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Development of novel strain- and subtype-independent influenza vaccines by targeting the conserved epitopes of the hemagglutinin surface protein

English title Development of novel strain- and subtype-independent influenza vaccines by targeting the conserved epitopes of the hemagglutinin surface protein.
Applicant Hangartner Lars
Number 146345
Funding scheme SNSF Professorships
Research institution Institut für Medizinische Virologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Immunology, Immunopathology
Start/End 01.09.2013 - 31.08.2015
Approved amount 392'199.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Methods of Epidemiology and Preventive Medicine

Keywords (6)

neutralization; human; vaccine; antibodies; influenza; protein engineering

Lay Summary (German)

Lead
Die heute erhältlichen Grippe-Impfungen sind zwar sehr effektiv, müssen aber jedes Jahr wiederholt werden. Sie schützen nicht gegen neue Grippeviren oder menschliche Grippeviren, die sich in vorhergesagter Weise verändert haben. Daher wäre es wünschenswert, wenn es eine neuartige Grippeimpfung gäbe, die gegen alle denkbaren Varianten des Virus schützen würde und die nur noch alle paar Jahre injiziert werden müsste. Das Ziel dieses Projektes ist es, eine solche Impfung zu entwickeln.
Lay summary

Durch eine Grippeinfektion oder -impfung bildet der Körper Antikörper, die ihn vor einer erneuten Infektion schützen. Grippeviren haben jedoch die unangenehme Fähigkeit, dass sie ihre Oberflächenstrukturen so verändern können, dass Antikörper ihre schützende Funktion verlieren und dass veränderte Viren einen immunen Wirt erneut infizieren können. In den letzten 10 Jahren sind immer wieder Vogel- oder Schweinegrippeviren auf den Menschen übergesprungen. Vogelgrippe-Viren, welche Menschen infizieren können, haben im Gegensatz zum Schweinegrippe-Virus H1N1 keine Ähnlichkeiten zu menschlichen Viren und bringen bis zu 60% der Infizierten um. Sollten diese Vogelgrippeviren je die Fähigkeit zur effizienten Mensch-zu-Mensch-Übertragung erwerben, wären die Folgen fatal.

Die heutige Grippeimpfung ist sehr wirksam, hat aber den Nachteil, dass sie kaum gegen veränderte Viren aktiv ist und jedes Jahr neu zusammengestellt, produziert und angewendet werden muss. Kürzlich konnte gezeigt werden, dass Grippeviren eine immunologische Achillesferse besitzen: Eine Oberflächenstruktur, die allen Grippeviren gemeinsam ist, die vom Virus kaum verändert werden kann und die – wenn Antikörper daran binden – bewirkt, dass das Virus nicht mehr infektiös ist. Wir versuchen daher, einen Impfstoff zu entwickeln, der das Immunsystem von den veränderlichen Regionen weg lotst und stattdessen bewirkt, dass die immunologische Achillesferse angegriffen wird. Ein solche Impfung hätte den Vorteil, dass sie nicht mehr jedes Jahr wiederholt werden müsste und dass sie gegen alle Grippeviren schützen würde, auch gegen gefährliche Vogelgrippen.

 


