encoding the spike extracellular domain (ECD) was inserted into a baculovirus backbone to express the protein in insect cell cultures. The spike ECD was formulated with Advax-SM adjuvant and first tested for immunogenicity in C57BL/6 and BALB/c mice. The Advax-SM adjuvanted vaccine induced high titers of binding antibody against spike protein that were able to neutralise the original wildtype virus on which the vaccine was based as well as the variant B.1.1.7 lineage virus. The Covax-19 vaccine also induced potent spike-specific CD4+ and CD8+ memory T-cells with a dominant Th1 phenotype, and this was shown to be associated with cytotoxic T lymphocyte killing of spike labelled target cells in vivo . Ferrets immunised with Covax-19 vaccine intramuscularly twice 2 weeks apart made spike receptor binding domain (RBD) IgG and were protected against an intranasal challenge with SARS-CoV-2 virus 2 weeks after the second immunisation. Notably, ferrets that received two 25 or 50μg doses of Covax-19 vaccine had no detectable virus in their lungs or in nasal washes at day 3 post-challenge, suggesting the possibility that Covax-19 vaccine may in addition to protection against lung infection also have the potential to block virus transmission. This data supports advancement of Covax-19 vaccine into human clinical trials.
Wind, Solar, and Photovoltaic Renewable Energy Systems with and without Energy Storage Optimization: A Survey of Advanced Machine Learning and Deep Learning Techniques
Publisher: MDPI AG
Date: 14-01-2022
DOI: 10.3390/EN15020578
Abstract: Nowadays, learning-based modeling methods are utilized to build a precise forecast model for renewable power sources. Computational Intelligence (CI) techniques have been recognized as effective methods in generating and optimizing renewable tools. The complexity of this variety of energy depends on its coverage of large sizes of data and parameters, which have to be investigated thoroughly. This paper covered the most resent and important researchers in the domain of renewable problems using the learning-based methods. Various types of Deep Learning (DL) and Machine Learning (ML) algorithms employed in Solar and Wind energy supplies are given. The performance of the given methods in the literature is assessed by a new taxonomy. This paper focus on conducting comprehensive state-of-the-art methods heading to performance evaluation of the given techniques and discusses vital difficulties and possibilities for extensive research. Based on the results, variations in efficiency, robustness, accuracy values, and generalization capability are the most obvious difficulties for using the learning techniques. In the case of the big dataset, the effectiveness of the learning techniques is significantly better than the other computational methods. However, applying and producing hybrid learning techniques with other optimization methods to develop and optimize the construction of the techniques is optionally indicated. In all cases, hybrid learning methods have better achievement than a single method due to the fact that hybrid methods gain the benefit of two or more techniques for providing an accurate forecast. Therefore, it is suggested to utilize hybrid learning techniques in the future to deal with energy generation problems.
Synthesis and characterization of pH-sensitive inulin conjugate of isoniazid for monocyte-targeted delivery
Publisher: MDPI AG
Date: 28-10-2019
DOI: 10.3390/PHARMACEUTICS11110555
Abstract: The use of particles for monocyte-mediated delivery could be a more efficient strategy and approach to achieve intracellular targeting and delivery of antitubercular drugs to host macrophages. In this study, the potential of inulin microparticles to serve as a drug vehicle in the treatment of chronic tuberculosis using a monocytes-mediated drug targeting approach was evaluated. Isoniazid (INH) was conjugated to inulin via hydrazone linkage in order to obtain a pH-sensitive inulin-INH conjugate. The conjugate was then characterized using proton nuclear magnetic resonance (1HNMR), Fourier transform infrared spectroscopy (FTIR) as well as in vitro, cellular uptake and intracellular Mycobacterium tuberculosis (Mtb) antibacterial efficacy. The acid-labile hydrazone linkage conferred pH sensitivity to the inulin-INH conjugate with ~95, 77 and 65% of the drug released after 5 h at pH 4.5, 5.2, and 6.0 respectively. Cellular uptake studies confirm that RAW 264.7 monocytic cells efficiently internalized the inulin conjugates into endocytic compartments through endocytosis. The intracellular efficacy studies demonstrate that the inulin conjugates possess a dose-dependent targeting effect against Mtb-infected monocytes. This was through efficient internalization and cleavage of the hydrazone bond by the acidic environment of the lysosome, which subsequently released the isoniazid intracellularly to the Mtb reservoir. These results clearly suggest that inulin conjugates can serve as a pH-sensitive intracellular drug delivery system for TB treatment.
Computationally repurposed drugs and natural products against RNA dependent RNA polymerase as potential COVID-19 therapies
Publisher: Springer Science and Business Media LLC
Date: 20-09-2021
DOI: 10.1186/S43556-021-00050-3
Abstract: Repurposing of existing drugs and drug candidates is an ideal approach to identify new potential therapies for SARS-CoV-2 that can be tested without delay in human trials of infected patients. Here we applied a virtual screening approach using Autodock Vina and molecular dynamics simulation in tandem to calculate binding energies for repurposed drugs against the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). We thereby identified 80 promising compounds with potential activity against SARS-Cov2, consisting of a mixture of antiviral drugs, natural products and drugs with erse modes of action. A substantial proportion of the top 80 compounds identified in this study had been shown by others to have SARS-CoV-2 antiviral effects in vitro or in vivo, thereby validating our approach. Amongst our top hits not previously reported to have SARS-CoV-2 activity, were eribulin, a macrocyclic ketone analogue of the marine compound halichondrin B and an anticancer drug, the AXL receptor tyrosine kinase inhibitor bemcentinib. Our top hits from our RdRp drug screen may not only have utility in treating COVID-19 but may provide a useful starting point for therapeutics against other coronaviruses. Hence, our modelling approach successfully identified multiple drugs with potential activity against SARS-CoV-2 RdRp.
The Role of Endoplasmic Reticulum Stress in Nonimmune Diabetes: NOD.k iHEL, a Novel Model of β Cell Death
Publisher: Wiley
Date: 11-2003
Abstract: The final common pathway in diabetes development is beta cell apoptosis. We herein describe a novel diabetes model based on transgenic NOD.k iHEL mice, wherein male mice develop diabetes due to nonimmune-mediated beta cell death. Histology and electron microscopy confirm endoplasmic reticulum (ER) abnormalities that are consistent with endoplasmic stress caused by the HEL transgene. The NOD.k iHEL model may be particularly useful for studying mechanisms of beta cell death secondary to ER stress and also for testing potential therapies designed to protect beta cells from stress-induced apoptosis. The observation that only male NOD.k iHEL mice develop diabetes and exhibit ER abnormalities is intriguing and suggests these mice may be useful in deciphering the link between hyperandrogenism, insulin resistance, and diabetes.
Delta Inulin Adjuvant Enhances Plasmablast Generation, Expression of Activation-Induced Cytidine Deaminase and B-Cell Affinity Maturation in Human Subjects Receiving Seasonal Influenza Vaccine
Publisher: Public Library of Science (PLoS)
Date: 15-07-2015
Advax-CpG55.2-adjuvanted monovalent or trivalent SARS-CoV-2 recombinant spike protein vaccine protects hamsters against heterologous infection with Beta or Delta variants
Publisher: Elsevier BV
Date: 10-2023
Advax-CpG Adjuvant Provides Antigen Dose-Sparing and Enhanced Immunogenicity for Inactivated Poliomyelitis Virus Vaccines
Publisher: MDPI AG
Date: 21-04-2021
DOI: 10.3390/PATHOGENS10050500
Abstract: Global immunization c aigns have resulted in a major decline in the global incidence of polio cases, with wild-type poliovirus remaining endemic in only two countries. Live oral polio vaccine (OPV) played a role in the reduction in polio case numbers however, the risk of OPV developing into circulating vaccine-derived poliovirus makes it unsuitable for eradication programs. Trivalent inactivated polio virus (TIPV) vaccines which contain formalin-inactivated antigens produced from virulent types 1, 2 and 3 reference polio strains grown in Vero monkey kidney cells have been advocated as a replacement for OPV however, TIPVs have weak immunogenicity and multiple boosts are required before peak neutralizing titers are reached. This study examined whether the incorporation of the novel polysaccharide adjuvant, Advax-CpG, could boost the immunogenicity of two TIPV vaccines, (i) a commercially available polio vaccine (IPOL®, Sanofi Pasteur) and (ii) a new TIPV formulation developed by Statens Serum Institut (SSI). Mice were immunized intramuscularly based on recommended vaccine dosage schedules and serum antibody titers were followed for 12 months post-immunization. Advax-CpG significantly enhanced the long-term immunogenicity of both TIPV vaccines and had at least a 10-fold antigen dose-sparing effect. An exception was the poor ability of the SSI TIPV to induce serotype type 1 neutralizing antibodies. Immunization with monovalent IPVs suggested that the low type 1 response to TIPV may be due to antigen competition when the type 1 antigen was co-formulated with the type 2 and 3 antigens. This study provides valuable insights into the complexity of the formulation of multivalent polio vaccines and supports the further development of adjuvanted antigen-sparing TIPV vaccines in the fight to eradicate polio.
Efficacy of an Adjuvanted Middle East Respiratory Syndrome Coronavirus Spike Protein Vaccine in Dromedary Camels and Alpacas
Publisher: MDPI AG
Date: 02-03-2019
DOI: 10.3390/V11030212
Abstract: MERS-CoV is present in dromedary camels throughout the Middle East and Africa. Dromedary camels are the primary zoonotic reservoir for human infections. Interruption of the zoonotic transmission chain from camels to humans, therefore, may be an effective strategy to control the ongoing MERS-CoV outbreak. Here we show that vaccination with an adjuvanted MERS-CoV Spike protein subunit vaccine confers complete protection from MERS-CoV disease in alpaca and results in reduced and delayed viral shedding in the upper airways of dromedary camels. Protection in alpaca correlates with high serum neutralizing antibody titers. Lower titers of serum neutralizing antibodies correlate with delayed and significantly reduced shedding in the nasal turbinates of dromedary camels. Together, these data indicate that induction of robust neutralizing humoral immune responses by vaccination of naïve animals reduces shedding that potentially could diminish the risk of zoonotic transmission.
Benefits and Safety of Long-Term Fenofibrate Therapy in People With Type 2 Diabetes and Renal Impairment: The FIELD Study
Publisher: American Diabetes Association
Date: 16-01-2012
DOI: 10.2337/DC11-1109
Abstract: Diabetic patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2) are at particular cardiovascular risk. Fenofibrate’s safety in these patients is an issue because it may elevate plasma creatinine. Furthermore, guidelines regarding fenofibrate dosing in renal impairment vary internationally. We investigated fenofibrate’s effects on cardiovascular and end-stage renal disease (ESRD) events, according to eGFR, in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Type 2 diabetic patients (aged 50–75 years) with eGFR ≥30 mL/min/1.73 m2 were randomly allocated to a fixed dose of fenofibrate (200 mg daily) (n = 4,895) or placebo (n = 4,900) for 5 years. Baseline renal function (Modification of Diet in Renal Disease equation) was grouped by eGFR (30–59, 60–89, and ≥90 mL/min/1.73 m2). The prespecified outcome was total cardiovascular events (composite of cardiovascular death, myocardial infarction, stroke, and coronary/carotid revascularization). Serious adverse events and instances of ESRD (plasma creatinine & μmol/L, dialysis, renal transplant, or renal death) were recorded. Analysis was by intention to treat. Overall, fenofibrate reduced total cardiovascular events, compared with placebo (hazard ratio 0.89 [95% CI 0.80–0.99] P = 0.035). This benefit was not statistically different across eGFR groupings (P = 0.2 for interaction) (eGFR 30–59 mL/min/1.73 m2: 0.68 [0.47–0.97], P = 0.035 eGFR ≥90 mL/min/1.73 m2: 0.85 [0.70–1.02], P = 0.08). ESRD rates were similar between treatment arms, without adverse safety signals of fenofibrate use in renal impairment. Patients with type 2 diabetes and moderate renal impairment benefit from long-term fenofibrate, without excess drug-related safety concerns compared with those with no or mild renal impairment. Fenofibrate treatment should not be contraindicated in moderate renal impairment, suggesting that current guidelines may be too restrictive.
Design Research Insights on Text Mining Analysis: Establishing the Most Used and Trends in Keywords of Design Research Journals
Publisher: MDPI AG
Date: 28-11-2022
DOI: 10.3390/ELECTRONICS11233930
Abstract: Design research topics attract exponentially more attention and consideration among researchers. This study is the first research article that endeavors to analyze selected design research publications using an advanced approach called “text mining”. This approach speculates its results depending on the existence of a research term (i.e., keywords), which can be more robust than other methods/approaches that rely on contextual data or authors’ perspectives. The main aim of this research paper is to expand knowledge and familiarity with design research and explore future research directions by addressing the gaps in the literature relying on the literature review, it can be stated that the research area in the design domain still not built-up a theory, which can unify the field. In general, text mining with these features allows increased validity and generalization as compared to other approaches in the literature. We used a text mining technique to collect data and analyzed 3553 articles collected in 10 journals using 17,487 keywords. New topics were investigated in the domain of design concepts, which included attracting researchers, practitioners, and journal editorial boards. Such issues as co-innovation, ethical design, social practice design, conceptual thinking, collaborative design, creativity, and generative methods and tools were subject to additional research. On the other hand, researchers pursued topics such as collaborative design, human-centered design, interdisciplinary design, design education, participatory design, design practice, collaborative design, design development, collaboration, design theories, design administration, and service roduct design areas. The key categories investigated and reported in this paper helped in determining what fields are flourishing and what fields are eroding.
Common sequence variation in the VEGFA gene predicts risk of diabetic retinopathy
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 12-2009
DOI: 10.1167/IOVS.09-3694
Abstract: Vascular endothelial growth factor (VEGF) is a multifunctional cytokine that plays a role in angiogenesis and microvascular permeability. This study was conducted to determine whether common sequence variation in the VEGFA gene plays a role in the development of diabetic retinopathy (DR). Five hundred fifty-four subjects with diabetes mellitus (DM) including 190 type 1 DM (T1DM) and 364 type 2 DM (T2DM) were recruited. The study group consisted of 235 participants without DR, 158 with nonproliferative DR (NPDR), 132 with proliferative DR (PDR), and 93 with clinically significant macular edema (CSME). Blinding DR was defined as severe NPDR, PDR, or CSME. Fifteen VEGFA tag single-nucleotide polymorphisms (SNPs) were genotyped in all subjects and tested for association with blinding DR. Multiple tag SNPs in the VEGFA gene were associated with blinding DR. After controlling for sex, HbA1c, and duration of disease, in T1DM, the AA genotype of rs699946 (P = 0.007, odds ratio [OR], 4.1 95% confidence interval [CI], 1.5-11.4) and the GG genotype of rs833068 (P = 0.017, OR, 3.1 95% CI, 1.3-7.2) were most significantly associated. In T2DM, the C allele of rs3025021 (P = 0.002 OR, 3.8 95% CI, 1.5-10.0) and the G allele of rs10434 (P = 0.002 OR, 2.6 95% CI, 1.3-5.3) were most significantly associated with blinding DR. Haplotype analyses suggested an important role for the haplotype TCCGCG in blinding DR (P = 0.0004). Sequence variation in the VEGFA gene is associated with risk of developing blinding DR in T1DM and T2DM. Identifying specific genetic markers will allow for refined screening algorithms and earlier intervention in patients at highest risk.
