Jenner Institute

Oxford, United Kingdom

Jenner Institute

Oxford, United Kingdom

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PubMed | Max Planck Genome Center, University of Bath, University of Oxford, University of Würzburg and Jenner Institute
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2016

Staphylococcus aureus is a major bacterial pathogen, which causes severe blood and tissue infections that frequently emerge by autoinfection with asymptomatically carried nose and skin populations. However, recent studies report that bloodstream isolates differ systematically from those found in the nose and skin, exhibiting reduced toxicity toward leukocytes. In two patients, an attenuated toxicity bloodstream infection evolved from an asymptomatically carried high-toxicity nasal strain by loss-of-function mutations in the gene encoding the transcription factor repressor of surface proteins (rsp). Here, we report that rsp knockout mutants lead to global transcriptional and proteomic reprofiling, and they exhibit the greatest signal in a genome-wide screen for genes influencing S. aureus survival in human cells. This effect is likely to be mediated in part via SSR42, a long-noncoding RNA. We show that rsp controls SSR42 expression, is induced by hydrogen peroxide, and is required for normal cytotoxicity and hemolytic activity. Rsp inactivation in laboratory- and bacteremia-derived mutants attenuates toxin production, but up-regulates other immune subversion proteins and reduces lethality during experimental infection. Crucially, inactivation of rsp preserves bacterial dissemination, because it affects neither formation of deep abscesses in mice nor survival in human blood. Thus, we have identified a spontaneously evolving, attenuated-cytotoxicity, nonhemolytic S. aureus phenotype, controlled by a pleiotropic transcriptional regulator/noncoding RNA virulence regulatory system, capable of causing S. aureus bloodstream infections. Such a phenotype could promote deep infection with limited early clinical manifestations, raising concerns that bacterial evolution within the human body may contribute to severe infection.


Jegerlehner A.,Cytos Biotechnology AG | Zabel F.,Cytos Biotechnology AG | Zabel F.,University of Zürich | Langer A.,Cytos Biotechnology AG | And 6 more authors.
PLoS ONE | Year: 2013

Although current influenza vaccines are effective in general, there is an urgent need for the development of new technologies to improve vaccine production timelines, capacities and immunogenicity. Herein, we describe the development of an influenza vaccine technology which enables recombinant production of highly efficient influenza vaccines in bacterial expression systems. The globular head domain of influenza hemagglutinin, comprising most of the protein's neutralizing epitopes, was expressed in E. coli and covalently conjugated to bacteriophage-derived virus-like particles produced independently in E.coli. Conjugate influenza vaccines produced this way were used to immunize mice and found to elicit immune sera with high antibody titers specific for the native influenza hemagglutinin protein and high hemagglutination-inhibition titers. Moreover vaccination with these vaccines induced full protection against lethal challenges with homologous and highly drifted influenza strains. © 2013 Jegerlehner et al.


Tregoning J.S.,Imperial College London | Buffa V.,Cell Medica | Oszmiana A.,Manchester Collaborative Center for Inflammation Research | Klein K.,Imperial College London | And 2 more authors.
PLoS ONE | Year: 2013

One potential strategy for the prevention of HIV infection is to induce virus specific mucosal antibody that can act as an immune barrier to prevent transmission. The mucosal application of chemokines after immunisation, termed "prime-pull", has been shown to recruit T cells to mucosal sites. We wished to determine whether this strategy could be used to increase B cells and antibody in the vaginal mucosa following immunisation with an HIV antigen. BALB/c mice were immunised intranasally with trimeric gp140 prior to vaginal application of the chemokine CCL28 or the synthetic TLR4 ligand MPLA, without antigen six days later. There was no increase in vaginal IgA, IgG or B cells following the application of CCL28, however vaginal application of MPLA led to a significant boost in antigen specific vaginal IgA. Follow up studies to investigate the effect of the timing of the "pull" stimulation demonstrated that when given 14 days after the initial immunisation MPLA significantly increased systemic antibody responses. We speculate that this may be due to residual inflammation prior to re-immunisation. Overall we conclude that in contrast to the previously observed effect on T cells, the use of "prime-pull" has only a modest effect on B cells and antibody. © 2013 Tregoning et al.


