63 results found
Groves HT, McDonald JU, Langat P, et al., 2018, Mouse Models of Influenza Infection with Circulating Strains to Test Seasonal Vaccine Efficacy, FRONTIERS IN IMMUNOLOGY, Vol: 9, ISSN: 1664-3224
Tregoning J, 2018, From parade ground to PI., Science, Vol: 359, Pages: 362-362
Vogel AB, Lambert L, Kinnear E, et al., 2018, Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses., Mol Ther, Vol: 26, Pages: 446-455
New vaccine platforms are needed to address the time gap between pathogen emergence and vaccine licensure. RNA-based vaccines are an attractive candidate for this role: they are safe, are produced cell free, and can be rapidly generated in response to pathogen emergence. Two RNA vaccine platforms are available: synthetic mRNA molecules encoding only the antigen of interest and self-amplifying RNA (sa-RNA). sa-RNA is virally derived and encodes both the antigen of interest and proteins enabling RNA vaccine replication. Both platforms have been shown to induce an immune response, but it is not clear which approach is optimal. In the current studies, we compared synthetic mRNA and sa-RNA expressing influenza virus hemagglutinin. Both platforms were protective, but equivalent levels of protection were achieved using 1.25 μg sa-RNA compared to 80 μg mRNA (64-fold less material). Having determined that sa-RNA was more effective than mRNA, we tested hemagglutinin from three strains of influenza H1N1, H3N2 (X31), and B (Massachusetts) as sa-RNA vaccines, and all protected against challenge infection. When sa-RNA was combined in a trivalent formulation, it protected against sequential H1N1 and H3N2 challenges. From this we conclude that sa-RNA is a promising platform for vaccines against viral diseases.
Astrand A, Wingren C, Benjamin A, et al., 2017, Dapagliflozin-lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 174, Pages: 836-847, ISSN: 0007-1188
Fischetti L, Zhong Z, Pinder CL, et al., 2017, The synergistic effects of combining TLR ligand based adjuvants on the cytokine response are dependent upon p38/JNK signalling, CYTOKINE, Vol: 99, Pages: 287-296, ISSN: 1043-4666
Gould VMW, Francis JN, Anderson KJ, et al., 2017, Nasal IgA provides protection against human influenza challenge in volunteers with low serum influenza antibody titre, Frontiers in Microbiology, Vol: 8, ISSN: 1664-302X
In spite of there being a number of vaccines, influenza remains a significant global cause of morbidity and mortality. Understanding more about natural and vaccine induced immune protection against influenza infection would help to develop better vaccines. Virus specific IgG is a known correlate of protection, but other factors may help to reduce viral load or disease severity, for example IgA. In the current study we measured influenza specific responses in a controlled human infection model using influenza A/California/2009 (H1N1) as the challenge agent. Volunteers were pre-selected with low haemagglutination inhibition (HAI) titres in order to ensure a higher proportion of infection; this allowed us to explore the role of other immune correlates. In spite of HAI being uniformly low, there were variable levels of H1N1 specific IgG and IgA prior to infection. There was also a range of disease severity in volunteers allowing us to compare whether differences in systemic and local H1N1 specific IgG and IgA prior to infection affected disease outcome. H1N1 specific IgG level before challenge did not correlate with protection, probably due to the pre-screening for individuals with low HAI. However, the length of time infectious virus was recovered from the nose was reduced in patients with higher pre-existing H1N1 influenza specific nasal IgA or serum IgA. Therefore, IgA contributes to protection against influenza and should be targeted in vaccines.
Kinnear E, Lambert L, McDonald JU, et al., 2017, Airway T cells protect against RSV infection in the absence of antibody, Mucosal Immunology, Vol: 11, Pages: 249-256, ISSN: 1933-0219
Tissue resident memory T (Trm) cells act as sentinels and early responders to infection. Respiratory syncytial virus (RSV)-specific Trm cells have been detected in the lungs after human RSV infection, but whether they have a protective role is unknown. To dissect the protective function of Trm cells, BALB/c mice were infected with RSV; infected mice developed antigen-specific CD8(+) Trm cells (CD103(+)/CD69(+)) in the lungs and airways. Intranasally transferring cells from the airways of previously infected animals to naïve animals reduced weight loss on infection in the recipient mice. Transfer of airway CD8 cells led to reduced disease and viral load and increased interferon-γ in the airways of recipient mice, while CD4 transfer reduced tumor necrosis factor-α in the airways. Because DNA vaccines induce a systemic T-cell response, we compared vaccination with infection for the effect of memory CD8 cells generated in different compartments. Intramuscular DNA immunization induced RSV-specific CD8 T cells, but they were immunopathogenic and not protective. Notably, there was a marked difference in the induction of Trm cells; infection but not immunization induced antigen-specific Trm cells in a range of tissues. These findings demonstrate a protective role for airway CD8 against RSV and support the need for vaccines to induce antigen-specific airway cells.Mucosal Immunology advance online publication, 24 May 2017; doi:10.1038/mi.2017.46.
