Toward a virosomal respiratory syncytial virus vaccine with a built-in lipophilic adjuvant: A vaccine candidate for the elderly and pregnant women

Julia Lederhofer

    Research output: ThesisThesis fully internal (DIV)

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    Abstract

    Respiratory syncytial virus (RSV) represents the single most important cause of severe acute respiratory infection (SARI) and viral bronchiolitis among infants and young children. RSV also causes serious illness among the elderly and immunocompromised individuals. A vaccine against RSV would significantly reduce the health burden caused by RSV infection.

    In this study, we describe the development and optimization of a virosomal RSV vaccine, specifically aimed at protection of the elderly and of infants, the latter through vaccination of pregnant women. RSV virosomes are reconstituted viral envelopes that contain the membrane glycoproteins F and G of the virus, but lack the viral nucleocapsid. Thus, the particles are incapable of replication and therefore not able to cause disease. Since the major viral antigens F and G are displayed on the virosomal surface, use of virosomes as a vaccine will lead to the induction of virus-neutralizing (VN) antibodies. In the present study, first the production of RSV virosomes and the incorporation of a lipophilic adjuvant have been optimized to eventually fulfill GMP production requirements. Specifically, we investigated the use of a synthetic variant of the adjuvant monophosphoryl lipid A (MPLA). Subsequently, we monitored the virosomes’ long-term stability and we evaluated their immunogenicity in a murine model system. Additionally, we improved the capacity of virosomes to induce VN antibodies by employing thermostable virus strains with enhanced glycoprotein F stability. Finally, we further optimized the vaccine’s concept by switching from virosomes to synthetic liposomes with conjugated recombinant stabilized preF-protein derived from the native viral F glycoprotein. We conclude that RSV virosomes, with a built-in synthetic MPLA adjuvant, represent a promising vaccine candidate against RSV infection.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Wilschut, Jan, Supervisor
    • Huckriede, Anke, Supervisor
    • de Haan, Aalzen, Co-supervisor
    • Stegmann, Antonius, Co-supervisor
    Award date10-Dec-2018
    Place of Publication[Groningen]
    Publisher
    Print ISBNs978-94-6375-132-2
    Publication statusPublished - 2018

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