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Publication
Featured researches published by Gerd Lipowsky.
European Journal of Immunology | 2002
Andrea Jegerlehner; Tazio Storni; Gerd Lipowsky; Markus Schmid; Paul Pumpens; Martin F. Bachmann
Epitope density and organization have been shown to be important factors for B cell activation in many animal model systems. However, it has been difficult to separate the role of antigen organization from the role of local antigen concentrations because highly organized antigens are usually particulate whereas non‐organized antigens are more soluble. Hence, highly organized and non‐organized antigens may interact with different cell types and in different locations within lymphoid organs. In order to assess the role of antigen organization in regulating B cell responses, we immunized mice with highly repetitive virus‐like particles, which exhibit different epitope densities covalently attached to them. Therefore, the same particulate structure was used to present identical epitopes that differed in their degree of organization. Induction of epitope‐specific IgM titers, reflecting early B cell activation, were unaffected by the degree of epitope density. Furthermore, the absence of Th cells or CD21/CD35 did not reduce the IgM response. In contrast, the degree of organization was a critical factor influencing the magnitude of the epitope‐specific IgG response. Moreover, the threshold for IgG responses was shifted in the absence of CD21/CD35, resulting in the requirement for higher epitope densities to allow efficient IgG responses. Thus, IgG but not IgM responses are regulated by epitope density and B cell costimulatory thresholds.
The Journal of Infectious Diseases | 2014
Michael J. Wacker; Linhui Wang; Meghan Dowd; Gerd Lipowsky; Amir Faridmoayer; Kelly Shields; Saeyoung Park; Cristina Alaimo; Kathryn A. Kelley; Martin Braun; Julien Quebatte; Veronica Gambillara; Paula Carranza; Michael Steffen; Jean C. Lee
BACKGROUND Staphylococcus aureus is a leading cause of superficial and invasive human disease that is often refractory to antimicrobial therapy. Vaccines have the potential to reduce the morbidity, mortality, and economic impact associated with staphylococcal infections. However, single-component vaccines targeting S. aureus have failed to show efficacy in clinical trials. METHODS A novel glycoengineering technology for creation of a multicomponent staphylococcal vaccine is described. Genes encoding S. aureus capsular polysaccharide (CP) biosynthesis, PglB (a Campylobacter oligosaccharyl transferase), and a protein carrier (detoxified Pseudomonas aeruginosa exoprotein A or S. aureus α toxin [Hla]) were coexpressed in Escherichia coli. Recombinant proteins N-glycosylated with S. aureus serotype 5 or 8 CPs were purified from E. coli. RESULTS Rabbits and mice immunized with the glycoprotein vaccines produced antibodies that were active in vitro in functional assays. Active and passive immunization strategies targeting the CPs protected mice against bacteremia, and vaccines targeting Hla protected against lethal pneumonia. The CP-Hla bioconjugate vaccine protected against both bacteremia and lethal pneumonia, providing broad-spectrum efficacy against staphylococcal invasive disease. CONCLUSIONS Glycoengineering technology, whereby polysaccharide and protein antigens are enzymatically linked in a simple E. coli production system, has broad applicability for use in vaccine development against encapsulated microbial pathogens.
Vaccine | 2010
Yu Zou; Ivo Sonderegger; Gerd Lipowsky; Gary T. Jennings; Nicole Schmitz; Marco Landi; Manfred Kopf; Martin F. Bachmann
Interleukin-5 (IL-5) is a cytokine which is essential for the maturation of eosinophils in bone marrow and for their release into the blood. Eotaxin is a CC type chemokine implicated in the recruitment of eosinophils in a variety of inflammatory disorders. Since eosinophil-activity is governed by these two pathways, we targeted both IL-5 and eotaxin by active vaccination to block eosinophilia. We produced two vaccines by chemically cross-linking IL-5 or eotaxin to a virus-like particle (VLP) derived from the bacteriophage Qbeta, yielding highly repetitive arrays of these cytokines on the VLP surface. Both vaccines overcame self-tolerance and induced high antibody titers against the corresponding self-molecules in mice. Immunization with either of the two vaccines reduced eosinophilic inflammation of the lung in an ovalbumin (OVA) based mouse model of allergic airway inflammation. Animals immunized with the two vaccines at the same time developed high antibody titers against both cytokines and also reduced eosinophil-infiltration of the lung. These data demonstrate that targeting either IL-5 or eotaxin may lower eosinophilia. Simultaneous immunization against IL-5 and eotaxin demonstrates that such a therapeutic approach may be used to treat complex disorders in which multiple mediators are involved.
