Project

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Immunoengineering a synthetic vaccine against emerging human pathogenic viruses

English title Immunoengineering a synthetic vaccine against emerging human pathogenic viruses
Applicant Swartz Melody
Number 143754
Funding scheme Interdisciplinary projects
Research institution Lab. de Mécanobiologie et de Morphogenèse EPFL- SV - IBI - LMBM
Institution of higher education EPF Lausanne - EPFL
Main discipline Chemical Engineering
Start/End 01.10.2012 - 30.09.2015
Approved amount 700'000.00
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All Disciplines (3)

Discipline
Chemical Engineering
Infectious Diseases
Immunology, Immunopathology

Keywords (11)

nanoparticle; neutralizing antibody; hemorrhagic fever; nanotechnology; antigen design; humoral response; Lassa fever; Machupo hemorrhagic fever; T cell response; adjuvant; immunomodulation

Lay Summary (English)

Lead
Lay summary

Over the past decades, human arenaviruses, which cause severe hemorrhagic fevers with high mortality, have emerged as a growing public health issue. Lacking effective treatment, there is an urgent need for protective vaccines against these viruses. Successful anti-viral vaccines most importantly must generate neutralizing antibodies (nAb) that stick specifically to the virus’ surface, prevent it from infecting the host and decrease the chances for disease development. Some of the most virulent arenaviruses (such as Lassa virus, endemic in western Africa), use decoy mechanisms to avoid the host nAb response. One such is to shed their surface coat and fool the body to make massive antibodies against the shed surface. This diverts the resources of the body, so nAb cannot be made sufficiently to prevent the disease. Despite much success in anti-viral vaccine design over the past decades, the development of safe vaccines capable of inducing nAbs of sufficient strength and breadth remains an unmatched challenge. We propose to contribute a more systematic understanding – in other words, build immunoengineering design strategies – for how to induce protective nAb responses against the coat of viruses - glycoprotein antigens. This research will join the expertise of two laboratories. The Swartz Lab’s strengths in bioengineering and vaccine immunology will team up with the Kunz Lab arenaviral glycoprotein immunobiology, biochemistry, and viral immunology. The Swartz lab, in collaboration with the Hubbell lab (a key collaborator on this project), have spent the last 8 years developing vaccines based on chemically defined virus-sized particles.  With this combined expertise at hand, we will set out to define design criteria to elicit an optimal anti-viral nAb response against dangerous arenaviruses for which vaccines do not exist: LASV and Machupo virus (MACV). If successful, this project will provide the basis for a much-needed arenavirus vaccine as well as develop, more generally, new rational design guidelines for immunoengineered vaccine formulations.

 


Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Collaboration

Group / person Country
Types of collaboration
Jeffrey Hubbell, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Thomas Bowden, University of Oxford Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Lars Hangartner, Assistant Professor, Institute of Medical Virology, University of Zurich. Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Erica Ollmann Saphire, Associate Professor, Department of Immunology and Microbial Sciences, Scripps United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
International conferences on negative strand viruses 2015 in Siena Poster Development of a novel vaccine against Lassa Virus 14.06.2015 Sienna, Italy Kunz Stefan; Galan Navarro Clara;


Associated projects

Number Title Start Funding scheme
135536 Targeting the processing of arenavirus glycoprotein for anti-viral therapy 01.04.2011 Project funding
132844 Host cell invasion by Lassa virus 01.01.2011 Project funding
120250 Targeting the processing of arenavirus glycoprotein for anti-viral therapy 01.04.2008 Project funding
160780 Viral Plasticity Underlying Tropism And Pathogenesis/ Innate Immune Evasion Of Emerging Viruses 01.11.2015 Sinergia
149746 Host cell invasion by Lassa virus 01.01.2014 Project funding

Abstract

Over the past decades, human arenaviruses, which cause severe hemorrhagic fevers with high mortality, have emerged as a growing public health issue. Lacking effective treatment, there is an urgent need for protective vaccines against these viruses. Successful anti-viral vaccines most importantly must generate neutralizing antibodies (nAb) that limit the initial burst of viral replication and thus provide a window of opportunity for the host’s cellular immune response to eliminate the virus. Some of the most virulent arenaviruses (such as Lassa virus (LASV)) use decoy mechanisms to avoid host nAb response, like shedding a part of their glycoprotein coat and drive massive production of ineffective polyclonal antibodies (pAb), thus diverting B cell production of nAbs. Because of this, and as live-attenuated vaccines can be dangerous for wide use, new vaccine strategies that enhance nAbs are badly needed. Despite much success in anti-viral vaccine design over the past decades, the development of safe vaccines capable of inducing nAbs of sufficient strength and breadth remains an unmatched challenge for such arenaviruses as well as many other major human pathogenic viruses, including HIV and hepatitis C virus. Considering the virulence of these pathogens, we need to build a more systematic understanding - in other words, immunoengineering design strategies - for how to induce protective nAb responses against glycoprotein antigens. We propose to combine nanoparticle engineering and targeting design strategies with arenaviral glycoprotein immunobiology and biochemistry to develop novel recombinant vaccine strategies against dangerous arenaviruses for which vaccines do not exist: LASV and Machupo virus (MACV). Our primary goal is to engineer the vaccines to generate potent nAbs to provide an important first line of protection against these highly virulent pathogens, and then to develop strategies to also activate cellular immunity as well, which represents an important second line of defense in the case that nAb do not achieve full protection. In doing so, we will also help to establish rational design strategies for enhancing nAb responses in synthetic vaccines, which would be widely applicable in vaccinology. Our aims are: 1. Determine how NP design parameters, such as surface modification and antigen release mechanisms, affect the quality of the immune response to NP vaccines against the glycoprotein GP1. Specifically, we will evaluate nAb, pAb, and cellular immune responses to MACV GP1 NP formulations.2.Using the most promising NP formulation from Aim 1, compare the immune responses to LASV GP1-NP with those of MACV GP1-NP, and engineer a new LASV GP epitope that will enhance nAb production. 3.Using LCMV as a challenge model, confirm Aim 1’s best CD8 responders with benchmarks.4.Test the most promising NP formulations from Aim 2, 3 in a challenge model using recombinant LCMV expressing LASV GP, comparing that which gave the best (a) nAb response, (b) CD8 response, and (c) a combination of the two.Our project combines bioengineering and vaccine immunology with virology and biochemistry of viral glycoproteins provided by the complementary expertise of our research laboratories, bioengineering/vaccines (Swartz) and virology/antigen epitope biochemistry (Kunz). The Swartz lab, in collaboration with the Hubbell lab (a key collaborator on this project), have spent the last 8 years developing nanoparticle vaccine design criteria upon which this proposal is based. Bioengineering approaches will be used to discover and define design criteria for the immunogen to elicit an optimal anti-viral nAb response. The required immunological tools and methods required for the work proposed here, including the LCMV infection models are established in the laboratory of Kunz. The combined expertise of our groups is unique for this endeavour. More specialized knowledge in immunology and pathophysiology will be integrated as collaborations from our excellent contacts to immunologists (see letter of support). If successful, this project will provide the basis for a much-needed arenavirus vaccine as well as develop, more generally, new rational design criteria for immunoengineered vaccine formulations.
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