Projects

Abstract

Collection of an extra blood sample from volunteers who recently took part in one of two clinical trials with candidate salmonella vaccines (H08_01TP and H02_01TP) which can be used for further research with regards to Salmonella vaccines.

Researcher(s)

• Promoter: De Coster Ilse

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

To date, invasive clinician-collected cervical samples, blood, and vaginal samples are still the primary methods to monitor disease and immune responses to vaccine-preventable genital tract infections. Replacing these samples with a specimen that is non-invasive and can be self-collected at home, such as the initial or first-void urine (FVU) stream, could have major acceptance and feasibility advantages and could drastically facilitate the logistics of clinical trials and future epidemiological studies. Initial results of experiments using FVU samples for immune response monitoring are promising. Nevertheless, overall standardization is essential for FVU to become the ideal genital tract liquid biopsy in vaccine research. With my PhD project, I wish to contribute to this aspect by using Human Papillomavirus (HPV) infection and vaccination as a model. Thereby, I will mainly focus on the immunogenicity of HPV vaccines and the monitoring of immune responses using FVU as a non-invasive liquid biopsy. As this will allow identification of anti-HPV antibodies as a normalized and standardized prediction tool for the immunization status of women, I believe this project will ultimately improve follow-up in HPV vaccination studies and programs. If my project proves successful, and FVU can replace other sample types, applications will largely extend the sexually transmitted infection (STI) field, contributing to the advancement of both personal and public health.

Researcher(s)

• Promoter: Vorsters Alex
• Co-promoter: Tjalma Wiebren
• Fellow: Bell Margo

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Pertussis is a contagious respiratory disease that mainly affects children under one year of age. Vaccines are available and can be administered from six weeks of age onwards, leaving infants unprotected in the first weeks of life. To close the susceptibility gap, vaccination in pregnancy has been implemented to enhance antibodies to cross the placenta towards the unborn child. However, also cell-mediated immune responses play an important role in clearing infections in the absence of antibodies, though research is lacking. The present study aims to investigate mother-to-child cytokine transport across the placenta after pertussis vaccination in pregnancy. Cytokine levels will be measured with the Meso Scale Discovery technology in maternal and cord blood samples at delivery from mother-infant pairs enrolled in a prior Belgian cohort study. This study will give deeper understanding of the immunobiology of maternal immunization and will further improve maternal/infant health.

Researcher(s)

• Promoter: Maertens Kirsten

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Due to the high susceptibility and vulnerability of pregnant women, foetuses and infants to infectious diseases, maternal immunization has gained interest. Nevertheless, the optimal timepoint for vaccination in pregnancy is still unknown. Also, dynamic changes in immune function occur during pregnancy if a vaccine is given at a different gestational age. This may affect vaccine response and kinetics of vaccine-induced antibodies in blood and breastmilk in pregnant and lactating women. Additionally, since several recommendations for vaccination in pregnancy and in the postpartum period are currently in place, the question arises whether the administration of different vaccines has an impact on the immune responses to these vaccines and possibly causes an interaction in the kinetics of antibodies induced by these vaccines. Within this project, we aim to determine the optimal time point for vaccination in pregnancy, compare antibody kinetics and investigate potential interactions in immune responses when administering different vaccines (e.g. pertussis, COVID-19) in pregnancy or in the postpartum. We develop conceptual frameworks in which we combine statistical approaches with mathematical models of infectious diseases to improve the analysis and the design of maternal immunization studies. The focus of the project is on pertussis and COVID-19, but outcomes can be applied to infectious diseases for which vaccines can be administered in pregnancy or in the postpartum period.

Researcher(s)

• Promoter: Maertens Kirsten

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Gender-neutral HPV vaccination is a flagship policy in Europe's Beating Cancer Plan. If implemented throughout the EU with high levels of uptake, it has the potential to eliminate all the cervical, anal, vaginal, penile, head and neck cancers caused by HPV, around 67,500 new cases a year in the Member States. A key challenge to achieving high vaccine uptake is overcoming vaccine hesitancy, often based on concerns about safety. In most countries, uptake is currently too low to achieve 'herd protection'. The PROTECT-EUROPE project aims to tackle this problem on two levels. First, it will provide information and training on optimising one-to-one communication with young people and their parents/carers for the wide range of healthcare professionals involved in HPV vaccination. The training programmes will be delivered online and will be cascaded into Member States via a training-the-trainers approach. Secondly, the project will provide Member States and civil society organisations with a role in public health with guidance and a set of campaign tools aimed at young people and their parents/carers that can be used to encourage vaccination. The campaign tools will be designed for use across a range of platforms, including social media, websites, posters and leaflets. The potential of sport, specifically soccer, as an influencer will be explored. Particular attention will be paid to addressing issues of equality and diversity. All the project's outputs will be made available via an accessible online hub and disseminated via a final project report and a high-level event. The whole project will be independently evaluated by an academic institution. 34 organisations from 17 countries and a wide range of backgrounds (including oncology, general practice, pharmacy, nursing, patients, young people, public health, soccer), plus a wide range of experts, are members of the PROTECT EUROPE consortium. Nine of the countries represented have a GNI inferior to 90% of the EU average.

Researcher(s)

• Promoter: Vorsters Alex

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Cervical cancer is a major impact on public health, causing approximately 150 deaths in Belgium each year. Despite that there is a screening program in Flanders, 37% of the population eligible for cervical cancer screening is not reached by the current program that is based on analysing cervical smears (pap smears). Here, self-sampling, potentially done at home, could pose an alternative strategy for this hard-to-reach population. Infection with the human papillomavirus (HPV) is the cause of nearly all cervical cancer cases. Consequently, HPV detection is currently implemented as screening test. In case HPV is detected, an additional test (triage) is necessary to avoid overtreatment as the majority of HPV infections are spontaneously cleared and do not result in cervical cancer. For this triage the presence of aberrant cells in the pap smear is assessed. HPV detection performs well on self-samples, however, triage by detecting aberrant cells is not possible in this sample type. We will develop a test in which the detection of HPV and triage can be performed in one step on self-samples (as well as traditional cervical samples). As such we hope to reach more women and disturb less. Indeed, fewer women will need to be referred for follow-up causing less (emotional) distress. Thus, in this project we aim to reach more women in cervical cancer screening and give them a better prediction of their cancer risk.

Researcher(s)

• Promoter: Vorsters Alex
• Co-promoter: Op de Beeck Ken
• Co-promoter: Van Camp Guy
• Co-promoter: Van Keer Severien

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Human challenge studies accelerate the development of prophylactic and curative treatments: with the use of Controlled Human Infectious Model (CHIM) studies, developers get a faster understanding of the "mechanism of action" and potential efficacy at an early stage of development. In addition, this method can also be used as a replacement for the large-scale phase 3 studies, which can be very difficult or not possible in some circumstances. This is e.g. the case for new 2nd and 3rd generation COVID vaccines and other infections, such as B. pertussis, where there is already a high vaccination coverage in the population. However, human challenge studies are complex and there is a lack of standardization. Both SGS and Vaccinopolis have experience and the capacity to conduct such complex studies, of course each with its own characteristics. Moreover, the organizations are complementary. To further highlight this strength, there is a joint interest and ambition to explore the future of human challenge trials by conducting a marketing study and setting up a collection of pathogenic strains (that can be used in such studies). This will allow to work out standardized protocols for the further development of these strains into a challenge agent as well as to reach a joint modus operandi between Vaccinopolis and SGS for setting up large studies. Consequently a unique setting can be offered towards capacity, knowledge, availability and standardization. Organizations as CEPI have already indicated their interest in such a concept and it is therefore the goal of SGS and Vaccinopolis to play an important role in this.