FREP: a database of functional repeats in mouse cDNAs
Publisher: Oxford University Press (OUP)
Date: 2004
DOI: 10.1093/NAR/GKH123
A Prospective Observational Cohort Comparison of SARS-CoV-2 Seroprevalence Between Paramedics and Matched Blood Donors in Canada During the COVID-19 Pandemic
Publisher: Elsevier BV
Date: 07-2022
Prediction of promiscuous peptides that bind HLA class I molecules
Publisher: Wiley
Date: 06-2002
DOI: 10.1046/J.1440-1711.2002.01088.X
Abstract: Promiscuous T-cell epitopes make ideal targets for vaccine development. We report here a computational system, MULTIPRED, for the prediction of peptide binding to the HLA-A2 supertype. It combines a novel representation of peptide/MHC interactions with a hidden Markov model as the prediction algorithm. MULTIPREDis both sensitive and specific, and demonstrates high accuracy of peptide-binding predictions for HLA-A*0201, *0204, and *0205 alleles, good accuracy for *0206 allele, and marginal accuracy for *0203 allele. MULTIPREDreplaces earlier requirements for in idual prediction models for each HLA allelic variant and simplifies computational aspects of peptide-binding prediction. Preliminary testing indicates that MULTIPRED can predict peptide binding to HLA-A2 supertype molecules with high accuracy, including those allelic variants for which no experimental binding data are currently available.
Neonatal vaccine effectiveness and the role of adjuvants
Publisher: Informa UK Limited
Date: 25-07-2019
Correction: Stewart et al. Adjuvant Strategies for More Effective Tuberculosis Vaccine Immunity. Microorganisms 2019, 7, 255
Publisher: MDPI AG
Date: 31-03-2022
DOI: 10.3390/MICROORGANISMS10040757
Abstract: The authors wish to make the following corrections to this paper [...]
The Future for Computational Modelling and Prediction Systems in Clinical Immunology
Publisher: Wiley
Date: 16-10-2003
Immunogenicity of Adjuvanted Psoralen-Inactivated SARS-CoV-2 Vaccines and SARS-CoV-2 Spike Protein DNA Vaccines in BALB/c Mice
Publisher: MDPI AG
Date: 19-05-2021
DOI: 10.3390/PATHOGENS10050626
Abstract: The development of a safe and effective vaccine to protect against COVID-19 is a global priority due to the current high SARS-CoV-2 infection rate. Currently, there are over 160 SARS-CoV-2 vaccine candidates at the clinical or pre-clinical stages of development. Of these, there are only three whole-virus vaccine candidates produced using β-propiolactone or formalin inactivation. Here, we prepared a whole-virus SARS-CoV-2 vaccine (SARS-CoV-2 PsIV) using a novel psoralen inactivation method and evaluated its immunogenicity in mice using two different adjuvants, alum and Advax-2. We compared the immunogenicity of SARS-CoV-2 PsIV against SARS-CoV-2 DNA vaccines expressing either full-length or truncated spike proteins. We also compared the psoralen-inactivated vaccine against a DNA prime, psoralen-inactivated vaccine boost regimen. After two doses, the psoralen-inactivated vaccine, when administered with alum or Advax-2 adjuvants, generated a dose-dependent neutralizing antibody responses in mice. Overall, the pattern of cytokine ELISPOT responses to antigen-stimulation observed in this study indicates that SARS-CoV-2 PsIV with the alum adjuvant promotes a Th2-type response, while SARS-CoV-2 PsIV with the Advax-2 adjuvant promotes a Th1-type response.
Addison's disease presenting in four adolescents with type 1 diabetes
Publisher: Hindawi Limited
Date: 12-2004
Immunoinformatics—The New Kid in Town
Publisher: Wiley
Date: 16-10-2003
Mucosal delivery of a multistage subunit vaccine promotes development of lung-resident memory T cells and affords interleukin-17-dependant protection against pulmonary tuberculosis
Publisher: Cold Spring Harbor Laboratory
Date: 25-02-2020
DOI: 10.1101/2020.02.25.964312
Abstract: The development of effective vaccines against bacterial lung infections requires the induction of protective, pathogen-specific immune responses without deleterious inflammation within the pulmonary environment. Here, we made use of a polysaccharide-adjuvanted vaccine approach to elicit resident pulmonary T cells to protect against aerosol Mycobacterium tuberculosis infection. Intratracheal administration of the multistage fusion protein CysVac2 and the delta-inulin adjuvant Advax™ (formulated with a TLR9 agonist) provided superior protection against aerosol M. tuberculosis infection in mice, compared to parenteral delivery. Surprisingly, removal of the TLR9 agonist did not impact vaccine protection despite a reduction in cytokine-secreting T cell subsets, particularly CD4 + IFN-γ + IL-2 + TNF + multifunctional T cells. CysVac2/Advax-mediated protection was associated with the induction of lung-resident, antigen-specific memory CD4 + T cells that expressed IL-17 and RORγt, the master transcriptional regulator of Th17 differentiation. IL-17 was identified as a key mediator of vaccine efficacy, with blocking of IL-17 during M. tuberculosis challenge reducing phagocyte influx, suppressing priming of pathogen-specific CD4 + T cells in local lymph nodes and ablating vaccine-induced protection. These findings suggest that tuberculosis vaccines such as CysVac2/Advax that are capable of eliciting Th17 lung-resident memory T cells are promising candidates for progression to human trials. Mycobacterium tuberculosis , the causative agent of tuberculosis (TB), kills more in iduals each year than any other single pathogen. The only approved vaccine, BCG, administered intradermally, is unreliable in protecting against pulmonary TB, therefore a more effective vaccine is critical for global control of the disease. Vaccination in the lung would be a rational way of inducing a local memory immune response to TB, however vaccine platforms would need to deliver antigens to delicate mucosal surfaces without inducing deleterious inflammatory responses. We developed a safe mucosal vaccine which induced protection against TB lung infection in mice by inducing high levels of lung-resident T cells expressing the cytokine IL-17. Removal of IL-17 limited the influx of phagocytic cells to the lung and completely ablated protection afforded by the vaccine. This study provides new insights into mechanisms of protection against M. tuberculosis and provides a promising candidate to protect against TB in humans.
The safety of an adjuvanted autologous cancer vaccine platform in canine cancer patients
Publisher: MDPI AG
Date: 12-10-2018
Abstract: Canine cancer rates are similar to humans, though the therapeutic options might be limited. Inducing a patient’s own immune system to have an anti-tumor response is an attractive approach to cancer therapy. In this safety study, autologous tumor vaccines produced specifically for each canine patient were combined with Advax™, a novel non-inflammatory immunomodulator and vaccine adjuvant and were tested for safety in a erse range of patient presentations alone or in combination with other treatments. Canine patients had their tumor biopsied, debulked or resected and the tumor antigens were processed into an autologous vaccine formulated with Advax™ adjuvant with or without rhizavidin as an additional immune stimulant. Patients treated early in the trial received two intramuscular (IM) doses, 2 weeks apart. As the study progressed and no issues of safety were observed, the protocol was changed to weekly vaccinations for 4 weeks followed by monthly booster shots. Over the 150 I.M injections delivered to date, the vaccine was found to be very safe and no significant adverse reactions were observed. These results justify ongoing development and future controlled studies of this autologous vaccine approach.
Advax adjuvant formulations promote protective immunity against aerosol Mycobacterium tuberculosis in the absence of deleterious inflammation and reactogenicity
Publisher: Cold Spring Harbor Laboratory
Date: 10-2020
DOI: 10.1101/2020.10.01.323105
Abstract: The development of safe and effective adjuvants is a critical goal of vaccine development programs. In this report, we defined the immunostimulatory profile and protective effect against aerosol Mycobacterium tuberculosis infection of vaccine formulations incorporating the semi-crystalline adjuvant δ-inulin (Advax). Advax formulated with CpG oligonucleotide and the QS-21 saponin (Advax CpQS ) was the most effective combination, demonstrated by the capacity of CysVac2/Advax CpQS to significantly reduce the bacterial burden in the lungs of M. tuberculosis -infected mice. CysVac2/Advax CpQS protection was associated with rapid influx of neutrophils, macrophages and monocytes to the site of vaccination and the induction of antigen-specific IFN-γ + /IL-2 + /TNF + polyfunctional CD4 + T cells in the lung. When compared to the highly potent adjuvant combination of monophosphoryl lipid A and dimethyldioctadecylammonium bromide (MPL/DDA), Advax CpQS imparted a similar level of protective efficacy yet without the profound stimulation of inflammatory cytokines and vaccination site ulceration observed with MPL/DDA. Addition of DDA to CysVac2/ Advax CpQS further improved the protective effect of the vaccine, which correlated with increased polyfunctional CD4 + T cells in the lung but with no increase in vaccine reactogenicity. The data demonstrate that Advax formulations can decouple protective tuberculosis immunity from reactogenicity, making them ideal candidates for human application. Advax adjuvant formulations improve pulmonary protection against aerosol Mycobacterium tuberculosis infection Different combinations of adjuvant components markedly influence the level of protection observed Protection is associated with the rapid influx of myeloid cells to the site of vaccination and the induction of antigen-specific polyfunctional CD4 + T cells in the lung. Advax formulations abrogate vaccine-site ulceration and inflammatory cytokine production
A Spike protein-based subunit SARS-CoV-2 vaccine for pets: safety, immunogenicity, and protective efficacy in juvenile cats
Publisher: Research Square Platform LLC
Date: 16-11-2021
DOI: 10.21203/RS.3.RS-1083984/V1
Abstract: Whereas multiple vaccine types have been developed to curb the spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) among humans, there are very few vaccines being developed for animals including pets. To combat the threat of human-to-animal, animal-to-animal and animal-to-human transmission and the generation of new virus variants, we developed a subunit SARS-CoV-2 vaccine which is based on recombinant spike protein extracellular domain expressed in insect cells then formulated with appropriate adjuvants. Sixteen 8-12-week-old outbred female and male kittens (n=4/group) were randomly assigned into four treatment groups: Group 1, Antigen alone Group 2, Sepivac SWE™ adjuvant Group 3, aluminum hydroxide adjuvant Group 4, PBS administered control animals. All animals were vaccinated twice at day 0 and 14, intramuscularly in a volume of 0.5 mL (Groups 1-3: 5 µg of Spike protein). On days 0 and 28 serum s les were collected to evaluate anti-spike IgG, inhibition of spike binding to angiotensin-converting enzyme 2 (ACE-2), neutralizing antibodies to Wuhan-01 SARS-CoV-2 D614G (wild-type) and Delta variant viruses, and whole blood for hematology studies. At day 28, all groups were challenged with SARS-CoV-2 wild-type virus 10 6 TCID 50 intranasally. On day 31, tissue s les (lung, heart, and nasal turbinates) were collected for histology, viral RNA detection and virus titration. Parameters evaluated in this study included safety, immunogenicity, and protection from infection with wild-type SARS-CoV-2 virus. After two immunizations, both vaccines induced high titers of serum anti-spike IgG, ACE-2 binding inhibitory and neutralizing antibodies against both wild-type and Delta variant virus in the juvenile cats. Both subunit vaccines provided protection of juvenile cats against virus shedding from the upper respiratory tract, and against viral replication in the lower respiratory tract and hearts. These promising data warrant ongoing evaluation of the vaccine’s ability to protect cats against SARS-CoV-2 Delta variant and in particular to prevent transmission of the infection to naïve cats, before proceeding with large-scale field trials.
Computational vaccinology and the ICoVax 2012 workshop
Publisher: Springer Science and Business Media LLC
Date: 03-2013
A novel hepatitis B vaccine containing Advax™, a polysaccharide adjuvant derived from delta inulin, induces robust humoral and cellular immunity with minimal reactogenicity in preclinical testing
Publisher: Elsevier BV
Date: 04-2013
Toll-like receptor (TLR) agonists as a driving force behind next-generation vaccine adjuvants and cancer therapeutics
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.CBPA.2022.102172
Abstract: Until recently, the development of new human adjuvants was held back by a poor understanding of their mechanisms of action. The field was revolutionized by the discovery of the toll-like receptors (TLRs), innate immune receptors that directly or indirectly are responsible for detecting pathogen-associated molecular patterns (PAMPs) and respond to them by activating innate and adaptive immune pathways. Hundreds of ligands targeting various TLRs have since been identified and characterized as vaccine adjuvants. This work has important implications not only for the development of vaccines against infectious diseases but also for immuno-therapies against cancer, allergy, Alzheimer's disease, drug addiction and other diseases. Each TLR has its own specific tissue localization and downstream gene signalling pathways, providing researchers the opportunity to precisely tailor adjuvants with specific immune effects. TLR agonists can be combined with other TLR or alternative adjuvants to create combination adjuvants with synergistic or modulatory effects. This review provides an introduction to the various classes of TLR adjuvants and their respective signalling pathways. It provides an overview of recent advancements in the TLR field in the past 2-3 years and discusses criteria for selecting specific TLR adjuvants based on considerations, such as disease mechanisms and correlates of protection, TLR immune biasing capabilities, route of administration, antigen compatibility, new vaccine technology platforms, and age- and species-specific effects.
X-ray crystal structure of rivoglitazone bound to PPARγ and PPAR subtype selectivity of TZDs
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.BBAGEN.2017.05.008
Abstract: Thiazolidinedione (TZD) compounds targeting the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) demonstrate unique benefits for the treatment of insulin resistance and type II diabetes. TZDs include rosiglitazone, pioglitazone and rivoglitazone, with the latter being the most potent. The TZDs are only marginally selective for the therapeutic target PPARγ as they also activate PPARα and PPARδ homologues to varying degrees, causing off-target effects. While crystal structures for TZD compounds in complex with PPARγ are available, minimal structural information is available for TZDs bound to PPARα and PPARδ. This paucity of structural information has h ered the determination of precise structural mechanisms involved in TZD selectivity between PPARs. To help address these questions molecular dynamic simulations were performed of rosiglitazone, pioglitazone and rivoglitazone in complex with PPARα, PPARδ, and PPARγ in order to better understand the mechanisms of PPAR selectivity. The simulations revealed that TZD interactions with residues Tyr314 and Phe318 of PPARα and residues Phe291 and Thr253 of PPARδ as well as the omega loop, are key determinants of TZD receptor selectivity. Notably, in this study, we solve the first X-ray crystal structure of rivoglitazone bound to any PPAR. Rivoglitazone forms a unique hydrogen bond network with the residues of the PPARγ co-activator binding surface (known as AF2) and makes more extensive contacts with helix 3 and the β-sheet as compared to model TZD compounds such as rosiglitazone.
Pharmacological Management of Endocrine Conditions in the Elderly Patient
Publisher: Wiley
Date: 02-04-2009
Novel human polysaccharide adjuvants with dual Th1 and Th2 potentiating activity
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.VACCINE.2005.01.107
Abstract: Pure soluble, recombinant and synthetic antigens, despite their better tolerability, are unfortunately often much less immunogenic than live or killed whole organism vaccines. Thus, the move towards the development of safer subunit vaccines has created a major need for more potent adjuvants. In particular, there is an urgent need for adjuvants capable of boosting cellular (Th1) immunity but without unacceptable toxicity. The adjuvant activity of aluminium compounds (aluminium phosphate or hydroxide) was first described by Glenny and colleagues in 1926. Surprisingly, despite the description of over one hundred adjuvants in the scientific literature, alum remains the only adjuvant approved for human use in the USA. Unfortunately, alum has no effect on cellular immunity and is faced with increasing concerns regarding potential for cumulative aluminium toxicity. Why then has alum not been replaced in human vaccines? Despite the enormous number of candidates, potency has invariably been associated with increased toxicity, and this more than anything else has precluded their use, particularly in prophylactic vaccines where safety issues are paramount. Hence, there is a major unmet need for a safe efficacious adjuvant capable of boosting cellular plus humoral immunity. The extensive data on inulin-based adjuvants indicate that these are excellent candidates to replace alum as the adjuvant of choice for many vaccines. Particular advantages offered by inulin-based adjuvants is that they induce cellular in addition to humoral immunity and offer excellent safety, tolerability, ease of manufacture and formulation. Thus, adjuvants based on inulin have enormous potential for use in vaccines against both pathogens and cancer.
