- Author
-
P.J.M. Brouwer
- Title
- Presenting viral glycoproteins on computationally designed two-component protein nanoparticles to improve neutralizing antibody responses
- Supervisors
-
R.W. Sanders
- Co-supervisors
-
N.P. King
- Award date
- 23 June 2021
- Number of pages
- 327
- ISBN
- 9789464166262
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
Recombinant prefusion-stabilized viral glycoproteins may serve as promising vaccine candidates as they allow easy large-scale manufacturing, are safe and harbour all or most (broadly) NAb epitopes while minimally exposing irrelevant non-NAb epitopes found on postfusion trimers. Indeed the generation of prefusion stabilized glycoproteins has enabled induction of high NAb titers against traditionally difficult targets such as human immunodeficiency virus 1 (HIV-1), and respiratory syncytial virus (RSV). Nevertheless the humoral immune system has evolved to recognize a repetitive array of glycoproteins such as those found on virus-like structures; not soluble glycoproteins. Thus, efforts to develop stable and antigenically sound prefusion glycoproteins have been paralleled by the design of nanoparticles that allow these glycoproteins to be presented in a multivalent fashion. Computationally designed two-component protein nanoparticles are an elegant platform that allow facile, controlled and scalable in vitro-assembly into a fixed geometry. In this thesis we explore the use of this nanoparticle system for the display of glycoproteins from HIV-1, Lassa virus and SARS-CoV-2, known as Env, GPC, and S protein, respectively. We describe the design and in-depth in vitro and in vivo characterization of these nanoparticle vaccine candidates, while generating insights in their immunogenicity, utility, and efficacy. In addition, we describe the isolation and characterization of GPC- and S protein-specific monoclonal (N)Abs, opening avenues for vaccine design while generating promising therapeutic candidates. This work reveals the versatility and potential of computationally designed nanoparticles as well as challenges that nanoparticle vaccines face in the context of heavily glycosylated and sequence diverse glycoproteins.
- Persistent Identifier
- https://hdl.handle.net/11245.1/2383e365-779b-4cc1-94a0-8257dca24b62
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: Introduction
Chapter 2: Enhancing and shaping the immunogenicity of native-like HIV-1 envelope trimers with a two-component protein nanoparticle
Chapter 3: Structural and functional evaluation of de novo-designed, two-component nanoparticle carriers for HIV Env trimer immunogens
Chapter 4: Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles
Chapter 5: Lassa virus glycoprotein nanoparticles elicit a neutralizing antibody that defines a new site of vulnerability
Chapter 6: Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability
Chapter 7: Two-component spike nanoparticle vaccine protects macaques from SARS-CoV-2 infection
Chapter 8: Discussion
Summary; Samenvatting; Dankwoord; Curriculum vitae; List of publications; Ph.D. portfolio; Author affiliations
- Supplementary materials
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