Researcher(s)

• Promoter: Van Meerbergen Bart
• Co-promoter: Van Riel Annick

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

37% of the population eligible for cervical cancer screening in Flanders is not reached by the current program. Here, self-sampling could pose an alternative strategy for this hard-to-reach population. Persistent infection with the human papillomavirus (HPV) is the cause of nearly all cervical cancer cases. Consequently, HPV DNA detection is considered the superior screening test to date due to its increased sensitivity as compared to cytology. However, it is associated with a lower clinical specificity as the majority of HPV infections are spontaneously cleared and do not result in clinically relevant disease. Thereby an additional triage step is necessary to prevent over-referral and potentially overtreatment which can be done by cytology. HPV DNA-based screening can already be performed on self-samples, however, this is not the case for cytology. By developing a fully molecular, combined screen and triage approach (one-step) based on HPV DNA detection, quantification, genotyping, and DNA methylation and that can be applied on self-samples (as well as cervical samples), we will provide a solution for the current screen and triage challenges. This will avoid over referral and allow better guided management of women needing treatment, while simultaneously increasing the participation rate. As such, the morbidity and mortality of cervical cancer could be reduced and both the health of the patients as well as the costs for the healthcare system would be positively affected.

Researcher(s)

• Promoter: Vorsters Alex
• Co-promoter: Op de Beeck Ken
• Co-promoter: Van Camp Guy
• Co-promoter: Van Keer Severien
• Fellow: van den Borst Eef

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

The ability to easily obtain appropriate and reliable biological samples is critical to advance life sciences and public/personal health. Having a sample that is non-invasive and can be self-collected at home has major acceptance and feasibility advantages. Our team demonstrated that first-void urine (FVU) samples can replace clinician collected cervical samples to prevent cervical cancer caused by the Human Papilloma virus (HPV). Using the initial or first void urine stream is crucial here. Indeed, the outer layers of the epithelium of the genital tract exfoliate and together with the genital mucus form the utero-cervico-vaginal-smear, it accumulates between the labia minora, around the urethral opening and upon initiation of urination this discharge is washed away with the FVU. URISAMP uses HPV infection and vaccination models to prove the hypothesis that FVU is the ideal liquid genital tract biopsy to monitor immune response for women. URISAMP will 1) identify and validate analytical methods to detect the relatively low and fluctuating concentration of potential biomarkers in FVU; 2) provide protocols to study neutralizing antibodies and look at antigen-antibody interaction; 3) demonstrate how FVU sampling can enhance our knowledge regarding the biology of HPV, genital tract immunology, mechanisms of infection and transmission, the biological basis of prevention and potential correlates of protection. URISAMP will contribute to simplify and facilitate sexually transmitted infection (STI) vaccine research and provide valuable data for disease modelling. Moreover, if URISAMP proves successful, and FVU can also replace other samples types (e.g.blood), applications will largely extend the STI field, and its impact as a novel diagnostic and prognostic tool for health assessment will be substantial.

Researcher(s)

• Promoter: Vorsters Alex
• Fellow: Vorsters Alex

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Chlamydia (C.) trachomatis is a highly prevalent sexually transmitted bacterial disease, with 127 million infections reported in 2016. In women, genital tract infections by C. trachomatis can cause severe complications, including infertility, ectopic pregnancy, and chronic pelvic pain. In addition, the impact on susceptibility and transmission of other pathogens, such as HIV, has been reported. There is a consensus that prophylactic vaccination against C. trachomatis would be an important tool in our fight to control the worldwide impact of C. trachomatis. However, vaccine development, already being investigated for more than a century, is hampered by insufficient knowledge of the complex biology of C. trachomatis and its adaptations to evade interactions with the immune system. Current know-how emphasizes the importance of IFNɣ production and neutralizing antibody production as part of a successful immune response. Interestingly, the specific correlates of protection against infection are still to be revealed. This PhD will build on the know-how that is being established by our group using a first-void urine (FVU) sample for monitoring the impact of HPV vaccination programs. We have demonstrated already that FVU sampling can be effectively used to detect the presence of HPV infection and to monitor the humoral immune response. The developed tools to study the pathogen-immune system interaction will be adjusted for the follow-up of C. trachomatis infection and potential vaccine impact.

Researcher(s)

• Promoter: Vorsters Alex
• Fellow: Van Caesbroeck Anne

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Disease and vaccine monitoring based on non-invasive genital tract liquid biopsy sampling. The ability to easily obtain appropriate and reliable biological samples is critical to advance life sciences and public/personal health. Having a sample that is non-invasive and can be self-collected at home has major acceptance and feasibility advantages. Our team demonstrated that first-void urine (FVU) samples can replace clinician collected cervical samples to prevent cervical cancer caused by the Human Papilloma virus (HPV). Using the initial or first void urine stream is crucial here. Indeed, the outer layers of the epithelium of the genital tract exfoliate and together with the genital mucus form the utero-cervico-vaginal-smear, it accumulates between the labia minora, around the urethral opening and upon initiation of urination this discharge is washed away with the FVU. URISAMP uses HPV infection and vaccination models to prove the hypothesis that FVU is the ideal liquid genital tract biopsy to monitor immune response for women. URISAMP will 1) identify and validate analytical methods to detect the relatively low and fluctuating concentration of potential biomarkers in FVU; 2) provide protocols to study neutralizing antibodies and look at antigen-antibody interaction; 3) demonstrate how FVU sampling can enhance our knowledge regarding the biology of HPV, genital tract immunology, mechanisms of infection and transmission, the biological basis of prevention and potential correlates of protection. URISAMP will contribute to simplify and facilitate sexually transmitted infection (STI) vaccine research and provide valuable data for disease modelling. Moreover, if URISAMP proves successful, and FVU can also replace other samples types (e.g.blood), applications will largely extend the STI field, and its impact as a novel diagnostic and prognostic tool for health assessment will be substantial.

Researcher(s)

• Promoter: Vorsters Alex

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

The goal of the ScreenUrSelf trial is to increase cervical cancer screening attendance and compliance to follow-up by offering a first-void urine self-sampling alternative to women who are currently not participating in the organized screening program (non-responders). Offering a cost-effective, fully molecular (primary high-risk Human Papillomavirus (hrHPV) testing, and if positive methylation marker triage) first-void urine self-test with high preference and compliance to follow-up has the potential to increase screening coverage among non-responders whilst reducing cervical cancer related morbidity and mortality. If embedded in the organized cervical cancer screening program, this could positively impact both the patient's health as well as reduce costs for the Flemish healthcare system. Thus, the primary scientific goal of this project is to evaluate the (cost-)effectiveness of four different self-sampling strategies (first-void urine vs vaginal self-sampling, via an opt-in or opt-out strategy) to women who do not participate in the Flemish organized cervical screening program, compared to the standard recall letter and no intervention. Secondly, a novel follow-up "reflex" test will be evaluated in self-samples that tested positive for hrHPV.