Vaccine | 2016
Germie Pjm van den Dobbelsteen; Kellen Faé; Jan Serroyen; Ingrid M. van den Nieuwenhof; Martin Braun; Micha A. Haeuptle; Dominique Sirena; Joerg Schneider; Cristina Alaimo; Gerd Lipowsky; Veronica Gambillara-Fonck; Michael J. Wacker; Jan T. Poolman
BACKGROUND Extra-intestinal pathogenic Escherichia coli (ExPEC) are major human pathogens; however, no protective vaccine is currently available. We assessed in animal models the immunogenicity and safety of a 4-valent E. coli conjugate vaccine (ExPEC-4V, serotypes O1, O2, O6 and O25 conjugated to Exotoxin A from Pseudomonas aeruginosa (EPA)) produced using a novel in vivo bioconjugation method. METHODS Three doses of ExPEC-4V (with or without aluminum hydroxide) were administered to rabbits (2μg or 20μg per O-antigen, subcutaneously), mice (0.2μg or 2μg per O-antigen, subcutaneously) and rats (0.4μg or 4μg per O-antigen, intramuscularly). Antibody persistence and boostability were evaluated in rats using O6-EPA monovalent conjugate (0.4μg O-antigen/dose, intramuscularly). Toxicity was assessed in rats (16μg total polysaccharide, intramuscularly). Serum IgG and IgM antibodies were measured by ELISA. RESULTS Robust antigen-specific IgG responses were observed in all animal models, with increased responses in rabbits when administered with adjuvant. O antigen-specific antibody responses persisted up to 168days post-priming. Booster immunization induced a rapid recall response. Toxicity of ExPEC-4V when administered to rats was considered to be at the no observed adverse effect level. CONCLUSIONS ExPEC-4V conjugate vaccine showed good immunogenicity and tolerability in animal models supporting progression to clinical evaluation.
Journal of Virology | 2012
Andris Kazaks; Andris Dislers; Gerd Lipowsky; Vizma Nikolajeva; Kaspars Tars
ABSTRACT Enterobacter cancerogenus is widely distributed in nature and is generally recovered from environmental or vegetal sources. In some cases, it has also been associated with human infections. In this study, the complete genomic sequence of virulent E. cancerogenus bacteriophage Enc34 was determined. The Enc34 genome is 60,364 bp in length and contains 80 open reading frames. To our knowledge, this is the first report of a bacteriophage infecting E. cancerogenus.
Journal of Molecular Biology | 2012
Kaspars Tars; Svetlana Kotelovica; Gerd Lipowsky; Monika Bauer; Roger R. Beerli; Martin F. Bachmann; Patrik Maurer
Nicotine is the principal addictive component of tobacco. Blocking its passage from the lung to the brain with nicotine-specific antibodies is a promising approach for the treatment of smoking addiction. We have determined the crystal structure of nicotine bound to the Fab fragment of a fully human monoclonal antibody (mAb) at 1.85 Å resolution. Nicotine is almost completely (>99%) buried in the interface between the variable domains of heavy and light chains. The high affinity of the mAb is the result of a charge-charge interaction, a hydrogen bond, and several hydrophobic contacts. Additionally, similarly to nicotinic acetylcholine receptors in the brain, two cation-π interactions are present between the pyrrolidine charge and nearby aromatic side chains. The selectivity of the mAb for nicotine versus cotinine, which is the major metabolite of nicotine and differs in only one oxygen atom, is caused by steric constraints in the binding site. The mAb was isolated from B cells of an individual immunized with a nicotine-carrier protein conjugate vaccine. Surprisingly, the nicotine was bound to the Fab fragment in an orientation that was not compatible with binding to the nicotine-carrier protein conjugate. The structure of the Fab fragment in complex with the nicotine-linker derivative that was used for the production of the conjugate vaccine revealed a similar position of the pyridine ring of the nicotine moiety, but the pyrrolidine ring was rotated by about 180°. This allowed the linker part to reach to the Fab surface while high-affinity interactions with the nicotine moiety were maintained.
Archive | 2013
Michael J. Wacker; Linhui Wang; Meghan Dowd; Gerd Lipowsky; Kelly Shields; Saeyoung Park; Cristina Alaimo; Kathryn A. Kelley; Julien Quebatte; Veronica Gambillara; Paula Carranza; Michael Steffen; C Jean; Jean C. Lee
Development of Vaccines: From Discovery to Clinical Testing | 2011
Gerd Lipowsky; Martin Bachmann
Archive | 2010
Martin Bachmann; Andrea Jegerlehner; Andris Kazaks; Alexander Link; Gerd Lipowsky; Kaspars Tars
Archive | 2002
Alain Tissot; Katrin Schwarz; Edwin Meijerink; Gerd Lipowsky; Martin Bachmann; Tazio Storni; Paul Pumpens; Indulis Cielens; Regina Renhofa; Patrik Maurer