Mechanisms of Accelerated Immune-Mediated Diabetes Resulting from Islet β Cell Expression of a Fas Ligand Transgene
Publisher: The American Association of Immunologists
Date: 15-05-2003
DOI: 10.4049/JIMMUNOL.170.10.4996
Abstract: Nonobese diabetic (NOD) mice transgenic for Fas ligand (FasL) on islet β cells (HIPFasL mice) exhibit an accelerated diabetes distinct from the normal autoimmune diabetes of NOD mice. This study was undertaken to define the mechanism underlying accelerated diabetes development in HIPFasL mice. It was found that diabetes in HIPFasL mice is dependent on the NOD genetic background, as HIPFasL does not cause diabetes when crossed into other mice strains and is lymphocyte dependent, as it does not develop in HIPFasLSCID mice. Diabetes development in NODSCID recipients of diabetic HIPFasL splenocytes is slower than when using splenocytes from diabetic NOD mice. β cells from HIPFasL mice are more susceptible to cytokine-induced apoptosis than wild-type NOD β cells, and this can be blocked with anti-FasL Ab. HIPFasL islets are more rapidly destroyed than wild-type islets when transplanted into nondiabetic NOD mice. This confirms that FasL+ islets do not obtain immune privilege, and instead NOD β cells constitutively expressing FasL are more susceptible to apoptosis induced by Fas-FasL interaction. These findings are consistent with the accelerated diabetes of young HIPFasL mice being a different disease process from the autoimmune diabetes of wild-type NOD mice. The data support a mechanism by which cytokines produced by the insulitis lesion mediate up-regulation of β cell Fas expression, resulting in suicide or fratricide of HIPFasL β cells that overexpress FasL.
PREDNOD, a prediction server for peptide binding to the H-2g7haplotype of the non-obese diabetic mouse
Publisher: Informa UK Limited
Date: 2006
DOI: 10.1080/08916930601062494
Abstract: The non-obese diabetic (NOD) mouse is a widely used animal model for study of autoimmune diseases, in particular human type 1 diabetes mellitus (T1DM). Identification of the subset of peptides that bind MHC molecules comprising the H-2g7 haplotype of NOD mouse and thereby representing potential NOD T-cell epitopes is important for research into the pathogenesis and immunotherapy of T1DM. The H-2g7 haplotype comprises the MHC class-I molecules Kd and Db and a single class-II molecule I-Ag7. We have developed a prediction system, PREDNOD, for accurate identification of peptides that bind the MHC molecules constituting the H-2g7 haplotype. PREDNOD is accessible at antigen.i2r.a-star.edu.sg/Ag7.
The need for a large-scale trial of fibrate therapy in diabetes: The rationale and design of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. [ISRCTN64783481]
Publisher: Springer Science and Business Media LLC
Date: 2004
Immunogenicity and safety of SpikoGen®, an adjuvanted recombinant SARS‐CoV‐2 spike protein vaccine as a homologous and heterologous booster vaccination: A randomized placebo‐controlled trial
Publisher: Wiley
Date: 13-07-2022
DOI: 10.1111/IMM.13540
Abstract: SpikoGen® is a subunit recombinant spike protein vaccine combined with Advax‐CpG55.2™ adjuvant. This COVID‐19 vaccine was shown to be safe, immunogenic and efficacious in previous clinical trials. This study aimed to assess the safety and immunogenicity of SpikoGen® vaccine as a homologous and heterologous booster vaccination. This double‐blind and randomized placebo‐controlled (5:1) trial was performed on 300 already vaccinated participants. SpikoGen® or saline placebo was administered as a booster dose to participants who had received a full two‐dose COVID‐19 vaccination course. Immunogenicity assessments were done 14 days after the booster dose with the primary immunogenicity outcome seroconversion rate of neutralizing antibodies. Safety outcomes included the incidence of solicited adverse events up to 7 days after the booster dose. SpikoGen® vaccine induced a robust humoral response both as a homologous and heterologous booster, when compared to the placebo. At Day 14, seroconversion of neutralizing antibodies was 76% (95% confidence interval [CI]: 69%–82%) in the SpikoGen® group versus 3% (95% CI: 0%–13%) in the placebo group. The most common local and systemic reported adverse events were injection site pain and fatigue. No serious adverse events were reported. The SpikoGen®‐booster induced cross‐neutralization of other SARS‐CoV‐2 variants. Irrespective of the primary vaccine course received, SpikoGen® vaccine showed promising effects as both a homologous and heterologous booster dose. This vaccine also had a good safety profile with no vaccine‐associated serious adverse events. On the basis of these results, SpikoGen® vaccine has been approved as a booster dose.
Ability of SpikoGen®, an Advax‐CpG adjuvanted recombinant spike protein vaccine, to induce cross‐neutralising antibodies against SARS‐CoV‐2 variants
Publisher: Wiley
Date: 18-05-2023
DOI: 10.1111/IMM.13661
Abstract: SpikoGen® vaccine is a subunit COVID‐19 vaccine expressed in insect cells comprising recombinant spike protein extracellular domain formulated with Advax‐CpG55.2™ adjuvant. A Phase 2 trial was conducted in 400 adult participants randomised 3:1 to receive two intramuscular doses of SpikoGen® vaccine or saline placebo 3 weeks apart. Some Phase 2 trial participants later enrolled in a separate booster study and received a third dose of SpikoGen® vaccine. This stored serum was used to assess the ability of SpikoGen® vaccine to induce cross‐neutralising antibodies against SARS‐CoV‐2 variants of concern. Sera taken at baseline and 2 weeks after the second vaccine dose from baseline seronegative Phase 2 subjects was evaluated using a panel of spike pseudotype lentivirus neutralisation assays for the ability to cross‐neutralise a wide range of SARS‐CoV‐2 variants, including Omicron BA.1, BA.2 and BA.4/5. Stored s les of subjects who participated in both the 2‐dose Phase 2 trial and a third dose booster trial 6 months later were also analysed for changes in cross‐neutralising antibodies over time and dose. Two weeks after the second dose, sera broadly cross‐neutralised most variants of concern, albeit with titres against Omicron variants being ~10‐fold lower. While Omicron titres fell to low levels 6 months after the second vaccine dose in most subjects, they showed a ~20‐fold rise after the third dose booster, after which there was only a ~2‐3‐fold difference in neutralisation of Omicron and the ancestral strains. Despite being based on the ancestral Wuhan sequence, after two doses, SpikoGen® vaccine induced broadly cross‐neutralising serum antibodies. Titres then reduced over time but were rapidly restored by a third dose booster. This resulted in high neutralisation including against the Omicron variants. This data supports ongoing use of SpikoGen® vaccine for protection against recent SARS‐CoV‐2 Omicron variants.
Multistage vaccines containing outer membrane, type III secretion system and inclusion membrane proteins protects against a Chlamydia genital tract infection and pathology
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.VACCINE.2017.05.063
Abstract: Pathogens with a complex lifecycles can effectively evade host immunity in part due to each developmental stage expressing unique sets of antigens. Multisubunit vaccines incorporating signature antigens reflecting distinct developmental stages (multistage vaccines) have proven effective against viral, bacterial and parasitic infection at preventing pathogen evasion of host immunity. Chlamydia trachomatis is characterized by a biphasic extra/intracellular developmental cycle and an acute ersistent (latent) metabolic state hence a multistage vaccine may prevent immune evasion and enhance clearance. Here we tested the efficacy of a multistage vaccine containing outer membrane (MOMP and PmpG), type three secretion system (T3SS) (CdsF and TC0873) and inclusion membrane proteins (IncA and TC0500) in mice against an intravaginal challenge with Chlamydia muridarum. Comparison of single (eg. MOMP) and double antigen vaccines (eg. MOMP and PmpG), largely targeting the extracellular stage, elicited significant yet comparable protection against vaginal shedding when compared to unimmunized control mice. Utilization of different adjuvants (ISCOMATRIX - IMX, PCEP olyI:C/IDR1002 - VIDO, CTA1-DD and ADVAX) and numerous immunization routes (subcutaneous - SQ and intranasal - IN) further enhanced protection against infection. However, a multistage vaccine elicited significantly greater protection against vaginal shedding and upper genital tract pathology than vaccines targeting only extra- or intracellular stages. This indicates that protection elicited by a vaccine targeting extracellular chlamydial antigens could be improved by including chlamydial antigen expressed during intracellular phase.
Physical characterization and in silico modeling of inulin polymer conformation during vaccine adjuvant particle formation
Publisher: Elsevier BV
Date: 06-2016
Analysis of the hydrolysis of inulin using real time 1H NMR spectroscopy
Publisher: Elsevier BV
Date: 05-2012
Management of dyspnea in advanced pulmonary arterial hypertension.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2010
Identifying SARS-CoV-2 Drugs Binding to the Spike Fatty Acid Binding Pocket Using In Silico Docking and Molecular Dynamics
Publisher: MDPI AG
Date: 20-02-2023
DOI: 10.3390/IJMS24044192
Abstract: Drugs against novel targets are needed to treat COVID-19 patients, especially as SARS-CoV-2 is capable of rapid mutation. Structure-based de novo drug design and repurposing of drugs and natural products is a rational approach to discovering potentially effective therapies. These in silico simulations can quickly identify existing drugs with known safety profiles that can be repurposed for COVID-19 treatment. Here, we employ the newly identified spike protein free fatty acid binding pocket structure to identify repurposing candidates as potential SARS-CoV-2 therapies. Using a validated docking and molecular dynamics protocol effective at identifying repurposing candidates inhibiting other SARS-CoV-2 molecular targets, this study provides novel insights into the SARS-CoV-2 spike protein and its potential regulation by endogenous hormones and drugs. Some of the predicted repurposing candidates have already been demonstrated experimentally to inhibit SARS-CoV-2 activity, but most of the candidate drugs have yet to be tested for activity against the virus. We also elucidated a rationale for the effects of steroid and sex hormones and some vitamins on SARS-CoV-2 infection and COVID-19 recovery.
The chronobiology of human cytokine production.
Publisher: Informa UK Limited
Date: 1998
DOI: 10.3109/08830189809043012
Abstract: Cytokine production in human whole blood exhibits diurnal rhythmicity. Peak production of the pro-inflammatory cytokines IFN-gamma, TNF-alpha, IL-1 and IL-12 occurs during the night and early morning at a time when plasma cortisol is lowest. The existence of a causal relationship between plasma cortisol and production is suggested by the finding that elevation of plasma cortisol within the physiological range by the administration of cortisone acetate results in a corresponding fall in pro-inflammatory cytokine production. Cortisol may not be the only neuroendocrine hormone that entrains cytokine rhythms other candidates include 17-hydroxy progesterone, melatonin and dihydroepiandrostene dione (DHEAS). The finding of diurnal cytokine rhythms may be relevant to understanding why immuno-inflammatory disorders such as rheumatoid arthritis or asthma exhibit night-time or early morning exacerbations and to the optimisation of treatment for these disorders. Diurnal rhythmicity of cytokine production also has implications for the timing of blood s les drawn for diagnostic T-cell assays. Finally, diurnal rhythmicity of immune function suggests that the nature of an immune response, for ex le in response to vaccination, may be modified by the time of day of antigen administration and raises the possibility that immune responses could be therapeutically manipulated by co-administration of immuno-regulatory hormones such as glucocorticoids.
Disproportionality analysis of adverse neurological and psychiatric reactions with the ChAdOx1 (Oxford-AstraZeneca) and BNT162b2 (Pfizer-BioNTech) COVID-19 vaccines in the United Kingdom
Publisher: Cold Spring Harbor Laboratory
Date: 10-2021
DOI: 10.1101/2021.09.28.21264245
Abstract: The information on neurologic or psychiatric adverse reactions to the COVID-19 vaccines is limited. Our objective was to examine the odds of neurological and psychiatric adverse reactions to BNT162b2 (Pfizer-BioNTech) and ChAdOx1 (Oxford-AstraZeneca) COVID-19 vaccines. We analyzed all Adverse Vaccine Reaction reports to the United Kingdom Medicines and Healthcare products Regulatory Agency between December 9, 2020 and June 30, 2021 that mentioned the BNT162b2 or ChAdOx1 vaccines. We compared the rates of adverse neurological and psychiatric reactions with ChAdOx1 to those with BNT162b2. P-values were obtained by a Bonferroni-adjusted Z-test for proportions. As of June 30, 2021, 53.2 M doses of ChAdOx1 and 46.1 M doses of BNT162b2 had been administered. We extracted information from 300,518 distinct reports. The number of in idual adverse neurologic or psychiatric reaction reports were less than 200/M doses administered, except headache which was reported in 1,550 and 395 cases/M doses of ChAdOx1 and BNT162b2, respectively. Compared to BNT162b2, cerebral hemorrhagic or thrombotic events, headaches and migraines, Guillain-Barre syndrome and paresthesias, tremor and freezing, delirium, hallucinations, nervousness, poor sleep quality, and postural dizziness were more frequently reported with ChAdOx1. Reactions more frequently reported with BNT162b2 than ChAdOx1 were Bell’s palsy, facial paralysis, dysgeusia, anxiety, and presyncope or syncope. Significant differences in the neurologic and psychiatric adverse event profiles of the ChAdOx1 and BNT162b2 vaccines may exist, emphasizing the need for additional research. The beneficial and protective effects of the COVID-19 vaccines far outweigh the low potential risk of neurologic and psychiatric reactions.
Unconventional Vaccines: Progress and Challenges
Publisher: OMICS Publishing Group
Date: 2013
Sensitivity of the Elecsys Nucleocapsid Assay for the Detection of Preceding SARS-CoV-2 Infections
Publisher: Oxford University Press (OUP)
Date: 26-07-2022
DOI: 10.1093/OFID/OFAC349
Abstract: Nucleocapsid serological assay sensitivity to identify severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections among vaccinees and for Omicron cases is unclear. In this prospective study, the Elecsys nucleocapsid assay was 89% sensitive in identifying SARS-CoV-2 infections 14–607 days pre–blood collection. Sensitivity was similar when comparing by vaccination status, and in Omicron (vs pre-Omicron) cases.
An Advax-CpG55.2 adjuvanted recombinant hemagglutinin vaccine provides immunity against H7N9 influenza in adult and neonatal mice
Publisher: Elsevier BV
Date: 08-2023
The future of human DNA vaccines
Publisher: Elsevier BV
Date: 12-2012
Intrapulmonary vaccination with delta-inulin adjuvant stimulates non-polarised chemotactic signalling and diverse cellular interaction
Publisher: Elsevier BV
Date: 05-2021
Adjuvant Strategies for More Effective Tuberculosis Vaccine Immunity.
Publisher: MDPI AG
Date: 12-08-2019
DOI: 10.3390/MICROORGANISMS7080255
Abstract: Tuberculosis (TB) caused by Mycobacterium tuberculosis infection is responsible for the most deaths by a single infectious agent worldwide, with 1.6 million deaths in 2017 alone. The World Health Organization, through its “End TB” strategy, aims to reduce TB deaths by 95% by 2035. In order to reach this goal, a more effective vaccine than the Bacillus Calmette-Guerin (BCG) vaccine currently in use is needed. Subunit TB vaccines are ideal candidates, because they can be used as booster vaccinations for in iduals who have already received BCG and would also be safer for use in immunocompromised in iduals in whom BCG is contraindicated. However, subunit TB vaccines will almost certainly require formulation with a potent adjuvant. As the correlates of vaccine protection against TB are currently unclear, there are a variety of adjuvants currently being used in TB vaccines in preclinical and clinical development. This review describes the various adjuvants in use in TB vaccines, their effectiveness, and their proposed mechanisms of action. Notably, adjuvants with less inflammatory and reactogenic profiles that can be administered safely via mucosal routes, may have the biggest impact on future directions in TB vaccine design.