Direct link to Lay Summary Last update: 26.06.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Heterosubtypic Antibodies to Influenza A Virus Have Limited Activity against Cell-Bound Virus but Are Not Impaired by Strain-Specific Serum Antibodies
Arkadiusz Wyrzucki Matteo Bianchi Ines Kohler Marco Steck Lars Hangart (2015), Heterosubtypic Antibodies to Influenza A Virus Have Limited Activity against Cell-Bound Virus but Are Not Impaired by Strain-Specific Serum Antibodies, in Journal of Virology, 89(6), 3136-3144.
The impact of vaccination on the breadth and magnitude of the antibody response to influenza A viruses in HIV-infected individuals
Ines Kohler (2015), The impact of vaccination on the breadth and magnitude of the antibody response to influenza A viruses in HIV-infected individuals, in AIDS, 29(14), 1803-1810.
Alternative recognition of the conserved stem epitope in influenza A virus hemagglutinin by a VH3-30-encoded heterosubtypic antibody.
Wyrzucki Arkadiusz, Dreyfus Cyrille, Kohler Ines, Steck Marco, Wilson Ian A, Hangartner Lars (2014), Alternative recognition of the conserved stem epitope in influenza A virus hemagglutinin by a VH3-30-encoded heterosubtypic antibody., in Journal of virology, 88(12), 7083-92.
Prevalence and Predictors for Homo- and Heterosubtypic Antibodies Against Influenza A Virus.
Kohler Ines, Scherrer Alexandra U, Zagordi Osvaldo, Bianchi Matteo, Wyrzucki Arkadiusz, Steck Marco, Ledergerber Bruno, Günthard Huldrych F, Hangartner Lars, Prevalence and Predictors for Homo- and Heterosubtypic Antibodies Against Influenza A Virus., in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

Collaboration

Group / person Country
Types of collaboration
University Hospital Zurich/ Clinic of Infectious Diseases Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
WHO CC for Influenza, London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
University of Zurich / Department of Biochemistry Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
The Scripps Research Insitute/The Wilson Lab United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
University of Zurich / Institute of Organic Chemistry Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
The Scripps Research Institute/The Burton Lab United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
St. Jude Children's Research Hospital/Department of Infectious Diseases United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
University of Zurich/Institute of Medical Virology Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Communication with the public

Communication Title Media Place Year
Media relations: radio, television Die Grippe 2015 Schweizer Radio 2 Kultur German-speaking Switzerland 2015
Media relations: radio, television 10vor10 SRF German-speaking Switzerland 2014
Media relations: radio, television PULS SRF German-speaking Switzerland 2014

Associated projects

Number Title Start Funding scheme
123429 Development of novel strain- and subtype-independent influenza vaccines by targeting the conserved epitopes of the hemagglutinin surface protein. 01.09.2009 SNSF Professorships

Abstract

Current influenza vaccines are unsatisfactory because they are only protective against viral variants closely related to the immunizing strain and require annual immunizations to account for the antigenic drift of the circulating viruses. Development of strain- and subtype-independent vaccines to influenza virus requires detailed knowledge of conserved antibody epitopes that are shared between the different strains and subtypes of influenza. With this project, I propose to continue research that I have started three years ago. First, I would like to continue with the characterization of monoclonal antibodies that we have obtained and that are able to neutralize a broad spectrum of human and non-human influenza isolates. In particular, I would like to assess the mode of action of these antibodies, with regard to neutralization kinetics and reversibility. In addition, I would like to assess the ability of these antibodies reach their epitopes in the context of saturating concentrations of strain-specific serum antibodies, and their ability to trigger B cell receptor signals under these circumstances. Second, I would like to continue with the development of an antigen in which the strain-specific epitopes have been dampened and which predominantly exposes the conserved epitope in the stem of the HA protein. Previous experiments demonstrated that this antigen can elicit antibodies of broad heterotypic specificity but these are not or only poorly neutralizing. Therefore, I would like to improve this antigen in an iterative process during which undesired epitopes are identified and then dampened before the modified antigen is tested again in mice. Third, I would like to address the alterations in the serum antibody spectrum induced by the arrival of the H1N1 pandemic in 2009, and, amongst others, investigate whether the proposed activation heterosubtypic B cells during the acute phase of the infection manifests itself in the serum antibody spectrum of the population. Vaccine candidates arising from this project should not only be able to reduce the number of immunizations required to protect against currently circulating strains of influenza A but they may also provide partial or total protections against emerging avian Influenza strains with pandemic potential. Moreover, with the data about a potential interference by pre-existing serum antibodies we hope to anticipate potential obstacles such a vaccine may encounter in humans.
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