Mallia P, Webber J, Gill SK, et al., 2017, Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease., J Allergy Clin Immunol
BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have increased susceptibility to respiratory tract infection, which contributes to disease progression and mortality, but mechanisms of increased susceptibility to infection remain unclear. OBJECTIVES: The aim of this study was to determine whether glucose concentrations were increased in airway samples (nasal lavage fluid, sputum, and bronchoalveolar lavage fluid) from patients with stable COPD and to determine the effects of viral infection on sputum glucose concentrations and how airway glucose concentrations relate to bacterial infection. METHODS: We measured glucose concentrations in airway samples collected from patients with stable COPD and smokers and nonsmokers with normal lung function. Glucose concentrations were measured in patients with experimentally induced COPD exacerbations, and these results were validated in patients with naturally acquired COPD exacerbations. Relationships between sputum glucose concentrations, inflammatory markers, and bacterial load were examined. RESULTS: Sputum glucose concentrations were significantly higher in patients with stable COPD compared with those in control subjects without COPD. In both experimental virus-induced and naturally acquired COPD exacerbations, sputum and nasal lavage fluid glucose concentrations were increased over baseline values. There were significant correlations between sputum glucose concentrations and sputum inflammatory markers, viral load, and bacterial load. Airway samples with higher glucose concentrations supported more Pseudomonas aeruginosa growth in vitro. CONCLUSIONS: Airway glucose concentrations are increased in patients with stable COPD and further increased during COPD exacerbations. Increased airway glucose concentrations might contribute to bacterial infections in both patients with stable and those with exacerbated COPD. This has important implications for the development of nonantibiotic therapeutic stra
McDonald JU, Zhong Z, Groves HT, et al., 2017, Inflammatory responses to influenza vaccination at the extremes of age, IMMUNOLOGY, Vol: 151, Pages: 451-463, ISSN: 0019-2805
Tregoning J, 2017, No researcher is too junior to fix science, NATURE, Vol: 545, Pages: 7-7, ISSN: 0028-0836
Tregoning JS, Russell RF, Kinnear E, 2017, Adjuvanted influenza vaccines., Hum Vaccin Immunother, Pages: 1-15
In spite of current influenza vaccines being immunogenic, evolution of the influenza virus can reduce efficacy and so influenza remains a major threat to public health. One approach to improve influenza vaccines is to include adjuvants; substances that boost the immune response. Adjuvants are particularly beneficial for influenza vaccines administered during a pandemic when a rapid response is required or for use in patients with impaired immune responses, such as infants and the elderly. This review outlines the current use of adjuvants in human influenza vaccines, including what they are, why they are used and what is known of their mechanism of action. To date, six adjuvants have been used in licensed human vaccines: Alum, MF59, AS03, AF03, virosomes and heat labile enterotoxin (LT). In general these adjuvants are safe and well tolerated, but there have been some rare adverse events when adjuvanted vaccines are used at a population level that may discourage the inclusion of adjuvants in influenza vaccines, for example the association of LT with Bell's Palsy. Improved understanding about the mechanisms of the immune response to vaccination and infection has led to advances in adjuvant technology and we describe the experimental adjuvants that have been tested in clinical trials for influenza but have not yet progressed to licensure. Adjuvants alone are not sufficient to improve influenza vaccine efficacy because they do not address the underlying problem of mismatches between circulating virus and the vaccine. However, they may contribute to improved efficacy of next-generation influenza vaccines and will most likely play a role in the development of effective universal influenza vaccines, though what that role will be remains to be seen.