JE-ADVAX vaccine protection against Japanese encephalitis virus mediated by memory B cells in the absence of CD8+ T cells and pre-exposure neutralizing antibody
Publisher: American Society for Microbiology
Date: 15-04-2013
DOI: 10.1128/JVI.03144-12
Abstract: JE-ADVAX is a new, delta inulin-adjuvanted, Japanese encephalitis (JE) candidate vaccine with a strong safety profile and potent immunogenicity that confers efficient immune protection not only against JE virus but also against related neurotropic flaviviruses such as West Nile virus. In this study, we investigated the immunological mechanism of protection by JE-ADVAX vaccine using knockout mice deficient in B cells or CD8 + T cells and poor persistence of neutralizing antibody or by adoptive transfer of immune splenocyte subpopulations. We show that memory B cells induced by JE-ADVAX provide long-lived protection against JE even in the absence of detectable pre-exposure serum neutralizing antibodies and without the requirement of CD8 + T cells. Upon virus encounter, these vaccine-induced memory B cells were rapidly triggered to produce neutralizing antibodies that then protected immunized mice from morbidity and mortality. The findings suggest that the extent of the B-cell memory compartment might be a better immunological correlate for clinical efficacy of JE vaccines than the currently recommended measure of serum neutralizing antibody. This may explain the paradox where JE protection is observed in some subjects even in the absence of detectable serum neutralizing antibody. Our investigation also established the suitability of a novel flavivirus challenge model (β 2 -microglobulin-knockout mice) for studies of the role of B-cell memory responses in vaccine protection.
An inactivated cell culture japanese encephalitis vaccine (JEADVAX) formulated with delta inulin adjuvant provides robust heterologous protection against west nile encephalitis via cross-protective memory B cells and neutralizing antibody
Publisher: American Society for Microbiology
Date: 15-09-2013
DOI: 10.1128/JVI.00480-13
Abstract: West Nile virus (WNV), currently the cause of a serious U.S. epidemic, is a mosquito-borne flavivirus and member of the Japanese encephalitis (JE) serocomplex. There is currently no approved human WNV vaccine, and treatment options remain limited, resulting in significant mortality and morbidity from human infection. Given the availability of approved human JE vaccines, this study asked whether the JE-ADVAX vaccine, which contains an inactivated cell culture JE virus antigen formulated with Advax delta inulin adjuvant, could provide heterologous protection against WNV infection in wild-type and β2-microglobulin-deficient (β2m −/− ) murine models. Mice immunized twice or even once with JE-ADVAX were protected against lethal WNV challenge even when mice had low or absent serum cross-neutralizing WNV titers prior to challenge. Similarly, β2m −/− mice immunized with JE-ADVAX were protected against lethal WNV challenge in the absence of CD8 + T cells and prechallenge WNV antibody titers. Protection against WNV could be adoptively transferred to naive mice by memory B cells from JE-ADVAX-immunized animals. Hence, in addition to increasing serum cross-neutralizing antibody titers, JE-ADVAX induced a memory B-cell population able to provide heterologous protection against WNV challenge. Heterologous protection was reduced when JE vaccine antigen was administered alone without Advax, confirming the importance of the adjuvant to induction of cross-protective immunity. In the absence of an approved human WNV vaccine, JE-ADVAX could provide an alternative approach for control of a major human WNV epidemic.
Immunome Research-Five Years On
Publisher: OMICS Publishing Group
Date: 2011
ALMS1 acts as a critical molecular switch that controls Insulin-stimulated glucose transport in adipocytes
Publisher: Bioscientifica
Date: 18-10-2016
Delta inulin polysaccharide adjuvant enhances the ability of split-virion H5N1 vaccine to protect against lethal challenge in ferrets
Publisher: Elsevier BV
Date: 08-2011
Design and Characterization of Inulin Conjugate for Improved Intracellular and Targeted Delivery of Pyrazinoic Acid to Monocytes
Publisher: MDPI AG
Date: 22-05-2019
DOI: 10.3390/PHARMACEUTICS11050243
Abstract: The propensity of monocytes to migrate into sites of mycobacterium tuberculosis (TB) infection and then become infected themselves makes them potential targets for delivery of drugs intracellularly to the tubercle bacilli reservoir. Conventional TB drugs are less effective because of poor intracellular delivery to this bacterial sanctuary. This study highlights the potential of using semicrystalline delta inulin particles that are readily internalised by monocytes for a monocyte-based drug delivery system. Pyrazinoic acid was successfully attached covalently to the delta inulin particles via a labile linker. The formation of new conjugate and amide bond was confirmed using zeta potential, Proton Nuclear Magnetic Resonance (1HNMR) and Fourier transform infrared spectroscopy (FTIR). Scanning electron microscopy (SEM) confirmed that no significant change in size after conjugation which is an important parameter for monocyte targeting. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were used to establish the change in thermal properties. The analysis of in-vitro release demonstrated pH-triggered drug cleavage off the delta inulin particles that followed a first-order kinetic process. The efficient targeting ability of the conjugate for RAW 264.7 monocytic cells was supported by cellular uptake studies. Overall, our finding confirmed that semicrystalline delta inulin particles (MPI) can be modified covalently with drugs and such conjugates allow intracellular drug delivery and uptake into monocytes, making this system potentially useful for the treatment of TB.
Immunoinformatics and its relevance to understanding human immune disease
Publisher: Informa UK Limited
Date: 05-2005
Developing Translational Vaccines against Heroin and Fentanyl through Investigation of Adjuvants and Stability
Publisher: American Chemical Society (ACS)
Date: 10-12-2020
DOI: 10.1021/ACS.MOLPHARMACEUT.0C00837
Abstract: The nearly insurmountable adversity that accompanies opioid use disorder (OUD) creates life-altering complications for opioid users. To worsen matters, existing small-molecule drugs continue to inadequately address OUD due to their engagement of the opioid receptor, which can leave the user to deal with side effects and financial hardships from their repeated use. An alternative therapeutic approach utilizes endogenously generated antibodies through active vaccination to reduce the effect of opioids without modulating the opioid receptor. Here, we explore different adjuvants and storage conditions to improve opioid vaccine efficacy and shelf life. Our results revealed that inulin-based formulations (Advax) containing a CpG oligodeoxynucleotide (ODN) acted as effective adjuvants when combined with a heroin conjugate: immunized mice showed excellent recovery from heroin-induced antinociception accompanied by high titer, high opioid affinity serum antibodies similar to the immunopotentiating properties of traditional alum-based adjuvants. Moreover, nonhuman primates vaccinated with a heroin/fentanyl combination vaccine demonstrated potent antibody responses against opioids when formulated with both inulin and alum adjuvants. Finally, storing a freeze-dried opioid vaccine formulation maintained efficacy for up 1 year at room temperature. The results from our studies represent an advance toward a clinically feasible opioid vaccine.
Mucosal delivery of a multistage subunit vaccine promotes development of lung-resident memory T cells and affords interleukin-17-dependent protection against pulmonary tuberculosis
Publisher: Springer Science and Business Media LLC
Date: 12-11-2020
DOI: 10.1038/S41541-020-00255-7
Abstract: The development of effective vaccines against bacterial lung infections requires the induction of protective, pathogen-specific immune responses without deleterious inflammation within the pulmonary environment. Here, we made use of a polysaccharide-adjuvanted vaccine approach to elicit resident pulmonary T cells to protect against aerosol Mycobacterium tuberculosis infection. Intratracheal administration of the multistage fusion protein CysVac2 and the delta-inulin adjuvant Advax™ (formulated with a TLR9 agonist) provided superior protection against aerosol M. tuberculosis infection in mice, compared to parenteral delivery. Surprisingly, removal of the TLR9 agonist did not impact vaccine protection despite a reduction in cytokine-secreting T cell subsets, particularly CD4 + IFN-γ + IL-2 + TNF + multifunctional T cells. CysVac2/Advax-mediated protection was associated with the induction of lung-resident, antigen-specific memory CD4 + T cells that expressed IL-17 and RORγT, the master transcriptional regulator of Th17 differentiation. IL-17 was identified as a key mediator of vaccine efficacy, with blocking of IL-17 during M. tuberculosis challenge reducing phagocyte influx, suppressing priming of pathogen-specific CD4 + T cells in local lymph nodes and ablating vaccine-induced protection. These findings suggest that tuberculosis vaccines such as CysVac2/Advax that are capable of eliciting Th17 lung-resident memory T cells are promising candidates for progression to human trials.
Intranasal powder live attenuated influenza vaccine is thermostable, immunogenic, and protective against homologous challenge in ferrets
Publisher: Springer Science and Business Media LLC
Date: 21-04-2021
DOI: 10.1038/S41541-021-00320-9
Abstract: Influenza viruses cause annual seasonal epidemics and sporadic pandemics vaccination is the most effective countermeasure. Intranasal live attenuated influenza vaccines (LAIVs) are needle-free, mimic the natural route of infection, and elicit robust immunity. However, some LAIVs require reconstitution and cold-chain requirements restrict storage and distribution of all influenza vaccines. We generated a dry-powder, thermostable LAIV (T-LAIV) using Preservation by Vaporization technology and assessed the stability, immunogenicity, and efficacy of T-LAIV alone or combined with delta inulin adjuvant (Advax™) in ferrets. Stability assays demonstrated minimal loss of T-LAIV titer when stored at 25 °C for 1 year. Vaccination of ferrets with T-LAIV alone or with delta inulin adjuvant elicited mucosal antibody and robust serum HI responses in ferrets, and was protective against homologous challenge. These results suggest that the Preservation by Vaporization-generated dry-powder vaccines could be distributed without refrigeration and administered without reconstitution or injection. Given these significant advantages for vaccine distribution and delivery, further research is warranted.
An adjuvanted subunit SARS-CoV-2 spike protein vaccine provides protection against Covid-19 infection and transmission
Publisher: Research Square Platform LLC
Date: 21-09-2021
DOI: 10.21203/RS.3.RS-902649/V1
Abstract: Recombinant protein approaches offer major promise for safe and effective vaccine prevention of SARS-CoV-2 infection. We developed a recombinant spike protein vaccine (called NARUVAX-C19) and characterized its ability when formulated with a nanoemulsion adjuvant to induce anti-spike antibody and T-cell responses and provide protection including against viral transmission in rodent. In mice, NARUVAX-C19 vaccine administered intramuscularly twice at 21-day interval elicited balanced Th1/Th2 humoral and T-cell responses with high titers of neutralizing antibodies against wild-type (D614G) and delta (B.1.617.2) variants. In Syrian hamsters, NARUVAX-C19 provided complete protection against wild-type (D614G) infection and prevented its transmission to naïve animals placed in the same cage as challenged animals. The results contrasted with only weak protection seen with a monomeric spike receptor binding domain (RBD) vaccine even when formulated with the same adjuvant. These encouraging results warrant ongoing development of this Covid-19 vaccine candidate.
An Advax-adjuvanted Inactivated Cell-culture Japanese Encephalitis Vaccine Induces Broadly Neutralising Anti-flavivirus Antibodies and T-cell Immunity and Provides Single Dose Protection
Publisher: MDPI AG
Date: 04-10-2021
DOI: 10.20944/PREPRINTS202110.0034.V1
Abstract: ccJE+Advax is an inactivated cell culture Japanese encephalitis (JE) vaccine formulated with Advax& trade , a novel polysaccharide adjuvant based on delta inulin. This vaccine has previously shown promise in murine and equine studies and the current study sought to better understand its mechanism of action and assess the feasibility of single dose vaccine protection. Mice immunised with ccJE-Advax had higher serum neutralisation titres than those immunised with ccJE alone or with alum adjuvant. ccJE+Advax induced extraordinarily broad cross-neutralising antibodies against multiple flaviviruses including West Nile virus (WNV), Murray Valley Encephalitis Virus (MVEV), St Louis Encephalitis virus (SLE) and Dengue-1 and -2 viruses. Notably, the DENV-2 cross-neutralising antibodies from ccJE+Advax immunised mice uniquely had no DENV-2 antibody dependent enhancement (ADE) activity, by contrast to high ADE activity seen with DENV-1 cross-reactive antibodies induced by mbJE or ccJE alone or with alum adjuvant. JEV-stimulated splenocytes from ccJE+Advax immunised mice showed increased IL-17 and IFN-& gamma production, consistent with a mixed Th1 and Th17 response, whereas ccJE-alum was associated with production of mainly Th2 cytokines. There is an ongoing lack of human vaccines against particular flaviviruses, including WNV, SLE and MVEV. Given its ability to provide single-dose JEV protection as well as to induce broadly neutralising antibodies free of ADE activity, ccJE+Advax vaccine could be highly useful in all situations where rapid protection is desirable but ADE needs to be avoided, e.g. during a local outbreak or for use in travellers or the military requiring rapid travel to JEV endemic regions.
Vaxine
Publisher: Informa UK Limited
Date: 31-05-2016
Information technologies for vaccine research.
Publisher: Informa UK Limited
Date: 06-2005
Abstract: Vaccinology is a combinatorial science which studies the ersity of pathogens and the human immune system, and formulations that can modulate immune responses and prevent or cure disease. Huge amounts of data are produced by genomics and proteomics projects and large-scale screening of pathogen-host and antigen-host interactions. Current developments in computational vaccinology mainly support the analysis of antigen processing and presentation and the characterization of targets of immune response. Future development will also include systemic models of vaccine responses. Immunomics, the large-scale screening of immune processes which includes powerful immunoinformatic tools, offers great promise for future translation of basic immunology research advances into successful vaccines.
Aldose Reductase Gene Polymorphism and Diabetic Retinopathy Susceptibility
Publisher: American Diabetes Association
Date: 27-04-2010
DOI: 10.2337/DC09-1893
Abstract: Aldose reductase (ALR) is involved in diabetic microvascular damage via the polyol pathway. A recent meta-analysis found genetic variation in the ALR gene (AKR1B1) to be significantly associated with diabetic retinopathy (DR). We investigated the genetic association of AKR1B1 with DR. The study enrolled 909 in iduals with diabetes. Participants were genotyped for an AKR1B1 (CA)n microsatellite and 14 tag single nucleotide polymorphisms, and ophthalmological assessment was performed. A total of 514 in iduals were found to have DR. rs9640883 was significantly associated with DR (P = 0.0005). However, AKR1B1 variation was not independently associated with DR development after adjusting for relevant clinical parameters. rs9640883 was associated with duration of diabetes (P = 0.002). Many previous reports have failed to account for known risk factors for DR. The commonly reported association of AKR1B1 with DR may be due to an association of the gene with younger age at onset of diabetes.
A M2 protein-based universal influenza vaccine containing Advax-SM adjuvant provides newborn protection via maternal or neonatal immunization
Publisher: Elsevier BV
Date: 08-2021
Macrophage Migration Inhibitory Factor: A Critical Neurohumoral Mediator
Publisher: KARGER
Date: 2001
DOI: 10.1159/000061060
HLA-matched control subjects are essential in studies of susceptibility to IDDM
Publisher: Springer Science and Business Media LLC
Date: 1995
DOI: 10.1007/BF02369368
Novel nanoparticle vaccines for Listeriosis
Publisher: Informa UK Limited
Date: 07-08-2015
Lessons learned from the H1N1 2009 pandemic
Publisher: Informa UK Limited
Date: 10-2010
Genome-wide association studies for diabetic macular edema and proliferative diabetic retinopathy
Publisher: Springer Science and Business Media LLC
Date: 08-05-2018
Whole Blood Assays and the Influence of Circadian Rhythmicity on Human Cytokine Measurement
Publisher: Humana Press
A vaccine targeting the L9 epitope of the malaria circumsporozoite protein confers protection from blood-stage infection in a mouse challenge model
Publisher: Cold Spring Harbor Laboratory
Date: 11-11-2021
DOI: 10.1101/2021.11.10.465032
Abstract: Pre-erythrocytic malaria vaccines that induce high-titer, durable antibody responses can potentially provide protection from infection. Here, we engineered a virus-like particle (VLP)-based vaccine targeting a recently described vulnerable epitope at the N-terminus of the central repeat region of the Plasmodium falciparum circumsporozoite protein (CSP) that is recognized by the potently inhibitory monoclonal antibody L9 and show that immunization with L9 VLPs induces strong antibody responses that provide protection from blood-stage malaria in a mouse infection model.
Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study
Publisher: Springer Science and Business Media LLC
Date: 22-08-2005
Abstract: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study is examining the effects of long-term fibrate therapy on coronary heart disease (CHD) event rates in patients with diabetes mellitus. This article describes the trial's run-in phase and patients' baseline characteristics. FIELD is a double-blind, placebo-controlled trial in 63 centres in 3 countries evaluating the effects of fenofibrate versus placebo on CHD morbidity and mortality in 9795 patients with type 2 diabetes mellitus. Patients were to have no indication for lipid-lowering therapy on randomization, but could start these or other drugs at any time after randomization. Follow-up in the study was to be for a median duration of not less than 5 years and until 500 major coronary events (fatal coronary heart disease plus nonfatal myocardial infarction) had occurred. About 2100 patients (22%) had some manifestation of cardiovascular disease (CVD) at baseline and thus high risk status. Less than 25% of patients without CVD had a (UKPDS determined) calculated 5-year CHD risk of %, but nearly all had a 5-year stroke risk of %. Despite this, half of the cohort were obese (BMI 30), most were men, two-thirds were aged over 60 years, and substantial proportions had NCEP ATP III features of the metabolic syndrome independent of their diabetes, including low HDL (60%), high blood pressure measurement or treatment for hypertension (84%), high waist measurement (68%), and raised triglycerides (52%). After a 6-week run-in period before randomisation with all participants receiving 200 mg comicronized fenofibrate, there were declines in total and LDL cholesterol (10%) and triglycerides (26%) and an increase in HDL cholesterol (6.5%). The study will show the effect of PPAR-alpha agonist action on CHD and other vascular outcomes in patients with type 2 diabetes including substantial numbers with low to moderate CVD risk but with the various components of the metabolic syndrome. The main results of the study will be reported in late 2005.
Cytokine-based human whole blood assay for the detection of antigen-reactive T cells
Publisher: Elsevier BV
Date: 10-1995
DOI: 10.1016/0022-1759(95)00127-V
Abstract: The measurement of cytokines produced by activated T cells refines assessment of cellular immune function and facilitates whole blood T cell assays. The latter approximate conditions in vivo and obviate the need to purify blood mononuclear cells. We have investigated the parameters of the whole blood assay in humans to standardize and optimize the detection of tetanus-specific T cell cytokine responses. Optimal conditions include the use of undiluted whole blood, an incubation time of 36-48 h and a minimum of delay between venesection and incubation of the blood with antigen. Blood should be drawn at a standard time of day to minimize inter-assay variation due to diurnal rhythmicity in cytokine production. Interferon-gamma or interleukin-2 are specific and reliable readouts other cytokines can be measured to further characterize the TH1 and TH2 elements of the T cell responses, although tetanus-stimulated IL-4 production is detected in only a minority of healthy in iduals. The whole blood assay is a potentially valuable tool for assessing cellular immune function and screening for antigen-reactive T cells in humans.
Molecular immunology databases and data repositories.
Publisher: Elsevier BV
Date: 04-2000
DOI: 10.1016/S0022-1759(00)00159-9
Abstract: Over recent years databases have become an extremely important resource for biomedical research. Immunology research is increasingly dependent on access to extensive biological databases to extract existing information, plan experiments, and analyse experimental results. This review describes 15 immunological databases that have appeared over the last 30 years. In addition, important issues regarding database design and the potential for misuse of information contained within these databases are discussed. Access pointers are provided for the major immunological databases and also for a number of other immunological resources accessible over the World Wide Web (WWW).
A vaccine targeting the L9 epitope of the malaria circumsporozoite protein confers protection from blood-stage infection in a mouse challenge model
Publisher: Springer Science and Business Media LLC
Date: 08-03-2022
DOI: 10.1038/S41541-022-00457-1
Abstract: Pre-erythrocytic malaria vaccines that induce high-titer, durable antibody responses can potentially provide protection from infection. Here, we engineered a virus-like particle (VLP)-based vaccine targeting a recently described vulnerable epitope at the N-terminus of the central repeat region of the Plasmodium falciparum circumsporozoite protein that is recognized by the potently inhibitory monoclonal antibody L9 and show that immunization with L9 VLPs induces strong antibody responses that provide protection from blood-stage malaria in a mouse infection model.
Cytokine-Related Genes Identified From the RIKEN Full-Length Mouse cDNA Data Set
Publisher: Cold Spring Harbor Laboratory
Date: 06-2003
DOI: 10.1101/GR.1016503
Abstract: To identify novel cytokine-related genes, we searched the set of 60,770 annotated RIKEN mouse cDNA clones (FANTOM2 clones), using keywords such as cytokine itself or cytokine names (such as interferon, interleukin, epidermal growth factor, fibroblast growth factor, and transforming growth factor). This search produced 108 known cytokines and cytokine-related products such as cytokine receptors, cytokine-associated genes, or their products (enhancers, accessory proteins, cytokine-induced genes). We found 15 clusters of FANTOM2 clones that are candidates for novel cytokine-related genes. These encoded products with strong sequence similarity to guanylate-binding protein (GBP-5), interleukin-1 receptor-associated kinase 2 (IRAK-2), interleukin 20 receptor α isoform 3, a member of the interferon-inducible proteins of the Ifi 200 cluster, four members of the membrane-associated family 1-8 of interferon-inducible proteins, one p27-like protein, and a hypothetical protein containing a Toll/Interleukin receptor domain. All four clones representing novel candidates of gene products from the family contain a novel highly conserved cross-species domain. Clones similar to growth factor-related products included transforming growth factor β-inducible early growth response protein 2 (TIEG-2), TGFβ-induced factor 2, integrin β-like 1, latent TGF-binding protein 4S, and FGF receptor 4B. We performed a detailed sequence analysis of the candidate novel genes to elucidate their likely functional properties.
A single-nucleotide polymorphism in the MicroRNA-146a gene is associated with diabetic nephropathy and sight-threatening diabetic retinopathy in Caucasian patients
Publisher: Springer Science and Business Media LLC
Date: 21-03-2016
DOI: 10.1007/S00592-016-0850-4
Abstract: This study aimed to investigate whether the single-nucleotide polymorphism (SNP) rs2910164 residing within microRNA-146a (miR-146a) is associated with diabetic microvascular complications diabetic nephropathy (DN), proliferative diabetic retinopathy (PDR) or diabetic macular oedema (DME) in either Caucasian patients with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus. Caucasian patients with T1DM (n = 733) or T2DM (n = 2215) were recruited from ophthalmology, renal and endocrine clinics in Australia and the UK. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be on treatment with oral hypoglycaemic drugs or insulin. In total, 890 participants had DN (168 with T1DM and 722 with T2DM), 731 had PDR (251 with T1DM and 480 with T2DM) and 1026 had DME (170 with T1DM and 856 with T2DM). Participants were genotyped for SNP rs2910164 in miR-146a. Analyses investigating association were adjusted for relevant clinical covariates including age, sex, DM duration, HbA1c and hypertension. A significant association was found between the C allele of rs2910164 and DN in the T1DM group (OR 1.93 CI 1.23-3.03 P = 0.004), but no association found in the T2DM group (OR 1.05 CI 0.83-1.32 P = 0.691). In the subset of T2DM patients, the C allele was specifically associated with DME (OR 1.25 CI 1.03-1.53 P = 0.025). No association with DME was found in the T1DM group (OR 0.87 CI 0.54-1.42) P = 0.583), or with PDR for either type of DM. Rs2910164 is significantly associated with microvascular complications DN in patients with T1DM and DME in patients with T2DM.
Advax™, a novel microcrystalline polysaccharide particle engineered from delta inulin, provides robust adjuvant potency together with tolerability and safety
Publisher: Elsevier BV
Date: 11-2015
Immunome research.
Publisher: Springer Science and Business Media LLC
Date: 2005
Use of Artificial Neural Networks in the Prediction of Kidney Transplant Outcomes
Publisher: Springer Berlin Heidelberg
Date: 2004
Vaccine adjuvants: Current state and future trends
Publisher: Wiley
Date: 28-09-2004
DOI: 10.1111/J.0818-9641.2004.01272.X
Abstract: The problem with pure recombinant or synthetic antigens used in modern day vaccines is that they are generally far less immunogenic than older style live or killed whole organism vaccines. This has created a major need for improved and more powerful adjuvants for use in these vaccines. With few exceptions, alum remains the sole adjuvant approved for human use in the majority of countries worldwide. Although alum is able to induce a good antibody (Th2) response, it has little capacity to stimulate cellular (Th1) immune responses which are so important for protection against many pathogens. In addition, alum has the potential to cause severe local and systemic side-effects including sterile abscesses, eosinophilia and myofascitis, although fortunately most of the more serious side-effects are relatively rare. There is also community concern regarding the possible role of aluminium in neurodegenerative diseases such as Alzheimer's disease. Consequently, there is a major unmet need for safer and more effective adjuvants suitable for human use. In particular, there is demand for safe and non-toxic adjuvants able to stimulate cellular (Th1) immunity. Other needs in light of new vaccine technologies are adjuvants suitable for use with mucosally-delivered vaccines, DNA vaccines, cancer and autoimmunity vaccines. Each of these areas are highly specialized with their own unique needs in respect of suitable adjuvant technology. This paper reviews the state of the art in the adjuvant field, explores future directions of adjuvant development and finally examines some of the impediments and barriers to development and registration of new human adjuvants.
Promoter polymorphism at the tumour necrosis factor/lymphotoxin-alpha locus is associated with type of diabetes but not with susceptibility to sight-threatening diabetic retinopathy
Publisher: SAGE Publications
Date: 28-01-2016
Abstract: To investigate, in a large cohort of 2494 in iduals with diabetes mellitus, whether functional single nucleotide polymorphisms in the promoter region of tumour necrosis factor ( TNF) and lymphotoxin-alpha ( LTA) genes are associated with type of diabetes or presence of diabetic retinopathy. A total of 334 type 1 diabetes and 999 type 2 diabetes participants with sight-threatening diabetic retinopathy, and 260 type 1 diabetes and 901 type 2 diabetes participants with no diabetic retinopathy or minimal non-proliferative diabetic retinopathy, were genotyped for two single nucleotide polymorphisms (rs1800629 and rs361525). The A allele of rs1800629 was associated with type 1 diabetes ( p 0.001 odds ratio = 0.62). After adjustment for age, sex, diabetes duration, HbA1c, hypertension and nephropathy, no significant association was found between rs1800629 or rs361525 and sight-threatening diabetic retinopathy. An association between the A allele of rs1800629 and type of diabetes was found. No association was found between two promoter variants of TNF and LTA, and diabetic retinopathy in a large cohort of Caucasian patients with type 1 diabetes and type 2 diabetes.
Rational structure-based drug design
Publisher: Elsevier
Date: 2018
Maternal immunization with adjuvanted RSV prefusion F protein effectively protects offspring from RSV challenge and alters innate and T cell immunity
Publisher: Elsevier BV
Date: 11-2020
Advax, a Delta Inulin Microparticle, Potentiates In-built Adjuvant Property of Co-administered Vaccines
Publisher: Elsevier BV
Date: 02-2017
Adjuvanted Fusion Protein Vaccine Induces Durable Immunity to Onchocerca volvulus in Mice and Non-Human Primates
Publisher: MDPI AG
Date: 06-07-2023
Abstract: Onchocerciasis remains a debilitating neglected tropical disease. Due to the many challenges of current control methods, an effective vaccine against the causative agent Onchocerca volvulus is urgently needed. Mice and cynomolgus macaque non-human primates (NHPs) were immunized with a vaccine consisting of a fusion of two O. volvulus protein antigens, Ov-103 and Ov-RAL-2 (Ov-FUS-1), and three different adjuvants: Advax-CpG, alum, and AlT4. All vaccine formulations induced high antigen-specific IgG titers in both mice and NHPs. Challenging mice with O. volvulus L3 contained within subcutaneous diffusion chambers demonstrated that Ov-FUS-1/Advax-CpG-immunized animals developed protective immunity, durable for at least 11 weeks. Passive transfer of sera, collected at several time points, from both mice and NHPs immunized with Ov-FUS-1/Advax-CpG transferred protection to naïve mice. These results demonstrate that Ov-FUS-1 with the adjuvant Advax-CpG induces durable protective immunity against O. volvulus in mice and NHPs that is mediated by vaccine-induced humoral factors.
Inferring Higher Functional Information for RIKEN Mouse Full-Length cDNA Clones With FACTS
Publisher: Cold Spring Harbor Laboratory
Date: 06-2003
DOI: 10.1101/GR.1019903
Abstract: FACTS (Functional Association/Annotation of cDNA Clones from Text/Sequence Sources) is a semiautomated knowledge discovery and annotation system that integrates molecular function information derived from sequence analysis results (sequence inferred) with functional information extracted from text. Text-inferred information was extracted from keyword-based retrievals of MEDLINE abstracts and by matching of gene or protein names to OMIM, BIND, and DIP database entries. Using FACTS, we found that 47.5% of the 60,770 RIKEN mouse cDNA FANTOM2 clone annotations were informative for text searches. MEDLINE queries yielded molecular interaction-containing sentences for 23.1% of the clones. When disease MeSH and GO terms were matched with retrieved abstracts, 22.7% of clones were associated with potential diseases, and 32.5% with GO identifiers. A significant number (23.5%) of disease MeSH-associated clones were also found to have a hereditary disease association (OMIM Morbidmap). Inferred neoplastic and nervous system disease represented 49.6% and 36.0% of disease MeSH-associated clones, respectively. A comparison of sequence-based GO assignments with informative text-based GO assignments revealed that for 78.2% of clones, identical GO assignments were provided for that clone by either method, whereas for 21.8% of clones, the assignments differed. In contrast, for OMIM assignments, only 28.5% of clones had identical sequence-based and text-based OMIM assignments. Sequence, sentence, and term-based functional associations are included in the FACTS database (facts.gsc.riken.go.jp/), which permits results to be annotated and explored through web-accessible keyword and sequence search interfaces. The FACTS database will be a critical tool for investigating the functional complexity of the mouse transcriptome, cDNA-inferred interactome (molecular interactions), and pathome (pathologies).
Combination Adjuvants Enhance Recombinant Protein Vaccine Protection against Fungal Infection
Publisher: American Society for Microbiology
Date: 31-08-2021
Abstract: Fungal disease remains a challenging clinical and public health problem. Despite medical advances, invasive fungal infections have skyrocketed over the last decade and pose a mounting health threat in immunocompetent and -deficient hosts, with worldwide mortality rates ranking 7th, even ahead of tuberculosis.
Freeing vaccine adjuvants from dangerous immunological dogma.
Publisher: Informa UK Limited
Date: 02-2008
Fat Aussie - A new Alstrom syndrome mouse showing a critical role for ALMS1 in obesity, diabetes, and spermatogenesis
Publisher: The Endocrine Society
Date: 07-2006
DOI: 10.1210/ME.2005-0494
Abstract: Mutations in the human ALMS1 gene are responsible for Alström syndrome, a disorder in which key metabolic and endocrinological features include childhood-onset obesity, metabolic syndrome, and diabetes, as well as infertility. ALMS1 localizes to the basal bodies of cilia and plays a role in intracellular trafficking, but the biological functions of ALMS1 and how these relate to the pathogenesis of obesity, diabetes, and infertility remain unclear. Here we describe a new mouse model of Alström syndrome, fat aussie, caused by a spontaneous mutation in the Alms1 gene. Fat aussie (Alms1 foz/foz) mice are of normal weight when young but, by 120 d of age, they become obese and hyperinsulinemic. Diabetes develops in Alms1 foz/foz mice accompanied by pancreatic islet hyperplasia and islet cysts. Female mice are fertile before the onset of obesity and metabolic syndrome however, male fat aussie mice are sterile due to a progressive germ cell loss followed by an almost complete block of development at the round-to-elongating spermatid stage of spermatogenesis. In conclusion, Alms1 foz/foz mouse is a new animal model in which to study the pathogenesis of the metabolic and fertility defects of Alström syndrome, including the role of ALMS1 in appetite regulation, pathogenesis of the metabolic syndrome, pancreatic islet physiology, and spermatogenesis.
