Approach to use the Engage Exchange Model for information management in crisis communication and animal disease control

This doctoral thesis is featured as a pseudo-cumulative work. Three independent chapters (2 to 4) are framed by an introductory and a concluding chapter (1 and 5). The objective of this thesis was to develop a concept proposal for improving information management of animal disease prevention and control, to assess the implementation by experts and to test it on a pilot application. The methodical-theoretical approach of the Engage Exchange Model was used. Initially the question was studied how the existing information and information structures of the private and public sector can meet the information needs of involved decision makers in case of an animal disease outbreak. Furthermore, 26 expert interviews provided statements on which potential has not been exhausted yet. A strategic alliance was proposed as an organizational concept for improved information management, consisting of farmers, inter-company network coordinators, who representing farmers, competent regional veterinary authorities and superior public institutions with managerial functions in case of an animal disease outbreak. To enable an assessment of the implementation level of a communication concept in a strategic alliance, a process reference model according to the maturity method of ISO 15504 was defined. Based on this model a concrete task list and time roadmap can be established for the integration of an individual organization into the strategic alliance. An exemplary maturity assessment was executed on 12 selected livestock trading organizations being on the path to private network coordinators, with particular regard to engage and exchange additional information with partners of the predefined alliance. Finally, the application of a technical support tool for communication according to the Engage Exchange Model was tested and assessed. The outbreak of Classical Swine Fever in an area near the Dutch German border served as crisis scenario to demonstrate the functionalities of the tool for specific user groups. A subsequent validation by a method combination of anonymous survey, demonstration and discussion panel in the framework of a workshop with 13 experts and potential applicants resulted in concrete statements about necessary developments in the future process of prototyping and possible further application areas of this approach for the field of feed and food control. The prototype presented and validated in this thesis serves as a support tool for public-private partnership alliances to facilitate an improved crisis communication. It represents a first technical-organizational concept proposal which should be implemented in future joint exercises for crisis management.Ansatz zur Nutzung des Aufschaltungs-Austausch-Modells für das Informationsmanagement in der Krisenkommunikation und Tierseuchenbekämpfung Die vorliegende Doktorarbeit ist als pseudo-kumulativen Schrift gestaltet. Drei in sich geschlossene Kapitel (2 bis 4) sind eingerahmt von einem einleitenden und einem zusammenfassenden Teil (1 und 5). Ziel der Arbeit war es, einen Vorschlag zur Verbesserung des Informationsmanagements in der Tierseuchenprävention und -bewältigung zu konzipieren, die Umsetzung durch Experten bewerten zu lassen und an einem Anwendungsbeispiel pilotmäßig zu erproben. Verwendung fand der methodisch-theoretischen Ansatz des Aufschaltungs-Austausch-Modells. Dabei wurde zunächst der Frage nachgegangen, in wie fern die existierenden Informationen und Informationsstrukturen der Privatwirtschaft und der Behörden den Informationsbedarf der beteiligten Entscheidungsträger im Tierseuchenfall decken können. Eine qualitative Auswertung von 26 Experteninterviews lieferte darüber hinaus Aussagen, welches Potential noch nicht ausgeschöpft werden konnte. Als organisatorisches Konzept zur Verbesserung des Informationsmanagements wird eine strategische Allianz vorgeschlagen, bestehend aus Tierhalter, die Tierhalter vertretenden privatwirtschaftlichen überbetrieblichen Netzwerkkoordinatoren, zuständigen regionalen Veterinärbehörden und ihnen übergeordnete öffentliche Einrichtungen mit koordinierenden Funktionen im Tierseuchenfall. Um den Grad der Umsetzung eines Kommunikationskonzepts in einer strategischen Allianz zu bewerten, wurde gemäß der Reifegradmethode nach ISO 15504 ein Prozess-Referenz-Modell definiert. Auf Grundlage dieses Modells lässt sich eine konkreter Aufgabenliste und zeitlicher Fahrplan zur Integration der jeweils eigenen Organisation in die strategische Allianz aufstellen. Exemplarisch wurde eine Reifegradbestimmung von 12 ausgewählten Viehvermarktungsorganisationen auf dem Weg zu privaten Netzwerkkoordinatoren durchgeführt, unter besonderer Berücksichtigung der Bereitstellung und des Austauschs von zusätzlichen Daten im Krisenfall mit Partnern der zuvor festgelegten Allianz. In einem letzten Schritt erfolgte die Erprobung und Bewertung der Anwendbarkeit eines technischen Tools zur Unterstützung der Kommunikation im Sinne des Aufschaltungs-Austausch-Modells. Als Krisenszenario diente der Ausbruch der Klassischen Schweinepest in einer Region nahe der deutsch-niederländischen Grenze, um die Funktionalitäten des Tools für unterschiedliche Nutzergruppen zu demonstrieren. Eine anschließende Validierung mit Hilfe einer Methodenkombination aus anonymer Umfrage, Demonstration und Diskussionsrunde im Rahmen eines Workshops mit 13 Experten und potentiellen Anwendern lieferte konkrete Aussagen zu Weiterentwicklungsmöglichkeiten und weitere Anwendungsfelder in der Futter- und Lebensmittelüberwachung. Der in dieser Arbeit vorgestellte und bewertete Prototyp eines Unterstützungstools für Public-Private Partnership Allianzen zur Erleichterung der Krisenkommunikation stellt einen ersten technisch-organisatorischen Konzeptvorschlag dar, der zukünftig in gemeinsamen Übungen für das Krisenmanagement umgesetzt werden soll