Researcher(s)

• Promoter: Van Damme Pierre
• Co-promoter: Bilcke Joke
• Co-promoter: Van Keer Severien
• Co-promoter: Vorsters Alex

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Detection of transudated antibodies in female genital secretions, washed away with the first fraction of urine – i.e. first-void (FV) urine –, has been confirmed. In addition, vaccine-induced HPV antibodies have been detected in FV urine of women using different immunoassays. Although good correlations between paired FV urine and serum samples have been observed, urinary antibody titres are at least 1000-fold lower than serum antibody titres. To be able to distinguish between both vaccinated vs. not-vaccinated and seroconverted unvaccinated vs. non-seroconverted unvaccinated women using FV urine, antibody yield and assay sensitivity need to be increased. The first step in our process to upgrade the detection of HPV-specific antibodies in FV urine, will be the production of HPV pseudovirions (PsV) for the quadrivalent vaccine types (HPV6, 11, 16, 18) to be used in a highly sensitive immunoassay (WP1). These PsV will be used to create HPV conformational monoclonal antibodies (mAbs) in mice using the hybridoma technology (WP2.1). These mAbs will be made type-specific by desensitisation for all other included HPV PsV types before immunisation with the HPV PsV type of interest. To evaluate the quality of the produced mAbs, a DELFIA time-resolved fluorescence (TRF) assay will be developed using the created PsV. In addition, the neutralizing abilities of the generated mAbs will be assessed using our in-house pseudovirion based neutralisation assay (WP2.2). The produced PsV and mAbs will then be used in a multiplex competitive highly sensitive ELISA using the TRF technology (WP3). It is clear that monitoring neutralizing HPV antibodies non-invasively by using FV urine samples has major advantages since it (i) is an easy to collect non-invasive sample, (ii) can also provide information about the infection by applying parallel DNA testing and, (iii) is suitability for at-home sampling (currently boosted by the COVID-19 pandemic). If successful, the created assay provides a very useful and almost unique tool to monitor neutralizing HPV antibodies. With only limited adaptations, the developed assay will be compatible with serum samples as well. Since there are limited HPV immunoassays available overall, and currently only one other assay (cLIA) detects specifically neutralizing antibodies, this assay will be of great value. In addition, the validated pseudovirions and HPV type-specific neutralizing mAbs will generate substantial interest and wide applications in the field.

Researcher(s)

• Promoter: Vorsters Alex
• Co-promoter: Delputte Peter
• Co-promoter: De Vos Winnok

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

VAXINFECTIO-PD is an established Industrial Research Fund (IOF) consortium, well equipped to build an ecosystem offering research, valorisation, innovation and development to answer existing and new challenges in the field of infectious diseases and vaccinology. These domains fall within one of the valorisation domains of the Antwerp University, and the newly established business unit Antwerp Valorisation & Development (AVD) of the UAntwerp. The VAXINFECTIO-PD consortium built up a unique and extensive track record through research, services, spin-off creation and innovative pathways, in generating product concepts/prototypes and research platforms that form the basis of medical innovation. The various core research units have had an important international image in the recent years with publications in leading journals, coordination of several European projects, as well as active presence and involvement in international scientific and policy forums. For the 6-year period the IOF-consortium will further focus on 5 interlinked valorisation avenues, all creating or guaranteeing growth on the parameters P3, P4, P5 and P6: translational vaccination platform for improved and new preventive and therapeutic vaccines, prognostic and diagnostic platforms, core facilities (for cellular vaccines, human challenge studies and biobanks), infectious disease and immune modelling and prediction, and improved vaccine delivery and medical devices through product development.

Researcher(s)

• Promoter: Van Damme Pierre
• Co-promoter: Beutels Philippe
• Co-promoter: Cools Nathalie
• Co-promoter: Hens Niel
• Co-promoter: Lion Eva
• Co-promoter: Malhotra Surbhi
• Co-promoter: Verwulgen Stijn
• Co-promoter: Vorsters Alex
• Fellow: Bamberger Martina

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

In view of its effectiveness to protect infants against several infectious diseases from immediately after birth, maternal immunization has gained interest in the last years. Yet, the optimal development of this vaccination strategy is still limited by the relatively poor understanding of the immunobiology of vaccine responses in pregnancy. Dynamic changes in immune function occur throughout the gestation which can impact vaccine responses in pregnant women when vaccinating at a different gestational age in pregnancy. Within this proposal, the effect of a different timing of vaccination in pregnancy on the cellular and on different aspects of the antibody-dependent immunity (titers, subclass, functionality, glycosylation) in blood will be studied. Also, the influence of this timing on the molecular basis of maternal antibody transfer across the placenta will be investigated. Additionally, a proof of concept investigating the impact of maternal vaccination and timing of maternal vaccination on breastmilk will be constructed. Within this proof of concept, quantitative and qualitative characteristics of breastmilk antibodies will be measured and an in-vitro M-cell model to measure the role of breastmilk in protecting infants from disease will be validated. Within this project, we will focus on pertussis as an example, but outcomes of this project can be applied to other infectious diseases for which vaccines can be administered in pregnancy like GBS, RSV, CMV, SARS-CoV-2…

Researcher(s)

• Promoter: Van Damme Pierre
• Co-promoter: Maertens Kirsten

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

This initiative serves to unite the efforts and resources of 4 partnering organizations, combining the efforts and expertise of colleagues from the International Vaccine Access Center at Johns Hopkins University (IVAC), Jhpiego, the Centre for the Evaluation of Vaccination at the University of Antwerp, and the Vaccine Confidence Project (VCP) at the London School of Hygiene and Tropical Medicine (LSHTM). Together, we are working to build and support optimized local programs, guide rapid country adoption of revisions in schedule recommendations, and accelerate HPV vaccine introduction. The overarching goal is efficient translation of implementation research findings to guide practice and more equitable access to immunization ideally within the context of a stable HPV vaccine market. The goal of this project is to accelerate progress in HPV vaccine introduction, access, and program optimization in Gavi-eligible countries.

Researcher(s)

• Promoter: Vorsters Alex

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Chagas is a neglected disease endemic in 21 Latin-American countries caused by Trypanosoma cruzi. It is the largest parasitic disease burden in the Americas (>11,000,000 chronic infections) and the first cause of cardiac morbidity in poor rural/suburban areas. It became a worldwide concern as a result of mass migration with reports in 19 nonendemic areas (>1.3 million carriers in EU/USA). Treatment is difficult since acute infections have mild symptoms and remain largely unnoticed evolving to chronicity. Drug therapy is also long, often associated with side effects (10-30% interruption) and only active during early infection. The main objective of CRUZIVAX is to bridge the gap between preclinical and clinical development by performing preclinical and clinical phase 1 studies of a needle-free vaccine against T. cruzi with proven efficacy in preclinical models. The vaccine is based on a structure-engineered trivalent chimeric antigen lacking immune decoy sequences and an adjuvant promoting self-limited locally-restricted immune activation stimulating humoral and cellular immunity, which is expected to protect as prophylactic or therapeutic (combined with Benznidazole) vaccine. To achieve this CRUZIVAX will: (i) conduct preclinical studies in mice to assess immunogenicity and efficacy of different vaccine formulations in prophylactic and therapeutic settings, (ii) analyse the immunogenicity and efficacy of the best vaccine formulation in dogs and non-human primates, (iii) produce cGMP antigen and adjuvant by cost-efficient manufacturing (facilitated uptake by health systems with limited resources), (iv) perform a preclinical safety assessment of the vaccine, (v) conduct a phase 1 vaccine clinical trial in healthy volunteers, and (vi) carry out a health economics analysis to identify critical target-product profile parameters. The vaccine will strengthen the pipeline of products for Chagas disease, aimed at reducing disease burden and its social and economic impact.

Researcher(s)

• Promoter: Van Damme Pierre
• Co-promoter: Revets Hilde

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Monitoring the impact of HPV vaccination through surveys of HPV DNA prevalence in urine samples from adolescents. Many low/middle-income countries are implementing national human papillomavirus (HPV) vaccination. Establishing baseline pre-vaccination prevalence is crucial to quantify later the impact of a vaccination program. HPV prevalence can be estimated in school-attending women aged 18 to 20 years by urine-based surveys according to a standardized protocol for study population recruitment, urine collection, DNA extraction, and HPV testing and genotyping. In addition to HPV also Chlamydia can be tested on the same samples.