Computational immunology: The coming of age
Publisher: Wiley
Date: 06-2002
DOI: 10.1046/J.1440-1711.2002.01093.X
Abstract: The explosive growth in biotechnology combined with major advances in information technology has the potential to radically transform immunology in the postgenomics era. Not only do we now have ready access to vast quantities of existing data, but new data with relevance to immunology are being accumulated at an exponential rate. Resources for computational immunology include biological databases and methods for data extraction, comparison, analysis and interpretation. Publicly accessible biological databases of relevance to immunologists number in the hundreds and are growing daily. The ability to efficiently extract and analyse information from these databases is vital for efficient immunology research. Most importantly, a new generation of computational immunology tools enables modelling of peptide transport by the transporter associated with antigen processing (TAP), modelling of antibody binding sites, identification of allergenic motifs and modelling of T-cell receptor serial triggering.
Adjuvant selection impacts the correlates of vaccine protection against Ebola infection
Publisher: Elsevier BV
Date: 06-2020
Technologies for enhanced efficacy of DNA vaccines.
Publisher: Informa UK Limited
Date: 02-2012
DOI: 10.1586/ERV.11.188
The Immunomodulatory Role of Adjuvants in Vaccines Formulated with the Recombinant Antigens Ov-103 and Ov-RAL-2 against Onchocerca volvulus in Mice
Publisher: Public Library of Science (PLoS)
Date: 07-07-2016
Comparative 6-Month Wild-Type and Delta-Variant Antibody Levels and Surrogate Neutralization for Adults Vaccinated with BNT162b2 versus mRNA-1273
Publisher: American Society for Microbiology
Date: 27-04-2022
DOI: 10.1128/SPECTRUM.02702-21
Abstract: The BNT162b2 and mRNA-1273 mRNA SARS-CoV-2 vaccines have demonstrated high efficacy for preventing short-term COVID-19. However, comparative long-term effectiveness is unclear, especially pertaining to the Delta variant.
Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene
Publisher: Springer Science and Business Media LLC
Date: 19-07-2015
DOI: 10.1007/S00125-015-3697-2
Abstract: Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study. Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot. The top ranked variant was rs3805931 with p = 2.66 × 10(-7), but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10(-5)) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10(-8)). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina. Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.
TLR2 Agonistic Small Molecules: Detailed Structure–Activity Relationship, Applications, and Future Prospects
Publisher: American Chemical Society (ACS)
Date: 21-12-2020
A Hybrid Decision Tree – Artificial Neural Networks Ensemble Approach for Kidney Transplantation Outcomes Prediction
Publisher: Springer Berlin Heidelberg
Date: 2005
DOI: 10.1007/11552451_16
Human Phase 1 trial of low-dose inactivated seasonal influenza vaccine formulated with Advax™ delta inulin adjuvant
Publisher: Elsevier BV
Date: 07-2016
Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes
Publisher: Springer Science and Business Media LLC
Date: 21-03-2016
DOI: 10.1038/NG.3531
PRED(TAP): a system for prediction of peptide binding to the human transporter associated with antigen processing.
Publisher: Springer Science and Business Media LLC
Date: 2006
BBS-Induced Ciliary Defect Enhances Adipogenesis, Causing Paradoxical Higher-Insulin Sensitivity, Glucose Usage, and Decreased Inflammatory Response
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.CMET.2012.08.005
Abstract: Studying ciliopathies, like the Bardet-Biedl syndrome (BBS), allow the identification of signaling pathways potentially involved in common diseases, sharing phenotypic features like obesity or type 2 diabetes. Given the close association between obesity and insulin resistance, obese BBS patients would be expected to be insulin resistant. Surprisingly, we found that a majority of obese BBS patients retained normal glucose tolerance and insulin sensitivity. Patient's adipose tissue biopsies revealed upregulation of adipogenic genes and decrease of inflammatory mediators. In vitro studies on human primary mesenchymal stem cells (MSCs) showed that BBS12 inactivation facilitated adipogenesis, increased insulin sensitivity, and glucose utilization. We generated a Bbs12(-/-) mouse model to assess the impact of Bbs12 inactivation on adipocyte biology. Despite increased obesity, glucose tolerance was increased with specific enhanced insulin sensitivity in the fat. This correlated with an active recruitment of MSCs resulting in adipose tissue hyperplasia and decreased in inflammation.
Investigation of the biodistribution, breakdown and excretion of delta inulin adjuvant
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.VACCINE.2017.06.045
Abstract: Insoluble, nanostructured delta inulin particles enhance the immunogenicity of co-administered protein antigens and consequently are used as a vaccine adjuvant (Advax™). To better understand their immunomodulatory properties, the in vitro hydrolysis and in vivo distribution of delta inulin particles were investigated. Delta inulin particle hydrolysis under bio-relevant acidic conditions resulted in no observable change to the bulk morphology using SEM, and HPLC results showed that only 6.1% of the inulin was hydrolysed over 21days. However, 65% of the terminal glucose groups were released, showing that acid hydrolysis relatively rapidly releases surface bound chemistries. This was used to explain in vivo biodistribution results in which delta inulin particles surface-labelled with fluorescein-5-thiosemicabizide were administered to mice using intramuscular (I.M.) or subcutaneous (S.C.) routes. Comparison analysis of the fluorescence of soluble inulin in the supernatants of homogenised tissues maintained at room temperature or heated to 100°C to solubilise particulate inulin was used to distinguish between fluorescent probe on soluble inulin and probe bound to inulin within particles. Following both I.M. and S.C. injection delta inulin exhibited a depot behaviour with local injection site residence for several weeks. Over this time, as injection site inulin reduced, there was measurable transport of intact delta inulin particles by macrophages to secondary lymphoid organs and the liver. Ultimately, the injected delta inulin became solubilised resulting in its detection in the plasma and in the urine. Thus injected delta inulin particles are initially taken up by macrophages at the site of injection, trafficked to secondary lymphoid tissue and the liver, and hydrolysed resulting in their becoming soluble and diffusing into the blood stream, from whence they are glomerularly filtered and excreted into the urine. These results provide important insights into the biodistribution of I.M. or S.C. injected delta inulin particles when used as vaccine adjuvants and their method of excretion.
Serological responses following influenza A H1N1 2009 infection in adults
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.JINF.2011.03.002
Abstract: The aim of this study was to determine the humoral immune response to influenza A H1N1 2009 and cross reactivity against seasonal H1N1 and H3N2 strains. Baseline and convalescent sera from 88 subjects with confirmed H1N1 2009 were screened for serological responses by HAI assay. Protective antibody titres to H1N1 2009 were present in 87% post-infection, but varied with age, sex and pregnancy. Some cross reactivity with seasonal influenza strains was observed. Females and pregnant subjects had an attenuated immune response to H1N1 2009 in comparison to the rest of the study population. Antibodies from the serum of H1N1 2009 infected subjects cross reacted with seasonal H1N1 and H3N2 influenza viruses.
Report from the field
Publisher: Informa UK Limited
Date: 07-2012
DOI: 10.4161/HV.19779
Abstract: When the next pandemic emerges, will we be ready? Experts say that the number of animal to human "species jumps" is bound to increase as populations increase and the speed of travel between continents accelerates. Typical pandemic timelines no longer apply.(1) Pandemic H1N1 traveled the world in just weeks, as did SARS, despite major efforts to contain both outbreaks. The danger of emerging infectious disease to global health is compounded by the potential threat for malevolent bioengineering of existing pathogens and their deliberate dissemination.(2)
Rapid development of analytical methods for evaluating pandemic vaccines: a COVID-19 perspective
Publisher: Future Science Ltd
Date: 12-2021
Abstract: Vaccines are key in charting a path out of the COVID-19 pandemic. However, development of new vaccines is highly dependent on availability of analytical methods for their design and evaluation. This paper highlights the challenges presented in having to rapidly develop vaccine analytical tools during an ongoing pandemic, including the need to address progressive virus mutation and adaptation which can render initial assays unreliable or redundant. It also discusses the potential of new computational modeling techniques to model and analyze key viral proteins and their attributes to assist vaccine production and assay design. It then reviews the current range of analytical tools available for COVID-19 vaccine application, ranging from in vitro assays for immunogen characterization to assays to measure vaccine responses in vivo. Finally, it provides a future perspective for COVID-19 vaccine analytical tools and attempts to predict how the field might evolve over the next 5–10 years.
Developmental and reproductive safety of Advax-CpG55.2™ adjuvanted COVID-19 and influenza vaccines in mice
Publisher: Elsevier BV
Date: 09-2023
Advax™, a polysaccharide adjuvant derived from delta inulin, provides improved influenza vaccine protection through broad-based enhancement of adaptive immune responses
Publisher: Elsevier BV
Date: 08-2012
Advax augments B and T cell responses upon influenza vaccination via the respiratory tract and enables complete protection of mice against lethal influenza virus challenge
Publisher: Elsevier BV
Date: 10-2018
Prospects for the prevention and reversal of type 1 diabetes mellitus
Publisher: Springer Science and Business Media LLC
Date: 2002
DOI: 10.2165/00003495-200262180-00005
Abstract: Type 1 (insulin-dependent) diabetes mellitus results from selective immune-mediated destruction of pancreatic islet beta cells. Strategies to prevent or reverse the development of diabetes can be ided into three groups, depending on whether they focus on beta-cell protection, regeneration or replacement. Prevention of immune beta-cell destruction involves either halting the immune attack directed against beta cells or making beta cells better able to withstand immune attack, for ex le, by making them resistant to free radical damage. The recent identification of beta-cell growth factors and development of stem cell technologies provides an alternative route to the reversal of diabetes, namely beta-cell regeneration. Interestingly, stem cell-derived islets appear to be less sensitive to recurrent immune destruction that is normally seen in response to islet transplantation. The last alternative is beta-cell replacement or substitution. This covers a wide range of interventions including human whole pancreas transplantation, xenotransplantation, genetically modified beta cells, mechanical insulin sensing and delivery devices, and the artificial pancreas. This review describes recent advances in each of these research areas and aims to provide clinicians with an idea of where and when an effective strategy to prevent or reverse diabetes development will become available.
Bioinformatics for characterisation of allergens, allergenicity and allergic crossreactivity
Publisher: Elsevier BV
Date: 05-2003
A truncated glycoprotein G vaccine formulated with Advax-CpG adjuvant provides protection of mice against genital herpes simplex virus 2 infection
Publisher: Elsevier BV
Date: 09-2021
Randomized controlled trial demonstrating the benefits of delta inulin adjuvanted immunotherapy in patients with bee venom allergy
Publisher: Elsevier BV
Date: 08-2019
Carbohydrate-based immune adjuvants.
Publisher: Informa UK Limited
Date: 04-2011
DOI: 10.1586/ERV.11.30
Identification and characterisation of T-cell epitopes for incorporation into dendritic cell-delivered Listeria vaccines
Publisher: Elsevier BV
Date: 09-2015
Relationship between DDAH gene variants and serum ADMA level in individuals with type 1 diabetes
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.JDIACOMP.2012.03.022
Abstract: Asymmetric dimethylarginine (ADMA) levels are elevated in diabetes and likely contribute to diabetic complications such as retinopathy and nephropathy. The DDAH enzymes are primarily responsible for ADMA metabolism. Polymorphisms in the dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 genes have been previously associated with serum ADMA levels in type 2 diabetes (T2DM). We sought to determine whether they are also associated with ADMA levels in in iduals with type 1 diabetes (T1DM). Serum ADMA concentrations were measured in 196 in iduals with T1DM. Twenty-six tag SNPs in the DDAH1 gene and 10 in the DDAH2 gene were genotyped. One SNP in the DDAH1 gene (rs3738111) and one in the DDAH2 gene (rs805293) showed a correlation with serum ADMA levels however, neither survived correction for multiple testing. We found limited evidence that genetic polymorphisms in DDAH genes influence serum ADMA levels in in iduals with T1DM. This differs to findings in T2DM and may be due to underlying differences in the cohorts or to fundamental differences in the pathogenesis of the two types of diabetes.
Vaccine Adjuvant Nanotechnologies
Publisher: Elsevier
Date: 2017
MicroRNA-Related Genetic Variants Are Associated With Diabetic Retinopathy in Type 1 Diabetes Mellitus.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 20-09-2019
Abstract: Few studies have explored the association of genetic variants in microRNA genes and binding sites with diabetic retinopathy (DR) in type 1 diabetes. We conducted a genome-wide scan for single nucleotide polymorphisms (SNPs) in these genes by using data from a genome-wide association study (GWAS). All known SNPs were imputed from our GWAS data (n = 325) of DR cases and diabetic controls (no DR). Relevant SNPS were extracted using miRNASNP and PolymiRTS (version 2) databases. χ2 tests and logistic regression (adjusting for age, sex, duration of diabetes, HbA1c, and hypertension) were used to test the association between the imputed SNPs and DR phenotypes (any DR, nonproliferative DR [NPDR], proliferative DR [PDR], diabetic macular edema [DME], and sight-threatening DR defined as PDR, severe NPDR, or clinically significant macula edema [CSME]) compared with diabetic controls. Top-ranking SNPs were genotyped in a larger cohort (N = 560) to confirm their association with DR. Three SNPs (rs10061133, rs1049835, rs9501255) were selected and genotyped in the final cohort. Rs10061133 in MIR449b was protective of sight-threatening DR (odds ratio [OR] = 0.32, P = 3.68 × 10-4) and PDR (OR = 0.30, P = 8.12 × 10-4), and the associations became more significant as the cohort increased in size. Rs10061133 in MIR449b is significantly associated with a decreased risk of PDR and sight-threatening DR in Caucasian patients with type 1 diabetes. This can guide future studies on genetic risk profiling and on developing microRNA-related therapies for sight-threatening DR.
Narrative Review: Obesity, Type 2 DM and Obstructive Sleep Apnoea—Common Bedfellows
Publisher: MDPI AG
Date: 08-08-2022
DOI: 10.3390/DIABETOLOGY3030033
Abstract: Obstructive sleep apnoea (OSA) and type 2 DM mellitus (T2DM) share obesity as a major risk factor. Furthermore, these conditions share overlapping mechanisms including inflammation, activation of the autonomic nervous system, and hypoxia-linked endocrinopathy. Hence, the pathogenesis of the two conditions may be more closely related than previously recognised. This raises the question of whether treatment of OSA might assist resolution of obesity and/or T2DM. Here, we present a narrative review of the literature to identify clinical and scientific data on the relationship between obstructive sleep apnoea and T2DM control. We found there is a paucity of adequately powered well-controlled clinical trials to directly test for a causal association. While routine screening of all T2DM patients with polysomnography cannot currently be justified, given the high prevalence of sleep disordered breathing in the overweight/obese population, all T2DM patients should at a minimum have a clinical assessment of potential obstructive sleep apnoea risk as part of their routine clinical care. In particular, screening questionnaires can be used to identify T2DM subjects at higher risk of OSA for consideration of formal polysomnography studies. Due to morbid obesity being a common feature in both T2DM and OSA, polysomnography should be considered as a screening tool in such high-risk in iduals.
Difficulties and dangers of vaccination strategies for asthma and other autoimmune disorders
Publisher: Elsevier BV
Date: 10-1994
Safety and immunogenicity of a delta inulin-adjuvanted inactivated Japanese encephalitis virus vaccine in pregnant mares and foals
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Temporal regulation of the human immune system
Publisher: Informa UK Limited
Date: 09-2005
Methods for Prediction of Peptide Binding to MHC Molecules: A Comparative Study
Publisher: Springer Science and Business Media LLC
Date: 03-2002
DOI: 10.1007/BF03402006
Dyspnea in Pulmonary Arterial Hypertension
Publisher: InTech
Date: 09-12-2011
DOI: 10.5772/26836
Norovirus drug candidates that inhibit viral capsid attachment to human histo-blood group antigens
Publisher: Elsevier BV
Date: 09-2016
Evidence for the viral aetiology of IDDM.