Challenges and opportunities in nasal subunt vaccine delivery : mechanistic studies using ovalbumin as a model antigen

Nasal vaccination has the potential to provide protection combined with more patient comfort and a higher safety profile than classical injectable vaccines. However, the nasal physiology and immunological aspects of the nasal epithelium hamper the efficacy of nasally administered vaccines. The aim of this thesis is therefore three-fold: __ to identify the principal hurdles to successful nasal vaccine delivery; __ to develop preclinical model systems to investigate these hurdles; __ to apply these principles to rationally design nasal subunit vaccine formulations in a preclinical setting.Drug Delivery Technolog

Determine the room for improvement of processes within the management of crisis and their prevention – the maturity mode

Crisis within the meat sector usually causes high economic losses for the affected sector and frequently for other sectors, too. Interrupted or poor communication channels are weak points in management-systems, especially in the management of crisis situations or of the prevention of crisis. In a consequence necessary information for a proper decision making is missing or not available in time

Tolerogenic vaccines for the treatment of cardiovascular diseases

Atherosclerosis is the main pathology behind most cardiovascular diseases. It is a chronic inflammatory disease characterized by the formation of lipid-rich plaques in arteries. Atherosclerotic plaques are initiated by the deposition of cholesterol-rich LDL particles in the arterial walls leading to the activation of innate and adaptive immune responses. Current treatments focus on the reduction of LDL blood levels using statins, however the critical components of inflammation and autoimmunity have been mostly ignored as therapeutic targets. The restoration of immune tolerance towards atherosclerosis-relevant antigens can arrest lesion development as shown in pre-clinical models. In this review, we evaluate the clinical development of similar strategies for the treatment of inflammatory and autoimmune diseases like rheumatoid arthritis, type 1 diabetes or multiple sclerosis and analyse the potential of tolerogenic vaccines for atherosclerosis and the challenges that need to be overcome to bring this therapy to patients.Biopharmaceutic

PLGA, PLGA-TMC and TMC-TPP Nanoparticles Differentially Modulate the Outcome of Nasal Vaccination by Inducing Tolerance or Enhancing Humoral Immunity