Researcher(s)

• Promoter: Vorsters Alex

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

The overall aim of EBOVAC3 is to support an essential part of remaining clinical and manufacturing activities required for licensure in the European Union (EU) and the United States (US) of a candidate heterologous prime-boost prophylactic vaccine regimen against Ebola virus disease.

Researcher(s)

• Promoter: Van Damme Pierre
• Co-promoter: Revets Hilde
• Co-promoter: Van geertruyden Jean-Pierre

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Pertussis (better known as whooping cough) is a vaccine-preventable respiratory tract infection mostly affecting infants who are too young to be protected by the currently available vaccines. To better protect these infants, pertussis vaccination during pregnancy has been introduced in a lot of countries worldwide. Vaccination with a tetanus, diphtheria, acellular pertussis vaccine raises the titer of disease-specific maternal antibodies in pregnant women which are then transferred to the newborn through transplacental transport and breastfeeding thereby providing passive protection to the infant in the first vulnerable weeks of life. Little evidence suggests that the antibodies ingested by the newborn via breastmilk provide local mucosal immunity in the enteric and respiratory tract, but whether they can actually be transported across the infant gut barrier into the circulation of the newborn possibly providing systemic protection is currently unexplored. The proposed project aims to develop and validate an in vitro microfold (M) cell model that mimics the infant gut barrier, to investigate the transport of secretory IgA (sIgA) antibodies in breastmilk from the enteric and respiratory tract into the systemic circulation. For this purpose, Caco-2 cells and Raji cells will be co-cultured on a transwell to form M cells, and the formation of M cells will be investigated with confocal microscopy. To validate the model, total sIgA antibodies in a limited number of breastmilk samples will be measured using ELISA before and after diffusion through the model. Once validated, total and pertussis-specific sIgA antibodies in breastmilk samples will be measured on a larger scale to determine the mucosal transport of antibodies across the infant gastrointestinal and respiratory tract . This model could be an effective and low-cost tool that contributes to exploring the impact of vaccination during pregnancy on protection provided by lactation. The project might also be the basis of more research within this field in the context of other immunoglobulins of importance and other infectious diseases for which vaccines can be administered during pregnancy.

Researcher(s)

• Promoter: Maertens Kirsten

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

An International Multicentre, Phase 2, Randomised, Adaptive study to determine need for, optimal timing of and immunogenicity of administering a booster mRNA vaccination dose against SARS-CoV-2 in the general population (18+ years) already fully vaccinated against SARS-CoV-2 (EU-COVAT-2 BOOSTAVAC). This clinical trial will be conducted in up to 26 sites in up to 9 countries in Europe.

Researcher(s)

• Promoter: De Coster Ilse

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

The Covid pandemic clearly demonstrated the need for faster development of vaccines. A human challenge trial offers the possibility to accelerate the development of vaccines and therapeutics and to gain valuable insights into efficacy early on in development. However, it requires a dedicated facility and highly trained staff to complete these complex clinical trials. Vaccinopolis offers already the possibility to conduct these trials in a one-of-a-kind facility in the world. In total, Vaccinopolis can house 30 volunteers in fully equipped rooms under Biosafety level 3 (BSL-3) conditions. The infrastructure ensures complete control on air, waste water and material flows to prevent any pathogen from escaping the facility or entering the facility in a uncontrolled way. However, in order to increase the confidence among industry and pharma partners even further and to embark on these complex trials, it would be needed to demonstrate safe operation of the facility and train the staff on all the various protocols. Hence, the goal of the project is to mimic a real life human challenge trial and test all the various operational and emergency protocols. Concretely, 20 volunteers will be recruited and will remain in the facility for 3 days. On day 1 and 2, the volunteers will remain in BSL-3 conditions. They represent the most stringent isolation conditions. In this setting also an evacuation with the fire dept will be simulated as well as an medical emergency. At the end of day 2 the conditions will be lowered to BSL-2 containment. In all conditions the operational procedures will be tested and optimized.

Researcher(s)

• Promoter: Van Damme Pierre

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project website

Project type(s)

• Research Project

Abstract

Systematic reviews have concluded that hrHPV DNA testing using target-amplification tests is as accurate on vaginal self-samples as on clinician-taken specimens for the detection of cervical precancer. However, insufficient evidence is available for specific HPV assay/self-sample device combinations. The VALHUDES protocol is designed as a diagnostic test accuracy study that aims to compare the clinical sensitivity and specificity of particular hrHPV assay(s) on vaginal self-samples and first-void-urine, collected in agreement with standardized protocols, with hrHPV testing on matched clinician-taken samples. Five hundred enrolled women referred to a colposcopy clinic are invited to collect a first-void urine sample and one or more vaginal self-samples with particular devices before collection of a cervical sample by a clinician. Sample sets are subsequently analysed in a laboratory accredited for HPV testing. Disease verification for all enrolled patients is provided by colposcopy combined with histological assessment of biopsies. A first VALHUDES study has started in Belgium in December 2017 with enrolment from four colposcopy centres. The following assays are foreseen to be evaluated: RealTime High Risk HPV assay (Abbott), cobas-4800 and -6800 (Roche), Onclarity (BD), Xpert HPV (Cepheid) and Anyplex II HPV HR (Seegene). Given empirical evidence that the relative accuracy of HPV-testing on self- vs clinician-samples is robust across clinical settings, the VALHUDES protocol offers a framework for validation of HPV assay/self-sample device combinations that can be translated to a primary screening setting.

Researcher(s)

• Promoter: Vorsters Alex

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Cervical cancer remains a significant problem worldwide, in Belgium, yearly over 200 women die from this disease. Almost all cervical cancer cases are caused by an infection with high-risk (hr) types of the Human Papillomavirus (HPV). Traditional screening programs based on cervical smear taking (Pap smear) detecting abnormal cells face limitations – including suboptimal cervical cancer screening coverage (approximately 65% in Flanders), urging the need for alternative screening approaches. Detection of primary hrHPV DNA in combination with more specific biomarkers such as methylation of host cell genes offer the opportunity to be detected in self-collected samples, like first-void urine. Within this project, we aim to provide data on the predictive value of primary hrHPV DNA and reflex methylation marker testing in first-void urine to identify cervical cancer precursor lesions that have a high short-term progression risk to cancer. Offering a fully molecular screen and triage strategy applicable on non-invasive, easily to collect first-void urine samples has the potential to increase screening participation among women currently not reached by the organized screening programs for cervical cancer.

Researcher(s)

• Promoter: Van Keer Severien

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Since pregnant women, fetuses and neonates are highly vulnerable to infectious diseases related morbidity and mortality, it of utmost important to understand barriers in the uptake of maternal vaccines to decrease vaccine hesitancy and increase vaccination coverage in fertile, pregnant and lactating women. Therefore a multidisciplinary team of experts at the University Antwerp is created, to investigate the different aspects of social media communication and its impact on vaccine confidence, acceptance and coverage in fertile, pregnant and lactating women. To study this, five research objectives are formulated: - Study the impact of the COVID-19 pandemic and increased social media communication and search behavior on attitude toward and confidence in maternal vaccines. - Develop a social listening and monitoring tool, specifically for maternal vaccination, that contributes to the systems map with social media data by identifying influential factors and that can monitor trends in vaccine hesitancy over time. - Identify interlinkage between influencing factors by using systemic thinking which may detect the dynamics among the factors that may lead to increase in vaccine confidence. - Experimental evaluation of the impact of potential social media communication strategies on behavior towards maternal vaccination. - Comparison of influential factors in different countries.