News Article | January 20, 2016
Site: www.biosciencetechnology.com

An interdisciplinary team of Oxford University researchers has devised a new technique to speed up the development of novel vaccines. Many vaccines are based around virus-like particles (VLPs). VLPs resemble viruses, but importantly don't carry pathogenic genetic material and thus cannot cause disease. These particles are engineered to display one part of a pathogen to the immune system, which can elicit strong protection upon any subsequent exposure to that pathogen. Karl Brune, leading the work in Professor Mark Howarth's lab in Oxford’s Department of Biochemistry explained: 'Current techniques to develop VLP-based vaccines take time and do not always work. Whilst getting the pathogen parts to stick to the carrier VLP, often problems such as misassembly or misfolding arise that make the vaccine ineffective at generating protective immunity.' This failure rate translates into high development costs in trying to create vaccines against major diseases such as malaria, HIV and cancer. 'A more reliable way of assembling candidate vaccines could make them much cheaper and improve the chances of vaccines against these illnesses. A faster way of assembling vaccines may also help with the rapid development of new vaccines against unforeseen disease outbreaks.', said Dr. Darren Leneghan, leading the immunisation work with Dr. Sumi Biswas and Professor Simon Draper in Oxford's Jenner Institute, which specialises in vaccine development. Karl Brune’s work has now overcome this key challenge in vaccine assembly using the lab's 'bacterial superglue'. This glue is made of two parts, a larger protein called SpyCatcher and a smaller protein part named SpyTag, both engineered from the bacterium Streptococcus pyogenes. When SpyTag and SpyCatcher meet, they form an unbreakable bond. The team succeeded in biologically encoding SpyCatcher on VLPs, which now enables scientists and engineers easily and relatively quickly to glue proteins with the small SpyTag to the SpyCatcher-VLPs. Karl Brune said: ‘We tested the SpyCatcher-VLP – SpyTag-antigen combination using a range of malarial and cancer-relevant antigens. This showed that linking can be done simply and quickly to produce stable vaccines that generated robust antibody responses. 'We need to do more research, both to see if we can use Tag/Catcher fusion with other diseases and to test effectiveness in live rather than lab conditions.' The team say that their technique should speed up developing new vaccines and also may help other medical applications of nanoparticles.


Many vaccines are based around virus-like particles (VLPs). VLPs resemble viruses, but importantly don't carry pathogenic genetic material and thus cannot cause disease. These particles are engineered to display one part of a pathogen to the immune system, which can elicit strong protection upon any subsequent exposure to that pathogen. Karl Brune, leading the work in Professor Mark Howarth's lab in Oxford's Department of Biochemistry explained: 'Current techniques to develop VLP-based vaccines take time and do not always work. Whilst getting the pathogen parts to stick to the carrier VLP, often problems such as misassembly or misfolding arise that make the vaccine ineffective at generating protective immunity.' This failure rate translates into high development costs in trying to create vaccines against major diseases such as malaria, HIV and cancer. 'A more reliable way of assembling candidate vaccines could make them much cheaper and improve the chances of vaccines against these illnesses. A faster way of assembling vaccines may also help with the rapid development of new vaccines against unforeseen disease outbreaks.', says Dr Darren Leneghan, leading the immunisation work with Dr Sumi Biswas and Professor Simon Draper in Oxford's Jenner Institute, which specialises in vaccine development. Karl Brune's work has now overcome this key challenge in vaccine assembly using the lab's 'bacterial superglue'. This glue is made of two parts, a larger protein called SpyCatcher and a smaller protein part named SpyTag, both engineered from the bacterium Streptococcus pyogenes. When SpyTag and SpyCatcher meet, they form an unbreakable bond. The team succeeded in biologically encoding SpyCatcher on VLPs, which now enables scientists and engineers easily and relatively quickly to glue proteins with the small SpyTag to the SpyCatcher-VLPs. Karl Brune said: 'We tested the SpyCatcher-VLP – SpyTag-antigen combination using a range of malarial and cancer-relevant antigens. This showed that linking can be done simply and quickly to produce stable vaccines that generated robust antibody responses. 'We need to do more research, both to see if we can use Tag/Catcher fusion with other diseases and to test effectiveness in live rather than lab conditions.' The team say that their technique should speed up developing new vaccines and also may help other medical applications of nanoparticles. Explore further: Combination vaccine protects monkeys from ebola and Marburg viruses More information: Karl D. Brune et al. Plug-and-Display: decoration of Virus-Like Particles via isopeptide bonds for modular immunization, Scientific Reports (2016). DOI: 10.1038/srep19234


PubMed | Roslin Institute, University of Nottingham, The Pirbright Institute and Jenner Institute
Type: | Journal: BMC genomics | Year: 2016

Campylobacter is the leading cause of foodborne diarrhoeal illness in humans and is mostly acquired from consumption or handling of contaminated poultry meat. In the absence of effective licensed vaccines and inhibitors, selection for chickens with increased resistance to Campylobacter could potentially reduce its subsequent entry into the food chain. Campylobacter intestinal colonisation levels are influenced by the host genetics of the chicken. In the present study, two chicken populations were used to investigate the genetic architecture of avian resistance to colonisation: (i) a back-cross of two White Leghorn derived inbred lines [(61 x N) x N] known to differ in resistance to Campylobacter colonisation and (ii) a 9(th) generation advanced intercross (61 x N) line.The level of colonisation with Campylobacter jejuni following experimental infection was found to be a quantitative trait. A back-cross experiment using 1,243 fully informative single nucleotide polymorphism (SNP) markers revealed quantitative trait loci (QTL) on chromosomes 7, 11 and 14. In the advanced intercross line study, the location of the QTL on chromosome 14 was confirmed and refined and two new QTLs were identified located on chromosomes 4 and 16. Pathway and re-sequencing data analysis of the genes located in the QTL candidate regions identified potential pathways, networks and candidate resistance genes. Finally, gene expression analyses were performed for some of the candidate resistance genes to support the results.Campylobacter resistance in chickens is a complex trait, possibly involving the Major Histocompatibility Complex, innate and adaptive immune responses, cadherins and other factors. Two of the QTLs for Campylobacter resistance are co-located with Salmonella resistance loci, indicating that it may be possible to breed simultaneously for enhanced resistance to both zoonoses.