Development of vaccines in autoimmune diseases has received wide attention over the last decade. However, many vaccines showed limited clinical efficacy. To enhance vaccine efficacy in infectious diseases, biocompatible and biodegradable polymeric nanoparticles have gained interest as antigen delivery systems. We investigated in mice whether antigen-encapsulated PLGA (poly-lactic-co-glycolic acid), PLGA-TMC (N-trimethyl chitosan) or TMC-TPP (tri-polyphosphate) nanoparticles can also be used to modulate the immunological outcome after nasal vaccination. These three nanoparticles enhanced the antigen presentation by dendritic cells, as shown by increased in vitro and in vivo CD4+ T-cell proliferation. However, only nasal PLGA nanoparticles were found to induce an immunoregulatory response as shown by enhanced Foxp3 expression in the nasopharynx associated lymphoid tissue and cervical lymph nodes. Nasal administration of OVA-containing PLGA particle resulted in functional suppression of an OVA-specific Th-1 mediated delayed-type hypersensitivity reaction, while TMC-TPP nanoparticles induced humoral immunity, which coincided with the enhanced generation of OVA-specific B-cells in the cervical lymph nodes. Intranasal treatment with Hsp70-mB29a peptide-loaded PLGA nanoparticles suppressed proteoglycan-induced arthritis, leading to a significant reduction of disease. We have uncovered a role for PLGA nanoparticles to enhance CD4+ T-cell mediated immunomodulation after nasal application. The exploitation of this differential regulation of nanoparticles to modulate nasal immune responses can lead to innovative vaccine development for prophylactic or therapeutic vaccination in infectious or autoimmune diseases

PLGA particulate delivery systems for subunit vaccines: linking particle properties to immunogenicity.

Among the emerging subunit vaccines are recombinant protein- and synthetic peptide-based vaccine formulations. However, proteins and peptides have a low intrinsic immunogenicity. A common strategy to overcome this is to co-deliver (an) antigen(s) with (an) immune modulator(s) by co-encapsulating them in a particulate delivery system, such as poly(lactic-co-glycolic acid) (PLGA) particles. Particulate PLGA formulations offer many advantages for antigen delivery as they are biocompatible and biodegradable; can protect the antigens from degradation and clearance; allow for co-encapsulation of antigens and immune modulators; can be targeted to antigen presenting cells; and their particulate nature can increase uptake and cross-presentation by mimicking the size and shape of an invading pathogen. In this review we discuss the pros and cons of using PLGA particulate formulations for subunit vaccine delivery and provide an overview of formulation parameters that influence their adjuvanticity and the ensuing immune response.Drug Delivery Technolog

Elastin-like polypeptide-based micelles as a promising platform in nanomedicine

NWO731.014.207Drug Delivery Technolog

Atomic force microscopy measurements of anionic liposomes reveal the effect of liposomal rigidity on antigen-specific regulatory T cell responses

Regulatory T cells (Tregs) are vital for maintaining a balanced immune response and their dysfunction is oftenassociated with auto-immune disorders. We have previously shown that antigen-loaded anionic liposomescomposed of phosphatidylcholine (PC) and phosphatidylglycerol (PG) and cholesterol can induce strong antigenspecificTreg responses. We hypothesized that altering the rigidity of these liposomes while maintaining theirsize and surface charge would affect their capability of inducing Treg responses. The rigidity of liposomes isaffected in part by the length and saturation of carbon chains of the phospholipids in the bilayer, and in part bythe presence of cholesterol. We used atomic force microscopy (AFM) to measure the rigidity of anionic OVA323-containing liposomes composed of different types of PC and PG, with or without cholesterol, in a molar ratio of4:1(:2) distearoyl (DS)PC:DSPG (Young's modulus (YM) 3611 ± 1271 kPa), DSPC:DSPG:CHOL(1498 ± 531 kPa), DSPC:dipalmitoyl (DP)PG:CHOL (1208 ± 538), DPPC:DPPG:CHOL (1195 ± 348 kPa),DSPC:dioleoyl (DO)PG:CHOL (825 ± 307 kPa), DOPC:DOPG:CHOL (911 ± 447 kPa), and DOPC:DOPG(494 ± 365 kPa). Next, we assessed if rigidity affects the association of liposomes to bone marrow-deriveddendritic cells (BMDCs) in vitro. Aside from DOPC:DOPG liposomes, we observed a positive correlation betweenliposomal rigidity and cellular association. Finally, we show that rigidity positively correlates with Treg responsesin vitro in murine DCs and in vivo in mice. Our findings underline the suitability of AFM to measureliposome rigidity and the importance of this parameter when designing liposomes as a vaccine delivery system