Researcher(s)

• Promoter: Maertens Kirsten
• Co-promoter: Daelemans Walter
• Co-promoter: Jacoby Alexis
• Co-promoter: Poels Karolien

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Assessment of the immunogenicity and safety of marketed vaccines for COVID-19 after regular schedule and adapted vaccine schedules and routes: BNT162b2 (Comirnaty®; Pfizer-BioNTech), mRNA-1273 Vaccine (COVID-19 Vaccine Moderna®; Moderna) and COVID-19 Vaccine (ChAdOx1-S [recombinant]) (Vaxzevria®, AstraZeneca). A A prospective, post marketing, randomized, partially single blind, multicenter, interventional study in 560 healthy adults 18-55y Most important exclusion criteria: • Confirmed previous covid-19-infection • Previous covid-19 vaccination Study will be carried out in 4 study centres, specialised in vaccination trials, in Belgium. Intervention: Vaccines: • BNT162b2: 30 mcg (IM), 20 mcg (IM) and 6mcg (ID) • mRNA-1273 Vaccine : 100mcg (IM) and 50mc (IM) • COVID-19 Vaccine (ChAdOx1-S [recombinant])

Researcher(s)

• Promoter: Steenackers Katie

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Women often want or need to be vaccinated during pregnancy or lactation. This may be with perspectives of a trip, booster vaccination or prevailing epidemics. Furthermore, vaccination during pregnancy is regarded as a valid method to provide immunological protection to the newborn. The systematic exclusion of pregnant and breastfeeding women from clinical vaccine studies means however that it often takes a long time before sufficient data are available on the effectiveness and safety of vaccination during these periods. This lack of data forces them to make uninformed risk-benefit decisions about their own health and the one of their newborn. In this prospective, multicohort, observational study, we aim to evaluate the safety and immunogenicity of COVID19-vaccination during pregnancy and lactation. Participants can freely choose to be vaccinated when they are invited through the governmental invitation scheme. Both mRNA vaccines and adenovector vaccines are accepted. To evaluate the immune response after vaccination against COVID-19, samples (blood, breastmilk, nasopharyngeal swabs) are taken at different timepoints before and after COVID-19 vaccination.

Researcher(s)

• Promoter: Maertens Kirsten

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

the project focuses during the COVID-19 pandemic on the assessment of the attitude in Belgium (different regions), towards COVID-19 vaccination and the reasons for hesitancy and low vaccination coverage.

Researcher(s)

• Promoter: Van Damme Pierre
• Co-promoter: Poels Karolien

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

In the past years the Centre for Evaluation of Vaccination (CEV) has received more and more demands of sponsors/consortia of vaccine clinical trials to collect peripheral blood mononuclear cells (PBMCs) during the clinical trial conduct. This is a consequence of the scientific communities' increasing need to evaluate not only the humoral immune response (e.g. antibodies) to vaccine exposure, but also the immune responses controlled by immune effector cells, such as specific T cells of a CD4+ helper phenotype which mediate the generation of cytotoxic T lymphocytes or the activation of innate immune effector cells. As the CEV does not have a PBMC service laboratory for isolating PBMCs, the CEV team started to collaborate in 2019 with Dr Nathalie Cools' laboratory (Laboratory for Experimental Hematology, University of Antwerp) for PBMC isolation. In the lab of Dr. Cools, 12 blood samples can be processed per day for PBMC isolation. Often there is more than 12 blood samples needed. As a consequence, our sponsors have to either reduce the subset/amount of PBMCs that are being collected during the trial conduct or they look for options outside the University of Antwerp for this service (e.g. the PBMC laboratory of the Center for vaccinology (CEVAC), University of Ghent, is able to process 30 blood samples per day for PBMC isolation). To meet the rising need of PBMC collection during vaccine clinical trials and to stay (and even become more) attractive to vaccine clinical trial sponsors/consortia, our goal is to establish a PBMC service laboratory at the CEV (CDE S2). Our initial goal is to set up a PBMC service laboratory which allows to perform 18 PBMC collections per day, while still collaborating with Dr. Cools for the same amount of samples as currently. In total, 30 PBMC collections per day could therefore be offered with this combined service. This would make the University of Antwerp more competitive with other Universities that provide this service as well (e.g. Ghent University) to perform vaccine trials for existing and future sponsors (external sources), in particular those that need a more detailed immunological analysis of responses to vaccines. In addition, it would give the CEV more independence from the laboratory of Dr. Cools, who also offers this service to other Parties (and can therefore not always assure availability). In a long term, there is also the option to increase the sample amount per day even further. Setting up the CEV PBMC service laboratory would be the first crucial step in this direction. Processing will include PBMC isolation by density gradient centrifugation, counting of viable cells and freezing of the samples. Consequently, to start up the PBMC service laboratory at the CEV, funding is needed for specific equipment (e.g. centrifuge, cell counter, cryogenic ultra-low freezer) and limited, temporary financial support for personnel. The aim is to establish a fully operational PBMC service laboratory by the end of this project. In further collaboration with Dr. Nathalie Cools' lab, a total of 30 samples a day could be processed in both labs (12 samples per lab). Once the PBMC service lab is established, the operational costs will be paid by the vaccine clinical trial sponsors/consortia.

Researcher(s)

• Promoter: Van Damme Pierre

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project website

Project type(s)

• Research Project

Abstract

The current coronavirus pandemic affects us all. As with all infections, certain subpopulations are more vulnerable to severe disease and even death and require therefore more research. In this pandemic, the elderly and immunologically fragile people are more prone to severe disease. Pregnant women and very young infants are traditionally also considered as immunologically different from the general population, certainly in view of infectious diseases. Since little to nothing is known to the scientific world of this new virus, researchers and health care personnel dealing with pregnant women and their neonates do have concerns on the risk they run. This project offers a unique opportunity to map the impact of the current pandemic in a vulnerable subpopulation of the society. The main objective of the project is to quantify the impact of the SARSCoV- 2 pandemic in pregnant women and their newborns/infants by assessing the rate of transmission, the overall health, mental well-being, immunological responses and clinical outcomes of clinicallysuspected and laboratory-confirmed COVID-19 infections in pregnant women and their neonates. Data will be collected through online questionnaires that will be send to pregnant women at a 2 week interval until 8 weeks postpartum. This will enables us to monitor possible COVID-19 infections in pregnancy and to look at possible adverse outcomes in pregnant women, fetuses and neonates. At 12 months postpartum, women will be contacted again to look at possible long-term consequences of COVID-19 infections in pregnancy on infants. Additionally, pregnant women participating in the surveillance study will be asked to provide maternal and cord blood samples at delivery to measure the prevalence of SARS-CoV-2 specific antibodies in pregnant women and newborns and to measure the transplacental transfer of SARS-CoV-2 specific antibodies from mother to infant during pregnancy. Data from this project will be used to formulate evidence-based recommendations on prevention, treatment and vaccination for COVID-19 in pregnant women and neonates. Additionally, this project will provide information for policy makers and experts in the field on public health measures and management of pregnant women and neonates during this pandemic.

