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Blockade of interferon-? of signalling - a novel class of adjuvants to improve vaccine-induced antibody responses

Applicant Egli Adrian
Number 154709
Funding scheme Ambizione
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.11.2014 - 31.10.2017
Approved amount 451'733.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Clinical Immunology and Immunopathology

Keywords (7)

Polymorphism; Vaccine; Immunity; Interferon lambda; Adjuvant; IL28B; Infection

Lay Summary (German)

Lead
Interferon lambda ist ein wichtiger Botenstoff des Immunsystems und hat potente modulierende Effekte auf die angeborene und erworbene Immunantwort. Im Zusammenhang mit Impfungen gegen z.B. Influenzaviren wurde die Bedeutung von Interferon lambda bisher nur schlecht untersucht. Das Projekt leistet dazu einen Beitrag.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Etwa 50% der europäischen Bevölkerung haben genetische Polymorphismen in Genen der Interferon lambda Signalkaskade. Diese Polymorphismen regulieren massgeblich die genetische Expression während einer Infektion mit Viren. Im Kontext von Impfungen führt zum Beispiel ein genetische Polymorphismus (rs8099917 TG oder GG) zu einer deutliche verbesserten Antikörper Antwort gegen Influenzaviren.

In Experimenten konnten wir zeigen, das rekombinantes Interferon lambda die Virus-induzierte Zytokinebalance kritisch beeinflusst und eine Senkung von sogenannten TH2 Zytokinen bewirkt, ausserdem kommt es zu einer Hemmung von B-Zellen und von Virus-spezifischer Sekretion von Antikörpern. Im Gegensatz dazu, zeigen blockierende Substanzen der Interferon lambda Signalkaskade eine Verbesserung der Antikörper Antwort. Dadurch könnten neuartige Hilfsstoffe, sogenannte Adjuvantien, entwickelt werden.

Das Projekt hat als Ziel in der ersten Phase, Substanzen welche die Interferon lambda Signalkaskade hemmen besser zu verstehen. In einer zweiten Phase werden diese möglichen Adjuvantien in Impfstoffen im Mausmodel getestet.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungspro-jekts

Das Projekt befasst sich mit translationeller Forschung am Immunsystem. Um die Immunantwort und insbesondere die Antikörperantwort gegen Influenza zu verbessern, ist es wichtig, modulierende Faktoren wie Interferon lambda besser zu verstehen. Diese Forschung könnte uns Helfen, dieses Signalsystem so zu modulieren, dass die Impfantwort besser wird und auch Patienten mit einer Immunschwäche besser vor Viruserkrankungen geschützt werden. Ein wichtiger Beitrag zur Entwicklung von neuartigen Adjuvantien könnte geleistet werden.

 