Lipid nanoparticle-based mRNA candidates elicit potent T cell responses

The induction of a potent T cell response is essential for successful tumor immunotherapy and protection against many infectious diseases. In the past few years, mRNA vaccines have emerged as potent immune activators and inducers of a robust T cell immune response. The recent approval of the Moderna and the Pfizer/BioNTech vaccines based on lipid nanoparticles (LNP) encapsulating antigen-encoding mRNA has revolutionized the field of vaccines. The advantages of LNPs are their ease of design and formulation resulting in potent, effective, and safe vaccines. However, there is still plenty of room for improvement with respect to LNP efficacy, for instance, by optimizing the lipid composition and tuning LNP for specific purposes. mRNA delivery is known to be strongly dependent on the lipid composition of LNPs and the efficiency is mainly determined by the ionizable lipids. Besides that, cholesterol and helper lipids also play important roles in mRNA transfection potency. Here, a panel of LNP formulations was studied by keeping the ionizable lipids constant, replacing cholesterol with β-sitosterol, and changing the fusogenic helper lipid DOPE content. We studied the ability of this LNP library to induce antigen presentation and T cell proliferation to identify superior LNP candidates eliciting potent T cell immune responses. We hypothesize that using β-sitosterol and increasing DOPE content would boost the mRNA transfection on immune cells and result in enhanced immune responses. Transfection of immortal immune cell lines and bone marrow dendritic cells (BMDCs) with LNPs was studied. Delivery of mRNA coding for the model antigen ovalbumin (OVA-mRNA) to BMDCs with a number of LNP formulations, resulted in a high level of activation, as evidenced by the upregulation of the co-stimulatory receptors (CD40 and CD86) and IL-12 in BMDCs. The enhancement of BMDC activation and T cell proliferation induced by the introduction of β-sitosterol and fusogenic DOPE lipids were cell dependent. Four LNP formulations (C12-200-cho-10%DOPE, C12-200-sito-10%DOPE, cKK-E12-cho-10%DOPE and cKK-E12-sito-30%DOPE) were identified that induced robust T cell proliferation and enhanced IFN-γ, TNF-α, IL-2 expression. These results demonstrate that T cell proliferation is strongly dependent on LNP composition and promising LNP-mRNA vaccine formulations were identified.Supramolecular & Biomaterials Chemistr

Hyaluronan molecular weight: effects on dissolution time of dissolving microneedles in the skin and on immunogenicity of antigen

Biomaterials used as matrix for dissolving microneedles (dMNs) may affect the manufacturing process as well as the potency of the active pharmaceutical ingredient, e.g. the immunogenicity of incorporated vaccine antigens. The aim of this study was to investigate the effect of the molecular weight of hyaluronan, a polymer widely used in the fabrication of dMNs, ranging in molecular weight from 4.8 kDa to 1.8 MDa, on the dissolution of microneedles in the skin in time as well as the antibody response in mice and T-cell activation in vitro. Hyaluronan molecular weight (HA-MWs) did not affect antibody responses (when lower than 150 kDa) nor CD4+ T-cell responses against model antigen ovalbumin. However, the HA-MWs had an effect on the fabrication of dMNs. The 1.8 MDa HA was not suitable for the fabrication of dMNs. Similarly, the 4.8 kDa HA generated dMN arrays less robust compared to the other HA-MWs requiring optimization of the drying conditions. Finally, higher HA-MWs led to longer application time of dMN arrays for a complete dissolution of microneedles into the skin. Specifically, we identified 20 kDa HA as the optimal HA-MW for the fabrication of dMNs as with this MW the dMNs are robust and dissolve fast in the skin without affecting immunogenicity