Researcher(s)

• Promoter: Maertens Kirsten
• Co-promoter: Leuridan Elke
• Co-promoter: Van Damme Pierre

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

The current coronavirus pandemic affects us all. As with all infections, certain subpopulations are more vulnerable to severe disease and even death and require therefore more research. In this pandemic, the elderly and immunologically fragile people are more prone to severe disease. Pregnant women and very young infants are traditionally also considered as immunologically different from the general population, certainly in view of infectious diseases. Since little to nothing is known to the scientific world of this new virus, researchers and health care personnel dealing with pregnant women and their neonates do have concerns on the risk they run. This project offers a unique opportunity to map the impact of the current pandemic in a vulnerable subpopulation of the society. The main objective of the project is to quantify the impact of the SARSCoV- 2 pandemic in pregnant women and their newborns/infants by assessing the rate of transmission, the overall health, mental well-being, immunological responses and clinical outcomes of clinicallysuspected and laboratory-confirmed COVID-19 infections in pregnant women and their neonates. Data will be collected through online questionnaires that will be send to pregnant women at a 2 week interval until 8 weeks postpartum. This will enables us to monitor possible COVID-19 infections in pregnancy and to look at possible adverse outcomes in pregnant women, fetuses and neonates. At 12 months postpartum, women will be contacted again to look at possible long-term consequences of COVID-19 infections in pregnancy on infants. Additionally, pregnant women participating in the surveillance study will be asked to provide maternal and cord blood samples at delivery to measure the prevalence of SARS-CoV-2 specific antibodies in pregnant women and newborns and to measure the transplacental transfer of SARS-CoV-2 specific antibodies from mother to infant during pregnancy. Data from this project will be used to formulate evidence-based recommendations on prevention, treatment and vaccination for COVID-19 in pregnant women and neonates. Additionally, this project will provide information for policy makers and experts in the field on public health measures and management of pregnant women and neonates during this pandemic.

Researcher(s)

• Promoter: Van Damme Pierre
• Co-promoter: Leuridan Elke
• Co-promoter: Maertens Kirsten

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

No abstract is available in English since this project is conducted on behalf of "Vlaams Agentschap Zorg en Gezondheid" and measures the vaccination coverage in toddlers, adolescents, pregnant women, health care workers in Flanders, Belgium.

Researcher(s)

• Promoter: Maertens Kirsten
• Co-promoter: Van Damme Pierre

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Back ground: Systematic reviews have concluded that hrHPV DNA testing using target-amplification tests is as accurate on vaginal self-samples as on clinician-taken specimens for the detection of cervical precancer. However, insufficient evidence is available for specific HPV assay/self-sample device combinations. Objectives: The VALHUDES protocol is designed as a diagnostic test accuracy study that aims to compare the clinical sensitivity and specificity of particular hrHPV assay(s) on vaginal self-samples and first-void-urine, collected in agreement with standardized protocols, with hrHPV testing on matched clinician-taken samples. Study design: Five hundred enrolled women referred to a colposcopy clinic are invited to collect a first-void urine sample and one or more vaginal self-samples with particular devices before collection of a cervical sample by a clinician. Sample sets are subsequently analysed in a laboratory accredited for HPV testing. Disease verification for all enrolled patients is provided by colposcopy combined with histological assessment of biopsies. Results: A first VALHUDES study has started in Belgium in December 2017 with enrolment from four colposcopy centres. The following assays are foreseen to be evaluated: RealTime High Risk HPV assay (Abbott), cobas-4800 and -6800 (Roche), Onclarity (BD), Xpert HPV (Cepheid) and Anyplex II HPV HR (Seegene). Conclusion: Given empirical evidence that the relative accuracy of HPV-testing on self- vs clinician-samples is robust across clinical settings, the VALHUDES protocol offers a framework for validation of HPV assay/self sample device combinations that can be translated to a primary screening setting

Researcher(s)

• Promoter: Vorsters Alex

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Cervical cancer remains a significant problem worldwide, in Belgium, yearly over 200 women die from this disease. Almost all cervical cancer cases are caused by an infection with high risk (HR) types of the Human Papillomavirus (HPV). Traditional screening programs based on cervical smear taking (pap smear) detecting abnormal cells face numerous limitations, urging the need for alternative screening approaches. Detection of highly sensitive HR-HPV DNA in combination with more specific biomarkers such as methylation of host cell genes offer the opportunity to be detected in self-collected samples, like first-void urine. Therefore, we aim to demonstrate the clinical accuracy of HPV testing in first-void urine (WP2), in combination with triage markers (WP3). Followed by a population based pilot study to evaluate the performance of this novel screen and triage algorithm compared to self- and clinician-collected samples (WP4). And hereto offer a highly-accepted screening solution to women, especially benefitting hard-to-reach populations. And by means of this, decreasing the burden of cervical cancer associated disease and mortality.

Researcher(s)

• Promoter: Van Damme Pierre
• Fellow: Van Keer Severien

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Infectious diseases (ID) and antimicrobial resistance (AMR) pose a continuous and serious threat to humans and animals (One Health). Five research units from the UAntwerpen, with strong international records and collaboration, will continue to jointly capitalize on their ID expertise. EVECO studies distribution, evolution and ecology of pathogens (plague, arenaviruses, …) and wildlife hosts, offering insights for emerging ID management. LMM has established large consortia (COMBACTE, PREPARE) leading to pan-European infrastructures for ID and antimicrobial consumption research. Next to developing rapid diagnostics, LMM investigates AMR mechanisms and pathogen dynamics in vitro, in humans/livestock, and in animal models to study host-immune response (biomarker discovery) and bacterial pathogenicity. LEH performs cutting-edge research on cell-based immunotherapies, in collaboration with the UZA Center for Cell Therapy & Regenerative Medicine. LEH investigates host-immune responses in vaccine trials using multi-parametric flow cytometry and systems biology to discover novel immune correlates of protection in next-generation vaccines. CEV studies the epidemiology of vaccine-preventable diseases and performs state-of-the-art vaccine trials with large national/international networks, including maternal immunization trials and quarantine studies with genetically-modified polioviruses. Given the global need for EID vaccines (Lassa, Ebola, …) , CEV engages in several innovative (non)-human challenge-phase 1-2 studies. CHERMID undertakes methodological and applied research on the intersection between health economics, biomedicine and mathematics. CHERMID is internationally renowned for developing models of dynamic ID processes within and between hosts and integrating these with cutting edge economic models. By integrating these complementary expertises, this COE will address current and future challenges in ID management.

Researcher(s)

• Promoter: Van Damme Pierre
• Co-promoter: Beutels Philippe
• Co-promoter: Leirs Herwig
• Co-promoter: Malhotra Surbhi
• Co-promoter: Van Tendeloo Vigor

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

The general objective of this project is to design the framework for the European Paediatric Translational Research Infrastructure (EPTRI), a new Research Infrastructure (RI) aimed to enhance technology-driven paediatric research in discovery and early development phases to be translated into clinical research and paediatric use of medicines. The starting point of the proposal is the serious lack of medicines for children in EU and worldwide as well as the lack of a developmental model for paediatric medicines that integrates technology-driven aspects with the methodological, ethical and regulatory framework. The design for this new RI will be based on the following main pillars: • to harness efficiency and delivery of paediatric research activities and services strengthening collaboration within the scientific paediatric community; • to be a complementary RI in the context of the existing RIs covering the current gaps, while avoiding any duplication; • to develop a one-stop-shop for advice in paediatric drug development. To prepare a valuable Conceptual Design Report (CDR), the project encompasses three phases. During the Context Analysis phase, that will be performed in 5 technical and scientific domains (1- Paediatric Medicines Discovery, 2- Paediatric Biomarkers and Biosamples, 3-Developmental Pharmacology, 4-Paediatric Medicines Formulations and Medical Devices, 5- Underpinning Medicines Development to Paediatric Clinical Studies) the perceived value and the possible gaps to be covered will be estimated by enquiring the scientific communities and many other Stakeholders. During the Operational phase, the different components of the new RI will be depicted including governance model strategies for interaction with national Authorities and the existing RIs, the IT-architecture model, services to be provided and a business plan. Finally, a Feasibility phase is proposed to develop virtual exercises simulating the operations of the RI. The final result of the project will be the CDR to realize EPTRI.

