Leiden University Scholarly Publications

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Szachniewicz, M.M. (2026)

A matter of delivery: nanocarriers and the engineering of protective immunity in tuberculosis vaccination

Doctoral Thesis
The development of effective subunit vaccines against Mycobacterium tuberculosis (Mtb) is limited by the absence of antigen delivery systems capable of inducing strong cellular immunity. Although nanoparticle (NP) technologies have transformed other areas of vaccinology and nanomedicine, their systematic application in tuberculosis (TB) vaccine development remains underexplored. This dissertation addresses this gap by focusing on the rational design and comparative evaluation of NP-based delivery platforms for TB subunit vaccines.
The research scope includes cationic liposomes, pH-sensitive liposomes, poly(lactic-co-glycolic) acid (PLGA) NPs, and lipid–PLGA hybrid systems formulated with the rationally designed Mtb fusion antigen Ag85B–ESAT6–Rv2034. In vitro studies using primary dendritic cells and epitope-specific T-cell assays were employed to assess cellular uptake and immune activation. Key techniques included NP physicochemical characterization,...Show moreThe development of effective subunit vaccines against Mycobacterium tuberculosis (Mtb) is limited by the absence of antigen delivery systems capable of inducing strong cellular immunity. Although nanoparticle (NP) technologies have transformed other areas of vaccinology and nanomedicine, their systematic application in tuberculosis (TB) vaccine development remains underexplored. This dissertation addresses this gap by focusing on the rational design and comparative evaluation of NP-based delivery platforms for TB subunit vaccines.
The research scope includes cationic liposomes, pH-sensitive liposomes, poly(lactic-co-glycolic) acid (PLGA) NPs, and lipid–PLGA hybrid systems formulated with the rationally designed Mtb fusion antigen Ag85B–ESAT6–Rv2034. In vitro studies using primary dendritic cells and epitope-specific T-cell assays were employed to assess cellular uptake and immune activation. Key techniques included NP physicochemical characterization, flow cytometry, cytokine and chemokine profiling, and functional T-cell readouts.
In vivo evaluation was performed in mouse models using subcutaneous and intradermal immunization, followed by intranasal challenge with virulent Mtb H37Rv. Immune responses were analyzed by multiparameter flow cytometry, antibody profiling, and bacterial burden assessment. By integrating in vitro mechanistic studies with in vivo mouse models, this thesis establishes a comprehensive framework for NP-based TB subunit vaccine development and contributes broadly to vaccine delivery and immunoengineering research.Show less
Tuberculosis subunit vaccines
Mycobacterium tuberculosis
Nanoparticle vaccine delivery
Cationic liposomes
pH-sensitive liposomes
PLGA nanoparticles
Lipid–polymer hybrid nanoparticles
Antigen presentation
Adjuvant co-delivery
Intradermal vaccination
All authors
Szachniewicz, M.M.
Supervisor
Ottenhoff, T.H.M.; Bouwstra, J.A.
Committee
Burg, S.H. van den; Meijer, A.H.; Barz, M.; Joosten, S.A.; Maaden, K. van der
Qualification
Doctor (dr.)
Awarding Institution
Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
Date
2026-02-04
ISBN (print)
9789493289994

Funding

Sponsorship
Sponsors The conducted research was supported by the Dutch Research Council (NWO) Domain Applied and Engineering Sciences grant, project number: 15240.