de Silva TI, Gould V, Mohammed NI, et al., 2017, Comparison of mucosal lining fluid sampling methods and influenza-specific IgA detection assays for use in human studies of influenza immunity, JOURNAL OF IMMUNOLOGICAL METHODS, Vol: 449, Pages: 1-6, ISSN: 0022-1759
Badamchi-Zadeh A, McKay PF, Korber BT, et al., 2016, A Multi-Component Prime-Boost Vaccination Regimen with a Consensus MOMP Antigen Enghances Chlamydia trachomatis Clearance, FRONTIERS IN IMMUNOLOGY, Vol: 7, ISSN: 1664-3224
Gill SK, Hui K, Farne H, et al., 2016, Increased airway glucose increases airway bacterial load in hyperglycaemia, Scientific Reports, Vol: 6, ISSN: 2045-2322
Diabetes is associated with increased frequency of hospitalization due to bacterial lung infection.We hypothesize that increased airway glucose caused by hyperglycaemia leads to increasedbacterial loads. In critical care patients, we observed that respiratory tract bacterial colonisationis significantly more likely when blood glucose is high. We engineered mutants in genesaffecting glucose uptake and metabolism (oprB, gltK, gtrS and glk) in Pseudomonas aeruginosa,strain PAO1. These mutants displayed attenuated growth in minimal medium supplemented withglucose as the sole carbon source. The effect of glucose on growth in vivo was tested usingstreptozocin-induced, hyperglycaemic mice, which have significantly greater airway glucose.Bacterial burden in hyperglycaemic animals was greater than control animals when infected withwild type but not mutant PAO1. Metformin pre-treatment of hyperglycaemic animals reducedboth airway glucose and bacterial load. These data support airway glucose as a criticaldeterminant of increased bacterial load during diabetes.
Lambert L, Kinnear E, McDonald JU, et al., 2016, DNA Vaccines Encoding Antigen Targeted to MHC Class II Induce Influenza-Specific CD8(+) T Cell Responses, Enabling Faster Resolution of Influenza Disease, FRONTIERS IN IMMUNOLOGY, Vol: 7, ISSN: 1664-3224
Mann JFS, Tregoning JS, Aldon Y, et al., 2016, CD71 targeting boosts immunogenicity of sublingually delivered influenza haemagglutinin antigen and protects against viral challenge in mice, JOURNAL OF CONTROLLED RELEASE, Vol: 232, Pages: 75-82, ISSN: 0168-3659
McDonald JU, Ekeruche-Makinde J, Ho MM, et al., 2016, Development of a custom pentaplex sandwich immunoassay using Protein-G coupled beads for the Luminex (R) xMAP (R) platform, JOURNAL OF IMMUNOLOGICAL METHODS, Vol: 433, Pages: 6-16, ISSN: 0022-1759
McDonald JU, Kaforou M, Clare S, et al., 2016, A Simple Screening Approach To Prioritize Genes for Functional Analysis Identifies a Role for Interferon Regulatory Factor 7 in the Control of Respiratory Syncytial Virus Disease, MSYSTEMS, Vol: 1, ISSN: 2379-5077
Porter JD, Watson J, Roberts LR, et al., 2016, Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium, JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, Vol: 71, Pages: 2767-2781, ISSN: 0305-7453
Russell RF, McDonald JU, Lambert L, et al., 2016, Use of the Microparticle Nanoscale Silicon Dioxide as an Adjuvant To Boost Vaccine Immune Responses against Influenza Virus in Neonatal Mice, JOURNAL OF VIROLOGY, Vol: 90, Pages: 4735-4744, ISSN: 0022-538X
Badamchi-Zadeh A, McKay PF, Holland MJ, et al., 2015, Intramuscular Immunisation with Chlamydial Proteins Induces Chlamydia trachomatis Specific Ocular Antibodies, PLOS ONE, Vol: 10, ISSN: 1932-6203
Kinnear E, Caproni LJ, Tregoning JS, 2015, A Comparison of Red Fluorescent Proteins to Model DNA Vaccine Expression by Whole Animal In Vivo Imaging, PLOS ONE, Vol: 10, ISSN: 1932-6203
Mastelic Gavillet B, Eberhardt CS, Auderset F, et al., 2015, MF59 Mediates Its B Cell Adjuvanticity by Promoting T Follicular Helper Cells and Thus Germinal Center Responses in Adult and Early Life., Journal of Immunology, Vol: 194, Pages: 4836-4845, ISSN: 0022-1767
The early life influenza disease burden calls for more effective vaccines to protect this vulnerable population. Influenza vaccines including the MF59 oil-in-water adjuvant induce higher, broader, and more persistent Ab responses in adults and particularly in young, through yet undefined mechanisms. In this study, we show that MF59 enhances adult murine IgG responses to influenza hemagglutinin (HA) by promoting a potent T follicular helper cells (TFH) response, which directly controls the magnitude of the germinal center (GC) B cell response. Remarkably, this enhancement of TFH and GC B cells is already fully functional in 3-wk-old infant mice, which were fully protected by HA/MF59 but not HA/PBS immunization against intranasal challenge with the homologous H1N1 (A/California/7/2009) strain. In 1-wk-old neonatal mice, MF59 recruits and activates APCs, efficiently induces CD4(+) effector T cells and primes for enhanced infant responses but induces few fully functional TFH cells, which are mostly follicular regulatory T cells, and poor GC and anti-HA responses. The B cell adjuvanticity of MF59 appears to be mediated by the potent induction of TFH cells which directly controls GC responses both in adult and early life, calling for studies assessing its capacity to enhance the efficacy of influenza immunization in young infants.