Publisher: Informa UK Limited
Date: 1997
DOI: 10.3109/08916939708994734
Abstract: Engagement in research misconduct by nurses may results in professional misconduct in the clinical setting, thereby jeopardizing the quality of patient care. We still know little about the research misconduct situation among nurses. Previous attempts also hardly reflected participants' actual knowledge level of research misconduct. This data article presents a novel dataset of a cross-sectional study investigating the research misconduct knowledge level and associated factors among nurses in China. Between March 2018 and March 2021, a national survey was conducted at 200 tertiary hospitals in 25 provinces. A multistage s ling (province, hospital, and participants) was applied and 4,112 nurses were recruited in this study. Participants completed questionnaires online through smartphones scanning a Quick Response (QR) code. The survey consisted of demographic characteristics, research activities, scientific misconduct knowledge, perceived reasons for research misconduct and perceived consequences for research misconduct. Data from 3,640 nurses were reserved in the dataset after data cleaning. This dataset may provide comprehensive information on research misconduct knowledge and associated factors, and important evidence for designing research integrity continuing training for nurses.
Inulin‐derived adjuvants efficiently promote both Th1 and Th2 immune responses
Publisher: Wiley
Date: 12-2004
DOI: 10.1111/J.1440-1711.2004.01290.X
Abstract: There has been a recent resurgence of interest into new and improved vaccine adjuvants. This interest has been stimulated by the need for new vaccines to combat problematic pathogens such as SARS and HIV, and to counter potential bioterrorist attacks. A major bottleneck in vaccine development is the low immunogenicity of purified subunit or recombinant proteins, creating the need for safe human adjuvants with high potency. A major problem in the search for the ideal adjuvant is that adjuvants that promote cell-mediated (Th1) immunity (e.g. Freund's complete adjuvant) generally have unacceptable local or systemic toxicity that precludes their use in human vaccines. There is a need for a safe, non-toxic adjuvant that is able to stimulate both cell-mediated and humoral immunity. Inulin-derived adjuvants that principally stimulate the innate immune system through their ability to activate the alternative complement pathway have proven ability to induce both cellular and humoral immunity. With their excellent tolerability, long shelf-life, low cost and easy manufacture, they offer great potential for use in a broad range of prophylactic and therapeutic vaccines. Based on successful animal studies in a broad range of species, human trials are about to get underway to validate the use of inulin-based adjuvants in prophylactic vaccines against hepatitis B, malaria and other pathogens. If such trials are successful, then it is possible that inulin-derived adjuvants will one day replace alum as the adjuvant of choice in most human prophylactic vaccines.
The Vaccine Renaissance
Publisher: Informa UK Limited
Date: 02-2011
DOI: 10.4161/HV.7.2.14321
A single immunization with inactivated H1N1 influenza vaccine formulated with delta inulin adjuvant (Advax™) overcomes pregnancy-associated immune suppression and enhances passive neonatal protection
Publisher: Elsevier BV
Date: 08-2014
Macrophage migration inhibitory factor exhibits a pronounced circadian rhythm relevant to its role as a glucocorticoid counter‐regulator
Publisher: Wiley
Date: 04-2003
DOI: 10.1046/J.0818-9641.2002.01148.X
Abstract: In humans, maximal expression of T helper 1 cytokines coincide with the nocturnal nadir of plasma cortisol, whereas T helper 2 cytokine responses are dominant during day-time. The pro-inflammatory cytokine, macrophage migration inhibitory factor counter-regulates glucocorticoid-mediated immune suppression. To determine the relationship between cortisol and macrophage migration inhibitory factor, healthy volunteers had blood drawn hourly for 24 h for measurement of plasma cortisol and basal- and stimulated-macrophage migration inhibitory factor. Similar to cortisol, macrophage migration inhibitory factor peaked during the late morning whereas interferon-gamma, tumour necrosis factor-alpha, interleukin-1 and interleukin-12 demonstrated a nocturnal peak. After oral cortisone, plasma macrophage migration inhibitory factor rose 2-4-fold, whereas the other cytokines decreased. There was no correlation between cortisol during the insulin tolerance test and plasma macrophage migration inhibitory factor. The late morning peak of macrophage migration inhibitory factor, by antagonizing cortisol-mediated pro-inflammatory cytokine suppression may prolong the duration of early morning inflammation. These observations explain the beneficial role of macrophage migration inhibitory factor neutralization in models of inflammatory arthritis.
Advax-Adjuvanted Recombinant Protective Antigen Provides Protection against Inhalational Anthrax That Is Further Enhanced by Addition of Murabutide Adjuvant
Publisher: American Society for Microbiology
Date: 04-2014
DOI: 10.1128/CVI.00019-14
Abstract: Subunit vaccines against anthrax based on recombinant protective antigen (PA) potentially offer more consistent and less reactogenic anthrax vaccines but require adjuvants to achieve optimal immunogenicity. This study sought to determine in a murine model of pulmonary anthrax infection whether the polysaccharide adjuvant Advax or the innate immune adjuvant murabutide alone or together could enhance PA immunogenicity by comparison to an alum adjuvant. A single immunization with PA plus Advax adjuvant afforded significantly greater protection against aerosolized Bacillus anthracis Sterne strain 7702 than three immunizations with PA alone. Murabutide had a weaker adjuvant effect than Advax when used alone, but when murabutide was formulated together with Advax, an additive effect on immunogenicity and protection was observed, with complete protection after just two doses. The combined adjuvant formulation stimulated a robust, long-lasting B-cell memory response that protected mice against an aerosol challenge 18 months postimmunization with acceleration of the kinetics of the anamnestic IgG response to B. anthracis as reflected by ∼4-fold-higher anti-PA IgG titers by day 2 postchallenge versus mice that received PA with Alhydrogel. In addition, the combination of Advax plus murabutide induced approximately 3-fold-less inflammation than Alhydrogel as measured by in vivo imaging of cathepsin cleavage resulting from injection of ProSense 750. Thus, the combination of Advax and murabutide provided enhanced protection against inhalational anthrax with reduced localized inflammation, making this a promising next-generation anthrax vaccine adjuvanting strategy.
Immunomodulation with microbial vaccines to prevent type 1 diabetes mellitus
Publisher: Springer Science and Business Media LLC
Date: 03-2010
Abstract: Selected bacteria, viruses, parasites and nonliving, immunologically active microbial substances prevent autoimmune diabetes in animal models. Such agents might also have a protective effect in humans by providing immune stimuli critical during childhood development. The 'hygiene hypothesis' proposes that reduced exposure to environmental stimuli, including microbes, underlies the rising incidence of childhood autoimmune diseases, including type 1 diabetes mellitus (T1DM). This hypothesis is supported by data that highlight the importance of infant exposure to environmental microbes for appropriate development of the immune system, which might explain the observation that administration of microbes or their components inhibits autoimmune disease in animals. This finding raises the possibility of using live, nonpathogenic microbes (for ex le, probiotics) or microbial components to modulate or 're-educate' the immune system and thereby vaccinate against T1DM. Progress has been assisted by the identification of receptors and pathways through which gut microbes influence development of the immune system. Such mechanistic data have moved a field that was once regarded as being on the scientific fringe to the mainstream, and support increased funding to advance this promising area of research in the hope that it might deliver the long awaited answer of how to safely prevent T1DM.
The Role of Fas Ligand in Beta Cell Destruction in Autoimmune Diabetes of NOD Mice
Publisher: Wiley
Date: 04-2002
DOI: 10.1111/J.1749-6632.2002.TB02970.X
Abstract: Fas ligand (FasL), a type 2 membrane protein belonging to the TNF family, plays an important role in the induction of cell death. Ligation of Fas receptors by FasL results in apoptosis of the Fas-expressing cell. Autoimmune diabetes results from beta cell destruction by islet-reactive T cells, a process that involves beta cell apoptosis. This raises the question of whether the FasL-Fas pathway plays a major role in beta cell death. To address this issue it is important to know whether beta cells express Fas and/or FasL and, if so, whether induction of these molecules leads to beta cell death. In fact, both Fas and FasL have been demonstrated to be expressed by beta cells in response to cytokine stimulation, although there remains an argument in the literature as to whether beta cells truly express FasL. This is largely because FasL expression has only been demonstrable by immunohistochemistry and not by flow cytometry. Transgenic NOD mice with beta cells expressing a FasL transgene develop an accelerated form of diabetes. We show here that beta cells from FasL transgenic NOD mice are more susceptible to cytokine-induced apoptosis than wild-type beta cells, consistent with the hypothesis that if beta cells express FasL then Fas-FasL interaction on the beta cell surface is able to mediate beta cell self-death in the absence of T cells. Interventions that block the Fas-FasL pathway may be useful, therefore, in the prevention or treatment of type 1 diabetes.
Development of a nasal vaccine for chronic hepatitis B infection that uses the ability of hepatitis B core antigen to stimulate a strong Th1 response against hepatitis B surface antigen
Publisher: Wiley
Date: 10-2004
DOI: 10.1111/J.0818-9641.2004.01278.X
Abstract: There are estimated to be 350 million chronic carriers of hepatitis B infection worldwide. Patients with chronic hepatitis B are at risk of liver cirrhosis with associated mortality because of hepatocellular carcinoma and other complications. An important goal, therefore, is the development of an effective therapeutic vaccine against chronic hepatitis B virus (HBV). A major barrier to the development of such a vaccine is the impaired immune response to HBV antigens observed in the T cells of affected patients. One strategy to overcome these barriers is to activate mucosal T cells through the use of nasal vaccination because this may overcome the systemic immune downregulation that results from HBV infection. In addition, it may be beneficial to present additional HBV epitopes beyond those contained in the traditional hepatitis B surface antigen (HbsAg) vaccine, for ex le, by using the hepatitis B core antigen (HBcAg). This is advantageous because HBcAg has a unique ability to act as a potent Th1 adjuvant to HbsAg, while also serving as an immunogenic target. In this study we describe the effect of coadministration of HBsAg and HBcAg as part of a strategy to develop a more potent and effective HBV therapeutic vaccine.
An inactivated Vero cell-grown Japanese encephalitis vaccine formulated with Advax, a novel inulin-based adjuvant, induces protective neutralizing antibody against homologous and heterologous flavivir
Publisher: Microbiology Society
Date: 03-02-2010
Randomized clinical trial of immunogenicity and safety of a recombinant H1N1/2009 pandemic influenza vaccine containing Advax™ polysaccharide adjuvant.
Publisher: Elsevier BV
Date: 08-2012
The coming of age of DNA vaccines.
Publisher: Bentham Science Publishers Ltd.
Date: 08-08-2014
Challenges in improving influenza vaccine protection in the elderly.
Publisher: Informa UK Limited
Date: 2011
DOI: 10.1586/ERV.10.153
Delta inulin-derived adjuvants that elicit Th1 phenotype following vaccination reduces respiratory syncytial virus lung titers without a reduction in lung immunopathology
Publisher: Informa UK Limited
Date: 24-05-2016
T-cell receptor signal sequences
Publisher: Elsevier BV
Date: 08-1995
Prevention of Autoimmune Diabetes through Immunostimulation with Q Fever Complement‐Fixing Antigen
Publisher: Wiley
Date: 11-2003
Abstract: The most promising strategies for prevention of type 1 diabetes seem to be in the categories of immunomodulation (e.g., nondepleting anti-CD3, Diapep, linomide) and/or immunostimulation (e.g., QFA, BCG). We are currently undertaking a research program directed toward better understanding of immunostimulants to help maximize the likelihood of success of future human clinical trials for diabetes prevention. This program is focused on the key areas of optimization of vaccine dose and route of administration, development of surrogate immune markers, and elucidation of the mechanism of protection. The mechanism whereby QFA protects against diabetes currently is not known. The elucidation of the mechanism should help identify the optimal way in which to administer QFA to provide diabetes protection. It may also assist the development of even more potent immunostimulatory vaccines.
Assessment of cardiovascular disease risk factors and diabetes mellitus in Australian prisons: is the prisoner population unhealthier than the rest of the Australian population?
Publisher: Elsevier BV
Date: 08-2005
DOI: 10.1111/J.1467-842X.2005.TB00200.X
Abstract: This paper compares the prevalence estimates of diabetes and cardiovascular disease (CVD) risk factors in the Indigenous and non-Indigenous New South Wales (NSW) prisoner population in 1996 and 2001, and also compares the 2001 prevalence estimates with Australian population data. In 1996 and 2001, 789 and 916 prisoners, respectively, in NSW underwent a face-to-face interview covering behavioural risks and physical and mental health. Weight, height and blood pressure were recorded and blood was taken for measurement of cholesterol and random blood sugar. The prevalence of hypertension, hypercholesterolaemia and smoking were lower in the 2001 prison survey as compared with the 1996 survey but the prevalence of smoking was extremely high in both the prison surveys (88% in 1996 and 79% in 2001). There were no differences in the age and sex-adjusted prevalence estimates for any condition except that the prison s le had a higher standardised morbidity ratio for angina than the AusDiab population. This study highlights the high prevalence of CVD risk factors, particularly in younger prisoners, when compared with the Australian non-prison population. Programs should be put in place to routinely screen for chronic disease conditions and to educate Australian prisoners regarding CVD and diabetes risk factors and their long-term management.
Alzheimer’s disease AdvaxCpG- adjuvanted MultiTEP-based dual and single vaccines induce high-titer antibodies against various forms of tau and Aβ pathological molecules
Publisher: Springer Science and Business Media LLC
Date: 07-2016
DOI: 10.1038/SREP28912
Abstract: Although β-amyloid (Aβ) may be the primary driver of Alzheimer’s disease (AD) pathology, accumulation of pathological tau correlates with dementia in AD patients. Thus, the prevention/inhibition of AD may require vaccine/s targeting Aβ and tau simultaneously or sequentially. Since high antibody titers are required for AD vaccine efficacy, we have decided to generate vaccines, targeting Aβ (AV-1959R), Tau (AV-1980R) or Aβ/tau (AV-1953R) B cell epitopes, based on immunogenic MultiTEP platform and evaluate the immunogenicity of these vaccines formulated with Advax CpG , delta inulin, Alhydrogel ® , Montanide- ISA51 , Montanide- ISA720 , MPLA-SM pharmaceutical grade adjuvants. Formulation of AV-1959R in Advax CpG induced the highest cellular and humoral immune responses in mice. The dual-epitope vaccine, AV-1953R, or the combination of AV-1959R and AV-1980R vaccines formulated with Advax CpG induced robust antibody responses against various forms of both, Aβ and tau pathological molecules. While anti-Aβ antibody titers after AV-1953R immunization were similar to that in mice vaccinated with AV-1959R or AV-1959R/AV-1980R combination, anti-tau titers were significantly lower after AV-1953R injection when compared to the AV-1980R or AV-1959R/AV-1980R. In silico 3D-modeling provided insight into the differences in immunogenicity of these vaccine constructs. In sum, AV-1959R and AV-1980R formulated with Advax CpG adjuvant were identified as promising immunogenic vaccines for ongoing pre-clinical assessment and future human clinical trials.
The relationship between the number of COVID-19 vaccines and infection with Omicron ACE2 inhibition at 18-months post initial vaccination in an adult cohort of Canadian paramedics
Publisher: Microbiology Society
Date: 17-10-2023
Synthesis and characterization of a novel inulin hydrogel crosslinked with pyromellitic dianhydride
Publisher: Elsevier BV
Date: 2019
Microfluidic formation of core-shell alginate microparticles for protein encapsulation and controlled release
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.JCIS.2018.12.075
Abstract: Alginate hydrogel particles are promising delivery systems for protein encapsulation and controlled release because of their excellent biocompatibility, biodegradability, and mild gelation process. In this study, a facile microfluidic approach is developed for making uniform core-shell hydrogel microparticles. To address the challenge of protein retention within the alginate gel matrix, poly(ethyleneimine) (PEI)- and chitosan-coated alginate microparticles were fabricated demonstrating improved protein retention as well as controlled release. Furthermore, a model protein ovalbumin was loaded along with delta inulin microparticulate adjuvant into the water-core of the alginate microparticles. Compared to those microparticles with only antigen loaded, the antigen + adjuvant loaded microparticles showed a delayed and sustained release of antigen. This microfluidic approach provides a convenient method for making well-controlled alginate microgel particles with uniform size and controlled properties, and demonstrates the ability to tune the release profiles of proteins by engineering microparticle structure and properties.