18. September 2014

Direct link to Lay Summary Last update: 18.09.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Influenza vaccination of cancer patients during PD-1 blockade induces serological protection but may raise the risk for immune-related adverse events
Läubli Heinz, Balmelli Catharina, Kaufmann Lukas, Stanczak Michal, Syedbasha Mohammedyaseen, Vogt Dominik, Hertig Astrid, Müller Beat, Gautschi Oliver, Stenner Frank, Zippelius Alfred, Egli Adrian, Rothschild Sacha I. (2018), Influenza vaccination of cancer patients during PD-1 blockade induces serological protection but may raise the risk for immune-related adverse events, in Journal for ImmunoTherapy of Cancer, 6(1), 40-40.
An Optimized Hemagglutination Inhibition (HI) Assay to Quantify Influenza-specific Antibody Titers.
Kaufmann Lukas, Syedbasha Mohameedyaseen, Vogt Dominik, Hollenstein Yvonne, Hartmann Julia, Linnik Janina E, Egli Adrian (2017), An Optimized Hemagglutination Inhibition (HI) Assay to Quantify Influenza-specific Antibody Titers., in Journal of Visualized experiments, 130, 1.
Interferon lambda: modulating immunity in infectious diseases
Syedbasha Mohammedyaseen, Egli Adrian (2017), Interferon lambda: modulating immunity in infectious diseases, in Frontiers in Immunology, 8(119), 1.
An ELISA based binding and competition method to rapidly determine ligand-receptor interactions
Syedbasha Mohameedyaseen, Linnik Janina E, Santer Deanna, O'Shea Daire, Barakat Khaled, Joyce Michael, Khanna Nina, Tyrrell Lorne, Houghton Michael, Egli Adrian (2016), An ELISA based binding and competition method to rapidly determine ligand-receptor interactions, in Journal of visualized experiments, 1.
A Cross-Sectional Study of Colonization Rates with Methicillin-Resistant Staphylococcus aureus (MRSA) and Extended-Spectrum Beta-Lactamase (ESBL) and Carbapenemase-Producing Enterobacteriaceae in Four
Piso Rein Jan, Käch Reto, Pop Roland, Zillig Daniel, Schibli Urs, Bassetti Stefano, Meinel Dominik, Egli Adrian (2016), A Cross-Sectional Study of Colonization Rates with Methicillin-Resistant Staphylococcus aureus (MRSA) and Extended-Spectrum Beta-Lactamase (ESBL) and Carbapenemase-Producing Enterobacteriaceae in Four, in Plos one, 1.
An ELISA based binding and competition method to rapidly determine ligand-receptor interactions
Syedbasha Mohammedyaseen, Linnik Jana, Santer Deanna, O'Shea Daira, Barakat Khaled, Joyce Michael, Khanna Nina, Tyrrell D. Lorne, Houghton Michael, Egli Adrian (2016), An ELISA based binding and competition method to rapidly determine ligand-receptor interactions, in J Vis Exp, 14(109), 1.
Impact of host genetic polymorphisms on vaccine induced antibody response
Linnik Janina E, Egli Adrian (2016), Impact of host genetic polymorphisms on vaccine induced antibody response, in Human Vaccines & Immunotherapeutics, 1.
Impact of MALDI-TOF MS based identification directly from positive blood cultures on patient management: a controlled clinical trial
Osthoff Michael, Gürtler Nicolas, Bassetti Stefano, Balestra Gianmarco, Marsch Stephan, Pargger Hans, Weisser Maja, Egli Adrian (2016), Impact of MALDI-TOF MS based identification directly from positive blood cultures on patient management: a controlled clinical trial, in Clin Microbiol Infect, 16, 1.
Outbreak investigation for toxigenic Corynebacterium diphtheria wound infections in refugees from Northeast Africa and Syria in Switzerland and Germany by whole genome sequencing
Meinel Dominik M., Kuehl Richard, Zbinden Reinhard, Boskova Victoria, Garzoni Christian, Fadini Davide, Dolina Marina, Blümel Benjamin, Weibel Thomas, Tschudin-Sutter Sarah, Widmer Andreas F., Bielicki Julia, Dierig Alexa, Heininger Ulrich, Konrad Regina, Berger Andrea, Hinic Vladimira, Goldenberger Daniel, Blaich Annette, Stadler Tanja, Battegay Manuel, Sing Andreas, Egli Adrian (2016), Outbreak investigation for toxigenic Corynebacterium diphtheria wound infections in refugees from Northeast Africa and Syria in Switzerland and Germany by whole genome sequencing, in Clin Microbiol Infect, 1.
The Technical and Biological Reproducibility of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) Based Typing: Employment of Bioinformatics in a Multicenter
Oberle Michael, Wohlwend Nadia, Jonas Daniel, Maurer Florian, Jost Geraldine, Tschudin-Sutter Sarah, Vranckx Katleen, Egli Adrian (2016), The Technical and Biological Reproducibility of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) Based Typing: Employment of Bioinformatics in a Multicenter, in Plos one, 1.
Complexity of Host Micro-RNA Response to Cytomegalovirus Reactivation After Organ Transplantation
Egli Adrian (2015), Complexity of Host Micro-RNA Response to Cytomegalovirus Reactivation After Organ Transplantation, in American Journal of Transplantation, 1-11.
Effect of Immunosuppression on T-Helper 2 and B-Cell Responses to Influenza Vaccination
Egli Adrian, Humar Atul, Widmer Lukas A., Lisboa Luiz F., Santer Deanna M., Mueller Thomas, Stelling Joerg, Baluch Aliyah, O'Shea Daire, Houghton Michael, Kumar Deepali (2015), Effect of Immunosuppression on T-Helper 2 and B-Cell Responses to Influenza Vaccination, in JOURNAL OF INFECTIOUS DISEASES, 212(1), 137-146.
The Fast Route to Microbe Identification Matrix Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS)
Dierig Alexa, Frei Reno, Egli Adrian (2015), The Fast Route to Microbe Identification Matrix Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS), in PEDIATRIC INFECTIOUS DISEASE JOURNAL, 34(1), 97-99.
Travelling activity and travel-related risks after allogeneic haematopoietic stem cell transplantation - a single centre survey
Hollenstein Yvonne, Elzi Luigia, Hatz Christoph, Passweg Jakob, Weisser Maja, Stoeckle Marcel, Halter Joerg P., Egli Adrian (2015), Travelling activity and travel-related risks after allogeneic haematopoietic stem cell transplantation - a single centre survey, in SWISS MEDICAL WEEKLY, 145, 1-9.