Warimwe G.M.,Kenya Medical Research Institute | Warimwe G.M.,Jenner Institute | Fegan G.,Kenya Medical Research Institute | Fegan G.,University of Oxford | And 12 more authors.
Science Translational Medicine | Year: 2012

PfEMP1 is a family of cytoadhesive surface antigens expressed on erythrocytes infected with Plasmodium falciparum, the parasite that causes the most severe form of malaria. These surface antigens play a role in immune evasion and are thought to contribute to the pathogenesis of the malaria parasite. Previous studies have suggested a role for a specific subset of PfEMP1 called "group A" in severe malaria. To explore the role of group A PfEMP1 in disease, we measured the expression of the var genes that encode them in parasites from clinical isolates collected from children suffering from malaria. We also looked at the ability of these clinical isolates to induce rosetting of erythrocytes, which indicates a cytoadhesion phenotype that is thought to be important in pathogenesis. These two sets of data were correlated with the presence of two life-threatening manifestations of severe malaria in the children: impaired consciousness and respiratory distress. Using regression analysis, we show that marked rosetting was associated with respiratory distress, whereas elevated expression of group A-like var genes without elevated rosetting was associated with impaired consciousness. The results suggest that manifestations of malarial disease may reflect the distribution of cytoadhesion phenotypes expressed by the infecting parasite population.


Meyer J.,Jenner Institute | McShane H.,Jenner Institute
Expert Review of Vaccines | Year: 2013

The control of TB is a global health priority. Over the last decade, considerable progress has been made in the field of TB vaccines with numerous vaccine candidates entering the clinic and two candidates now in Phase IIb efficacy trials. Nevertheless, the lack of predictive animal models and biomarkers of TB vaccine efficacy prevents rational vaccine down-selection and necessitates prolonged and expensive clinical efficacy trials in target populations. Advances in molecular technology and progress in the development of human as well as animal mycobacterial challenge models make the identification of one or more immune correlates of protection a genuine prospect over the next decade. Moreover, the increasing pace, extent and coordination of global research efforts in TB promises to broaden understanding and inform the next generation of vaccine candidates against TB as well as related globally important pathogens. © 2013 2013 Expert Reviews Ltd.


Harris S.A.,Jenner Institute | Meyer J.,Jenner Institute | Satti I.,Jenner Institute | Marsay L.,Jenner Institute | And 5 more authors.
Journal of Infectious Diseases | Year: 2014

Background. A new vaccine is urgently needed to combat tuberculosis. However, without a correlate of protection, selection of the vaccines to take forward into large-scale efficacy trials is difficult. Use of bacille Calmette-Guérin (BCG) as a surrogate for human Mycobacterium tuberculosis challenge is a novel model that could aid selection.Methods. Healthy adults were assigned to groups A and B (BCG-naive) or groups C and D (BCG-vaccinated). Groups B and D received candidate tuberculosis vaccine MVA85A. Participants were challenged with intradermal BCG 4 weeks after those who received MVA85A. Skin biopsies of the challenge site were taken 2 weeks post challenge and BCG load quantified by culture and quantitative polymerase chain reaction (qPCR).Results. Volunteers with a history of BCG showed some degree of protective immunity to challenge, having lower BCG loads compared with volunteers without prior BCG, regardless of MVA85A status. There was a significant inverse correlation between antimycobacterial immunity at peak response after MVA85A and BCG load detected by qPCR.Conclusion. Our results support previous findings that this BCG challenge model is able to detect differences in antimycobacterial immunity induced by vaccination and could aid in the selection of candidate tuberculosis vaccines for field efficacy testing.Clinical Trials Registration NCT01194180. © 2013 The Author 2013.


Replication defective adenoviruses are promising vectors for the delivery of vaccine antigens. However, the potential of a vector to elicit transgene-specific adaptive immune responses is largely dependent on the viral serotype used. HAdV-5 (Human adenovirus C) vectors are more immunogenic than chimpanzee adenovirus vectors from species Human adenovirus E (ChAdOx1 and AdC68) in mice, though the mechanisms responsible for these differences in immunogenicity remain poorly understood. In this study, superior immunogenicity was associated with markedly higher levels of transgene expression in vivo, particularly within draining lymph nodes. To investigate the viral factors contributing to these phenotypes, we generated recombinant ChAdOx1 vectors by exchanging components of the viral capsid reported to be principally involved in cell entry with the corresponding sequences from HAdV-5. Remarkably, pseudotyping with the HAdV-5 fiber and/or penton RGD loop had little to no effect on in vivo transgene expression or transgene-specific adaptive immune responses despite considerable species-specific sequence heterogeneity in these components. Our results suggest that mechanisms governing vector transduction after intramuscular administration in mice may be different from those described in vitro.

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