Researcher(s)

• Promoter: Van Damme Pierre

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Despite successful universal pertussis vaccination programs, the disease remains an important public health problem and is nowadays still one of the most common vaccine-preventable diseases in the world. The highest incidence and disease burden can be found in infants below one year of age, too young to be completely protected by the available vaccines and vaccinations schedules. To better protect these infants, maternal pertussis vaccination has been introduced in a number of countries, including Belgium. Scientific evidence on several aspects of this vaccination strategy has boomed over the last years. However, some aspects of this vaccination strategy such as the long-term effect of the strategy on the infant's immune system and the recommended time frame between repeat booster Tdap vaccinations in successive pregnancies have never been investigated. To fill these knowledge gaps, we will look at the humoral immune response in children from mothers vaccinated with Tdap during pregnancy compared to children from unvaccinated mothers before and after a booster dose with a tetravalent aP containing vaccine in the first year of primary school. Also, we will look at antibody concentrations in mothers at delivery and cord blood upon a subsequent delivery. Results from these laboratory tests will feed a mathematical model to describe kinetics of antibodies in children in the presence and absence of maternal antibodies and will help us to make a recommendation on the recommended time frame between repeat booster Tdap vaccinations to have sufficient maternal antibodies at a next delivery. The present proposal will enable fine-tuning of the maternal vaccinations recommendations and existing booster policies in children after maternal vaccination.

Researcher(s)

• Promoter: Maertens Kirsten

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Despite successful universal pertussis vaccination programs, the disease remains an important public health problem and is still one of the most common vaccine-preventable diseases in the world. The highest incidence and disease burden can be found in infants below one year, too young to be completely protected by the available vaccines and vaccination schedules. To protect these infants, alternative vaccination strategies are needed. During recent years, maternal pertussis vaccination has been introduced in a number of countries. Scientific evidence on several aspects of this strategy has boomed over the last years. While interference of maternal pertussis immunization was shown on the infant's immune response after priming and first booster dose in the second year of life, knowledge on several other aspects, such as the long-term effects of the strategy on the immune responses of children later in life, is lacking. Therefore, we will look at both humoral and cellular immune responses and functionality of antibodies before and after a second booster dose of a tetravalent aP containing vaccine in children from mothers vaccinated with a Tdap vaccine during pregnancy compared to children from unvaccinated mothers. Results from these laboratory tests will feed a mathematical model to describe kinetics of antibodies in the presence or abscense of maternal antibodies in those children. The present proposal will enable fine-tuning of existing booster policies after maternal vaccination.

Researcher(s)

• Promoter: Maertens Kirsten

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Feasibility of first-void (FV) urine sampling to monitor the impact of Human Papillomavirus (HPV) vaccination has been demonstrated, mainly focusing on urine as sample to assess viral endpoints. However, equally important to confirm immunogenicity of the prophylactic HPV vaccines, in addition to the absence of persistent HPV DNA infections, is monitoring immune response against HPV. It is assumed that the presence of neutralizing anti-HPV antibodies that transudate or exudate at the anogenital sites are critical for vaccine induced protective immunity. As such, detection of anti-HPV antibodies will be an important addition to the existing viral endpoints. Interestingly, the presence of transudated HPV vaccine-induced anti-HPV antibodies, in cervicovaginal secretions (CVS) has already been confirmed by several groups, justifying our idea to look for these antibodies in FV urine. Based on the same theory behind identifying HPV DNA in FV urine, this sample may also harbor anti-HPV antibodies originating from mucus and exfoliated cells from the female genital organs, including the cervix. To the best of our knowledge, the presence of anti-HPV antibodies in (FV) urine has never been investigated. Being able to assess these in an easy and non-invasive manner will be a major advantage for epidemiological and large population studies and for follow-up of HPV vaccination trials and programs. As a result of this project, ample new applications in other fields will be created, benefiting from monitoring the humoral immune response non-invasively at large scale, reducing the need for blood-sampling.

Researcher(s)

• Promoter: Vorsters Alex
• Co-promoter: Revets Hilde

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Varicella-zoster virus (VZV) causes chickenpox in children and remains latent in neural ganglia afterwards. VZV reactivation causes shingles (herpes zoster, HZ). In WP1, we will prospectively recruit 150 HZ patients and 150 controls. We aim to show that the affinity of Major Histocompatibility Complex class I (MHC-I) molecules to bind VZV peptides, as needed for the development of VZV-specific Tcells, is reduced in HZ patients. Next, we will assess whether this reduced affinity leads to a reduced diversity of T-cell receptors directed against VZV, thereby implying a narrower scope of protection against VZV, or at least against several key VZV proteins. Finally, we will develop induced pluripotent stem cells (iPSC) derived sensory neurons from healthy individuals, infect these with VZV and assess whether addition of VZV-protein specific T-cells affects the control of VZV reactivation. In WP2, we aim to show that following primary VZV infection, glial cells, which are immune-responsive cells in the central nervous system, recognize VZV and subsequently produce protective cytokines. Moreover, we will assess whether mutations in AT-rich DNA sensor POL III in children with encephalitis, cerebellitis or stroke/vasculitis due to chickenpox cause a defective recognition of VZV and subsequently increased VZV proliferation in central neurons. We will do this by differentiating iPSC from patients and controls into neurons and glial cells, and subsequently infecting these with VZV.

Researcher(s)

• Promoter: Van Damme Pierre
• Fellow: Ogunjimi Benson

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Despite the availability of successful universal pertussis vaccination programs, the disease remains an important global public health problem and is nowadays one of the most common vaccinepreventable diseases in the world. The highest incidence and disease burden can be found in infants below one year of age, too young to be completely protected by the currently available vaccines and vaccination schedules. To protect these vulnerable infants, alternative vaccination strategies, such as maternal vaccination, are needed. During the last years, maternal pertussis vaccination has been introduced in an increasing number of countries. Scientific evidence on different effects of this vaccination strategy has boomed during the last years. However, knowledge on several important aspects of this strategy is still lacking. Therefore, the overall aim of this research proposal is to unravel the basic principles behind the maternal (pertussis) vaccination strategy. To achieve this, eight different aims are formulated in this research proposal each looking at a different immunological aspect of the vaccination strategy. We are convinced that the results of this research proposal will not only be supportive for the current recommendation on maternal pertussis vaccination, but will also help to understand the immunological mechanisms that will be used in new vaccines that are currently under development and have the potential to be used in pregnant women like GBS, RSV, CMV, Zika….

Researcher(s)

• Promoter: Van Damme Pierre
• Fellow: Maertens Kirsten

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

General use of vaccines against Streptococcus pneumoniae (S. pneumoniae) in infants has led to a decrease in the presence of the serotypes against which the vaccine was developed. It is a pathogen of which more than 90 different serotypes exist, of whom 10 to 13 are covered by the current vaccines. In order to gain a clear understanding of the S. pneumoniae serotypes carried by infants, and the impact of the vaccine used in the vaccination program, the current study was set up. As early as the first months of our lives S. pneumoniae is present in the nasal cavity and in the pharynx, mostly only temporary and innocuous, yet in some cases, in infants it may lead to infections such as otitis, pneumonia or meningitis. Since the presence of S. pneumoniae is more abundant in some circumstances, the current study focuses on infants between the age of 6 and 30 months either healthy and residing in day-care centres or suffering from an acute middle ear infection. Over a 4 year period, a swab will be taken from the nasal cavity of these infants (700 in first year, 900 in subsequent years, 6800 in total) to investigate presence, density and type of S. pneumoniae carriage, if any, as well as its resistance against antibiotics. The presence of some other pathogens that can cause airway or ear infections will be investigated too. The findings of this study will be extremely valuable to guide decisions on vaccine development, vaccine program, and recommendations on antibiotic treatment.