Adaptive failure to high-fat diet characterizes steatohepatitis in Alms1 mutant mice
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.BBRC.2006.02.032
Abstract: The biochemical differences between simple steatosis, a benign liver disease, and non-alcoholic steatohepatitis, which leads to cirrhosis, are unclear. Fat aussie is an obese mouse strain with a truncating mutation (foz) in the Alms1 gene. Chow-fed female foz/foz mice develop obesity, diabetes, and simple steatosis. We fed foz/foz and wildtype mice a high-fat diet. Foz/foz mice developed serum ALT elevation and severe steatohepatitis with hepatocyte ballooning, inflammation, and fibrosis wildtype mice showed simple steatosis. Biochemical pathways favoring hepatocellular lipid accumulation (fatty acid uptake lipogenesis) and lipid disposal (fatty acid beta-oxidation triglyceride egress) were both induced by high-fat feeding in wildtype but not foz/foz mice. The resulting extremely high hepatic triglyceride levels were associated with induction of mitochondrial uncoupling protein-2 and adipocyte-specific fatty acid binding protein-2, but not cytochrome P4502e1 or lipid peroxidation. In this model of metabolic syndrome, transition of steatosis to steatohepatitis was associated with hypoadiponectinemia, a mediator of hepatic fatty acid disposal pathways.
Macrophage Migration Inhibitory Factor (MIF): A Critical Neurohumoral Mediator
Publisher: Wiley
Date: 2000
Potential COVID-19 Therapies from Computational Repurposing of Drugs and Natural Products against the SARS-CoV-2 Helicase
Publisher: MDPI AG
Date: 12-07-2022
DOI: 10.3390/IJMS23147704
Abstract: Repurposing of existing drugs is a rapid way to find potential new treatments for SARS-CoV-2. Here, we applied a virtual screening approach using Autodock Vina and molecular dynamic simulation in tandem to screen and calculate binding energies of repurposed drugs against the SARS-CoV-2 helicase protein (non-structural protein nsp13). Amongst the top hits from our study were antivirals, antihistamines, and antipsychotics, plus a range of other drugs. Approximately 30% of our top 87 hits had published evidence indicating in vivo or in vitro SARS-CoV-2 activity. Top hits not previously reported to have SARS-CoV-2 activity included the antiviral agents, cabotegravir and RSV-604 the NK1 antagonist, aprepitant the trypanocidal drug, aminoquinuride the analgesic, antrafenine the anticancer intercalator, epirubicin the antihistamine, fexofenadine and the anticoagulant, dicoumarol. These hits from our in silico SARS-CoV-2 helicase screen warrant further testing as potential COVID-19 treatments.
Recent Advances in Harris Hawks Optimization: A Comparative Study and Applications
Publisher: MDPI AG
Date: 20-06-2022
DOI: 10.3390/ELECTRONICS11121919
Abstract: The Harris hawk optimizer is a recent population-based metaheuristics algorithm that simulates the hunting behavior of hawks. This swarm-based optimizer performs the optimization procedure using a novel way of exploration and exploitation and the multiphases of search. In this review research, we focused on the applications and developments of the recent well-established robust optimizer Harris hawk optimizer (HHO) as one of the most popular swarm-based techniques of 2020. Moreover, several experiments were carried out to prove the powerfulness and effectivness of HHO compared with nine other state-of-art algorithms using Congress on Evolutionary Computation (CEC2005) and CEC2017. The literature review paper includes deep insight about possible future directions and possible ideas worth investigations regarding the new variants of the HHO algorithm and its widespread applications.
In silico comparison of SARS-CoV-2 spike protein-ACE2 binding affinities across species and implications for virus origin
Publisher: Springer Science and Business Media LLC
Date: 24-06-2021
DOI: 10.1038/S41598-021-92388-5
Abstract: The devastating impact of the COVID-19 pandemic caused by SARS–coronavirus 2 (SARS-CoV-2) has raised important questions about its origins and the mechanism of its transfer to humans. A further question was whether companion or commercial animals could act as SARS-CoV-2 vectors, with early data suggesting susceptibility is species specific. To better understand SARS-CoV-2 species susceptibility, we undertook an in silico structural homology modelling, protein–protein docking, and molecular dynamics simulation study of SARS-CoV-2 spike protein’s ability to bind angiotensin converting enzyme 2 (ACE2) from relevant species. Spike protein exhibited the highest binding to human (h)ACE2 of all the species tested, forming the highest number of hydrogen bonds with hACE2. Interestingly, pangolin ACE2 showed the next highest binding affinity despite having a relatively low sequence homology, whereas the affinity of monkey ACE2 was much lower despite its high sequence similarity to hACE2. These differences highlight the power of a structural versus a sequence-based approach to cross-species analyses. ACE2 species in the upper half of the predicted affinity range (monkey, hamster, dog, ferret, cat) have been shown to be permissive to SARS-CoV-2 infection, supporting a correlation between binding affinity and infection susceptibility. These findings show that the earliest known SARS-CoV-2 isolates were surprisingly well adapted to bind strongly to human ACE2, helping explain its efficient human to human respiratory transmission. This study highlights how in silico structural modelling methods can be used to rapidly generate information on novel viruses to help predict their behaviour and aid in countermeasure development.
A Microfluidic Tumor‐on‐a‐Chip for Assessing Multifunctional Liposomes' Tumor Targeting and Anticancer Efficacy
Publisher: Wiley
Date: 14-03-2019
Abstract: Two principal methods for cancer drug testing are widely used, namely, in vitro 2D cell monolayers and in vivo animal models. In vitro 2D culture systems are simple and convenient but are unable to capture the complexity of biological processes. Animal models are costly, time-consuming, and often fail to replicate human activity. Here a microfluidic tumor-on-a-chip (TOC) model designed for assessing multifunctional liposome cancer targeting and efficacy is presented. The TOC device contains three sets of hemispheric wells with different sizes for tumor spheroid formation and evaluation of liposomes under a controlled flow condition. There is good agreement between time-elapsed tumor targeting of fluorescent liposomes in the TOC model and in in vivo mouse models. Evaluation of the anticancer efficacy of four PTX-loaded liposome formulations shows that compared to 2D cell monolayers and 3D tumor spheroid models, the TOC model better predicts the in vivo anticancer efficacy of targeted liposomes. Lastly, the TOC model is used to assess the effects of flow rates and tumor size on treatment outcome. This study demonstrates that the TOC model provides a convenient and powerful platform for rapid and reliable cancer drug evaluation.
Pediatric influenza immunization.
Publisher: Informa UK Limited
Date: 05-2011
DOI: 10.1586/ERV.11.53
Computational tools for the study of allergens
Publisher: Wiley
Date: 17-10-2003
DOI: 10.1034/J.1398-9995.2003.00224.X
Abstract: Allergy is a major cause of morbidity worldwide. The number of characterized allergens and related information is increasing rapidly creating demands for advanced information storage, retrieval and analysis. Bioinformatics provides useful tools for analysing allergens and these are complementary to traditional laboratory techniques for the study of allergens. Specific applications include structural analysis of allergens, identification of B- and T-cell epitopes, assessment of allergenicity and cross-reactivity, and genome analysis. In this paper, the most important bioinformatic tools and methods with relevance to the study of allergy have been reviewed.
Flavivirus DNA Vaccine Design and Adjuvant Selection
Publisher: Springer US
Date: 22-09-2020
Characterisation of adjuvants for use in dromedary immunisation
Publisher: Diva Enterprises Private Limited
Date: 2015
Immunotherapy – 2076. A controlled study of delta inulin-adjuvanted honey bee venom immunotherapy
Publisher: Elsevier BV
Date: 2013
Genetic study of diabetic retinopathy: Recruitment methodology and analysis of baseline characteristics
Publisher: Wiley
Date: 28-10-2014
DOI: 10.1111/CEO.12239
Abstract: Diabetic retinopathy (DR) is a blinding disease of increasing prevalence that is caused by a complex interplay of genetic and environmental factors. Here we describe the patient recruitment methodology, case and control definitions, and clinical characteristics of a study s le to be used for genome-wide association analysis to detect genetic risk variants of DR. One thousand six hundred sixty-nine participants with either type 1 (T1) or type 2 (T2) diabetes mellitus (DM) aged 18 to 95 years were recruited in Australian hospital clinics. In iduals with T2DM had disease duration of at least 5 years and were taking oral hypoglycaemic medication, and/or insulin therapy. Participants underwent ophthalmic examination. Medical history and biochemistry results were collected. Venous blood was obtained for genetic analysis. Six hundred eighty-three diabetic cases (178 T1DM and 505 T2DM participants) with sight-threatening DR, defined as severe non-proliferative DR, proliferative DR or diabetic macular oedema were included in this analysis. Eight hundred twelve in iduals with DM but no DR or minimal non-proliferative DR were recruited as controls (191 with T1DM and 621 with T2DM). The presence of sight-threatening DR was significantly correlated with DM duration, hypertension, nephropathy, neuropathy, HbA1C and body mass index. Diabetic macular oedema was associated with T2DM (P < 0.001), whereas proliferative DR was associated with T1DM (P < 0.001). Adoption of a case-control study design involving extremes of the DR phenotype makes this a suitable cohort, for a well-powered genome-wide association study to detect genetic risk variants for DR.
Advax4 delta inulin combination adjuvant together with ECMX, a fusion construct of four protective mTB antigens, induces a potent Th1 immune response and protects mice against Mycobacterium tubercu
Publisher: Informa UK Limited
Date: 22-09-2017
Identification of pathologs (disease-related genes) from the RIKEN mouse cDNA dataset using human curation plus FACTS, a new biological information extraction system
Publisher: Springer Science and Business Media LLC
Date: 29-04-2004
Influenza immunization during pregnancy: Benefits for mother and infant
Publisher: Informa UK Limited
Date: 05-08-2016
Rationale, design and recruitment characteristics of a large, simple international trial of diabetes prevention: the DREAM trial
Publisher: Springer Science and Business Media LLC
Date: 21-08-2004
DOI: 10.1007/S00125-004-1485-5
Abstract: Diabetes is a rapidly rising independent risk factor for atherosclerosis and serious illness. This risk can be reduced by lifestyle changes and/or various drugs. Novel therapies to prevent diabetes, as well as new risk factors for diabetes, atherosclerosis and obesity require testing and identification. People with impaired fasting glucose or impaired glucose tolerance were randomised to ramipril (15 mg/day) or placebo and rosiglitazone (8 mg/day) or placebo with a 2x2 factorial design. They are assessed semi-annually for the primary outcome (diabetes or death). Diabetes is diagnosed if two consecutive plasma glucose levels exceed diagnostic thresholds (i.e. fasting >/=7.0 mmol/l or 2-h >/=11.1 mmol/l) within a 3-month period. Assuming an annual primary outcome incidence of 5%, there is more than 90% power to detect a 22% reduction. Approximately 20% of participants are having annual carotid ultrasounds to assess the effects on atherosclerosis. Patients screened but not randomised are being followed prospectively to identify determinants of obesity, diabetes and related disorders. A total of 24,872 in iduals in 21 countries were screened over 2 years and are eligible for follow-up. Of these, 5269 were randomised: 1835 (35%) had isolated impaired glucose tolerance, 739 (14%) had isolated impaired fasting glucose, and 2692 (51%) had both disorders. Annual carotid ultrasounds are currently being performed in 1406 randomised in iduals. The DREAM trial and related studies will determine if ramipril or rosiglitazone reduces the number of cases of diabetes and atherosclerosis, and will identify novel risk factors for diabetes.
Elevated Lymphocyte Expression of CLIP Is Associated with Type 1 Diabetes and May Be a Useful Marker of Autoimmune Susceptibility
Publisher: Wiley
Date: 12-2004
Abstract: Type 1 diabetes (T1D) susceptibility in humans and in the non-obese diabetic mouse is linked to MHC class II molecules characterized by an amino acid substitution at position 57 of the beta-chain (nonAspB57). The mechanism whereby nonAspB57 MHC molecules contribute to diabetes susceptibility is not currently known. As CLIP is displaced from MHC class II molecules upon peptide binding, if nonAspB57 haplotypes are associated with high CLIP expression, this may reflect a defect in peptide loading. Non-obese diabetic mice have higher mononuclear cell CLIP expression than non-diabetes prone strains, raising the question of whether humans with T1D also exhibit increased CLIP levels. We therefore sought to test whether subjects with T1D have higher levels of leukocyte CLIP expression. Cell surface expression of CLIP was measured on lymphocytes and monocytes using a FITC-conjugated antibody against human CLIP (Pharmingen). Leukocyte CLIP expression was significantly higher in the blood of T1D patients compared to non-diabetic controls. Increased CLIP expression was not a secondary effect of hyperglycemia as CLIP expression was not increased in subjects with type 2 diabetes. This confirms that elevated CLIP expression is a feature of T1D and may be a useful marker for T1D susceptibility.
Related Organisations
Jahan Naghshe Pardaz Consulting Engineers Co.
Location: Iran (Islamic Republic of)
Related Funding Activities
High-throughput Screening For Novel Adjuvant Discovery For Vaccines Against Influenza Virus
Start Date: 2014
End Date: 2018
Funder: National Institute of Allergy and Infectious Diseases
View Funded ActivityNanotechnology-Enhanced Vaccines: New Inulin Bioconjugates To Defeat Global Pandemic Threats
Start Date: 2008
End Date: 2010
Funder: Australian Research Council
View Funded ActivityMultistage Vaccines For The Prevention Of Tuberculosis
Start Date: 2016
End Date: 2019
Funder: National Health and Medical Research Council
View Funded ActivityCLIP Expression In Type 1 Diabetes
Start Date: 2004
End Date: 2005
Funder: Juvenile Diabetes Research Foundation
View Funded ActivityHigh-throughput Screening For Novel Adjuvant Discovery For Vaccines Against Influenza Virus
Start Date: 2014
End Date: 2018
Funder: National Institute of Allergy and Infectious Diseases
View Funded ActivityEngineering Improved Technology For Nanoparticle-based Adjuvant Manufacture
Start Date: 2014
End Date: 2017
Funder: Australian Research Council
View Funded ActivityMultistage Vaccines For The Prevention Of Tuberculosis
Start Date: 2016
End Date: 2019
Funder: National Health and Medical Research Council
View Funded ActivityNovel Vaccine Adjuvants To Counter Bioterrorist Threats
Start Date: 2005
End Date: 2011
Funder: National Institute of Allergy and Infectious Diseases
View Funded ActivityThe Immunomodulatory Potential Of Natural Killer T Cells
Start Date: 2014
End Date: 2017
Funder: Australian Research Council
View Funded ActivityThe Genetic Study Of Diabetic Eye Disease
Start Date: 2010
End Date: 2012
Funder: National Health and Medical Research Council
View Funded ActivityDrug Targeting To Immune Cells Using Modified Inulin Particles
Start Date: 2015
End Date: 2018
Funder: Australian Research Council
View Funded ActivityLinkage Projects - Grant ID: LP0882596
Start Date: 11-2008
End Date: 02-2012
Amount: $135,000.00
Funder: Australian Research Council
View Funded ActivityLinkage Projects - Grant ID: LP140100920
Start Date: 12-2014
End Date: 06-2018
Amount: $590,922.00
Funder: Australian Research Council
View Funded ActivityLinkage Projects - Grant ID: LP140100142
Start Date: 05-2015
End Date: 06-2019
Amount: $330,000.00
Funder: Australian Research Council
View Funded ActivityIndustrial Transformation Training Centres - Grant ID: IC190100034
Start Date: 12-2020
End Date: 12-2025
Amount: $3,574,272.00
Funder: Australian Research Council
View Funded ActivityLinkage Projects - Grant ID: LP140100424
Start Date: 01-2015
End Date: 04-2019
Amount: $300,000.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE210100163
Start Date: 2021
End Date: 05-2023
Amount: $860,365.00
Funder: Australian Research Council
View Funded Activity