Russell RF, McDonald JU, Ivanova M, et al., 2015, Partial Attenuation of Respiratory Syncytial Virus with a Deletion of a Small Hydrophobic Gene Is Associated with Elevated Interleukin-1 beta Responses, JOURNAL OF VIROLOGY, Vol: 89, Pages: 8974-8981, ISSN: 0022-538X
Siggins MK, Gill SK, Langford PR, et al., 2015, PHiD-CV induces anti-Protein D antibodies but does not augment pulmonary clearance of nontypeable Haemophilus influenzae in mice, VACCINE, Vol: 33, Pages: 4954-4961, ISSN: 0264-410X
Veazey RS, Siddiqui A, Klein K, et al., 2015, Evaluation of mucosal adjuvants and immunization routes for the induction of systemic and mucosal humoral immune responses in macaques, HUMAN VACCINES & IMMUNOTHERAPEUTICS, Vol: 11, Pages: 2913-2922, ISSN: 2164-5515
Harker JA, Yamaguchi Y, Culley FJ, et al., 2014, Delayed Sequelae of Neonatal Respiratory Syncytial Virus Infection Are Dependent on Cells of the Innate Immune System, JOURNAL OF VIROLOGY, Vol: 88, Pages: 604-611, ISSN: 0022-538X
Tregoning JS, Kinnear E, 2014, Using Plasmids as DNA Vaccines for Infectious Diseases.
DNA plasmids can be used to induce a protective (or therapeutic) immune response by delivering genes encoding vaccine antigens. That naked DNA (without the refinement of coat proteins or host evasion systems) can cross from outside the cell into the nucleus and be expressed is particularly remarkable given the sophistication of the immune system in preventing infection by pathogens. As a result of the ease, low cost, and speed of custom gene synthesis, DNA vaccines dangle a tantalizing prospect of the next wave of vaccine technology, promising individual designer vaccines for cancer or mass vaccines with a rapid response time to emerging pandemics. There is considerable enthusiasm for the use of DNA vaccination as an approach, but this enthusiasm should be tempered by the successive failures in clinical trials to induce a potent immune response. The technology is evolving with the development of improved delivery systems that increase expression levels, particularly electroporation and the incorporation of genetically encoded adjuvants. This review will introduce some key concepts in the use of DNA plasmids as vaccines, including how the DNA enters the cell and is expressed, how it induces an immune response, and a summary of clinical trials with DNA vaccines. The review also explores the advances being made in vector design, delivery, formulation, and adjuvants to try to realize the promise of this technology for new vaccines. If the immunogenicity and expression barriers can be cracked, then DNA vaccines may offer a step change in mass vaccination.
Walters AA, Kinnear E, Shattock RJ, et al., 2014, Comparative analysis of enzymatically produced novel linear DNA constructs with plasmids for use as DNA vaccines, Gene Therapy, Vol: 21, Pages: 645-652, ISSN: 1476-5462
Everitt AR, Clare S, McDonald JU, et al., 2013, Defining the Range of Pathogens Susceptible to Ifitm3 Restriction Using a Knockout Mouse Model, PLOS ONE, Vol: 8, ISSN: 1932-6203
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.