Collaboration

Group / person Country
Types of collaboration
Haematology/University Hospital of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Pinschewer/Department Biomedicine/University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Weisser/Infectious Diseases/University Hospital of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Houghton/Li Ka Shing Institute of Virology/University of Alberta Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
DBM Research Day Talk given at a conference Virus-specific immunity and transmission of pathogens 26.01.2017 Basel, Switzerland Egli Adrian;
Immune Retreat: Department of Biomedicine Talk given at a conference Computational Modelling of Interferon 02.11.2015 Engelberg, Switzerland Egli Adrian;
Immunomeeting, Department of Biomedicine Talk given at a conference Ligand - Receptor interactions of Interferons 19.10.2015 Basel, Switzerland Egli Adrian;
Donnerstagskonferenz, Universitätsspital Basel Individual talk Impfung bei Immunsuppression - funktioniert das? 18.07.2015 Basel, Switzerland Egli Adrian;


Awards

Title Year
Alumnipreis 2015 Medizinische Fakultät Universität Basel 2015

Abstract

Blockade of interferon-lambda signalling - a novel class of adjuvants to improve vaccine-induced antibody responses.Vaccination reduces the burden of many infectious diseases including infections with influenza viruses. Seroconversion may, however, be inadequate in specific populations as young children, pregnant women, the elderly, and patients with immunosuppression. Adjuvants act to boost the immune response. Nevertheless, most adjuvants induce nonspecific inflammation as opposed to a specific modulation of immune signalling. Novel adjuvants with an optimized and tailored activity profile are required. Antigen presenting cells are crucial for the interplay between innate and adaptive immunity and therefore ideal targets for adjuvants. Interferon (IFN)-alpha and -lambda activate and polarize macrophages and dendritic cells, which later regulate the priming of T- and B-cells. IFN-lambda is a newly discovered class of IFN and its effects in the context of vaccination have not been explored in detail. Single nucleotide polymorphisms (SNPs) in the IL-28B (IFN-lambda3) promoter region have a minor allele frequency of up to 40% in Caucasians and may alter vaccine-induced immunity - possibly impacting vaccination schedules. Own research: Interestingly, in solid organ transplant recipients with a SNP in the IL-28B promoter region (rs8099917, TG or GG) a significantly increased rate of seroconversion following influenza vaccination was observed. The rs8099917 TG and GG SNP is associated with a lower influenza-induced IL-28B gene expression. This suggests that a lower IL28B expression could lead to a reduced humoral immune response.Indeed, recombinant IL-28B reduced H1N1-induced Th2 cytokines, B-cell proliferation and antibody secretion. Next, we designed antagonistic peptides to block the IFN-lambda signaling. This increased the in vitro antibody secretion of PBMCs. Therefore, blockade of IFN-lambda may represent a novel adjuvant method to improve vaccine-induced antibody responses.Aims: Part I focuses on the adjuvant function of IFN-lambda blockade and aims to explore IL-28R antagonistic compounds (peptides, antibodies and small molecules) as novel adjuvants mediating enhanced antibody induction. Additionally, the immune-modulatory activity on macrophage, dendritic cells, and subsequent T- and B-cell activating effects will be examined. The impact of IL-28R blocking compounds will be evaluated in mouse models of influenza vaccination to demonstrate adjuvant efficacy in generating specific antibodies.Part II aims to explore the role of IFN-lambdas and SNPs on vaccine-induced antibody response (seroconversion and absolute titers) after trivalent non-adjuvanted influenza vaccine in a high-risk allogeneic haematopoietic stem cell transplant (HSCT) population. Hypotheses: Part I: Antagonistic compounds against the IL-28R block the IFN-lambda signalling and act as adjuvants in vitro and in vivo by mediating an increase in vaccine-induced antibody secretion.Part II: IL-28B SNPs affect the antibody production during vaccination of HSCT recipients.Rationale: This project carries high potential to (i) develop a novel tailored class of adjuvant in a highly translational setting; (ii) use IFN-lambda modulating compounds to further comprehend the impact of IFN-lambdas signalling in vitro and in vivo; (iii) develop in detail a highly innovative approach to study vaccine responses possible impacting vaccination schedules in distinct populations based on the genotype background; (iv) form an international collaborative network with leading institutions to improve patient outcomes.
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