Researcher(s)

• Promoter: Van Damme Pierre
• Co-promoter: Malhotra Surbhi
• Co-promoter: Theeten Heidi
• Fellow: Wouters Ine

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

General use of vaccines against Streptococcus pneumoniae (S. pneumoniae) in infants has led to a decrease in the presence of the serotypes against which the vaccine was developed. More than 90 different serotypes of this bacterium exist, of whom the 10 to 13 most pathogenic ones are covered by the current vaccines. As early as the first months of our lives S. pneumoniae is present in the nasal cavity and in the pharynx, mostly temporary and innocuous, yet in some cases, it may lead to infections such as otitis, pneumonia or meningitis. In order to gain a clear understanding of the S. pneumoniae serotypes carried by infants, and the impact of the vaccine used in the vaccination program, a carriage study was set up that is running 3 years from 2016 onward. The carriage study focuses on infants between the age of 6 and 30 months since the presence of S. pneumoniae is more abundant at this age. Swabs are taken from their nasal cavity to investigate presence and dominant type of S. pneumoniae carriage. To detect and monitor hidden carriage of vaccine serotypes or other pathogenic serotypes that can be present next to the dominant serotype, additional laboratory testing will be performed on a subsample of the collected swabs in the first and third year (245 each). The findings of this study will be extremely valuable to enhance insight in transmission of S pneumoniae and to guide decisions on vaccine development, vaccine program, and recommendations on antibiotic treatment.

Researcher(s)

• Promoter: Theeten Heidi

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Cervical cancer remains a significant problem worldwide, in Belgium, yearly over 200 women die from this disease. Almost all cervical cancer cases are caused by an infection with high-risk (hr) types of the Human Papillomavirus (HPV). Traditional screening programs based on cervical smear taking (pap smear) detecting abnormal cells face numerous limitations, urging the need for alternative screening approaches. Detection of hrHPV DNA instead of abnormal cervical cells has proven more sensitive in detecting cervical cancer cases, however, it lacks clinical specificity, i.e. the ability to detect solely those women who require follow-up or immediate referral for colposcopy. Therefore, the major objective of this study is to analyse candidate biomarkers for diagnosis of cervical (pre)cancer and disease monitoring in home-collected first-void (FV) urine samples, followed by translation of the presence of (1) hrHPV DNA and (2) these biomarkers into a novel screening algorithm for cervical cancer. Hereto, we will conduct two clinical trial studies, where women (=30 years) diagnosed with an abnormal pap smear will be asked to provide a FV morning urine sample. In the first study, we aim to identify accurate biomarkers for respectively low-, and high-grade squamous intraepithelial lesions. In a second study, multiple samples will be collected over time (longitudinal sample collection) to identify biomarkers that can predict pro- or regression of HPV infection/precancerous lesions.

Researcher(s)

• Promoter: Van Damme Pierre
• Co-promoter: Tjalma Wiebren
• Co-promoter: Van Ostade Xaveer
• Fellow: Van Keer Severien

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand the client. UA provides the client research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Leuridan Elke

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Integrated vaccine and microbiological research with a focus on increasing the understanding of the immune response in prophylactic and therapeutic vaccines (including tumour vaccines) and on the containment of antibiotic resistance. Several innovative research topics are ongoing or in the pipeline: potential development of theranostic devices (e.g. rapid Point of Care Diagnostics, optical biosensors, lab-on-chip, microarrays) for pathogen detection and associated resistance in collaboration with several European research partners; potential development of new rapid diagnostic tests and injection devices; potential development of patient-specific cellular vaccines for targeted antiviral and anticancer therapy.

Researcher(s)

• Promoter: Van Damme Pierre
• Co-promoter: Berneman Zwi
• Co-promoter: Goossens Herman
• Co-promoter: Verwulgen Stijn
• Fellow: Bamberger Martina
• Fellow: Revets Hilde

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

To date fundamental knowledge is lacking regarding anatomical and physiological characteristics of the skin and skin thickness in children aged 0 to 18 years. Which results in the absence of applicable devices for accurate intradermal injections in this population. This doctoral MedTech research project aims to gather the anatomical and physiological characteristics of children and adolescents aged 0 to 18 years. First research will be done to gather anatomical and physiological characteristics of the skin of children and adolescents (WP 1). High-Frequency Ultrasound will be used to visualise the skin of children and measure thickness of the two outer skin layers. Both forearm and deltoid region will be evaluated as possible injection sites. Secondly the needle parameters will be investigated in an animal model (WP 2). Three species will be incorporated: mice, rats and piglets. Third, device prototypes will be tested in living piglets to evaluate for injection depth and distribution of the injected fluid. Lastly prototypes will be part of a clinical trial with vaccine antigen in children to evaluate for acceptability (pain perception and safety aspect) and immunogenicity. With this research, Novosanis, aims to development of a new device platform for intradermal injection.

Researcher(s)

• Promoter: Theeten Heidi
• Fellow: Van Mulder Timothi

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Berneman Zwi
• Promoter: Van Damme Pierre
• Co-promoter: Van Bockstaele Dirk
• Co-promoter: Van Tendeloo Vigor

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

T-cells are not only crucial actors in our defense against microbes but play an important role in protecting us from cancer. T-cells recognize their targets via its T-cell Receptor (TCR), which consists of a TCRa and TCRb chain. It has been shown that the cancer tissue TCR repertoire holds capacity in predicting which cancer patients will respond to checkpoint-inhibitor therapy, thereby supporting the concept that the tissue-specific TCR repertoire may be considered a stratification biomarker. Decoding the paired TCRab repertoire from the routinely obtained FFPE tissue, necessitates the development of a new single cell workflow method that will allow FFPE tissue paired TCRab sequencing. This would potentially represent a revolution, not only in oncology, but in autoimmunity diseases too where rogue Tcells could be found in affected tissues. In this project, we will create, develop and validate an experimental protocol to obtain paired TCRab data from FFPE tissue.

Researcher(s)

• Promoter: Ogunjimi Benson
• Co-promoter: Vandamme Timon

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

T-cells are increasingly recognized to be pivotal actors in the development of vaccine-induced immune responses. Through their T-cell receptor (TCR) on their cell surface, T-cells can recognize antigens derived from pathogens or vaccines. The strength of the interaction between the TCRs and the vaccine antigens will direct the T-cell dynamics after vaccination. In this project, we will analyse the TCR repertoires from participants from three distinct vaccination cohorts prior to vaccination and after vaccination. We will develop a computational tool (later to be transformed into a software package) that will allow us to accurately predict, by using the baseline TCR data alone, which vaccinees will develop a robust immune response after vaccination. This tool holds the potential to have an important impact on different aspects and actors of vaccinology ranging from the vaccine industry to public health researchers.

Researcher(s)

• Promoter: Ogunjimi Benson

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

Current serology-based testing methods to support Lyme disease (LD) diagnosis are critically flawed: they lack sensitivity (25–50%) and specificity for early LD diagnosis, and are unable to differentiate active from past infections in the burdensome late LD stages such as Lyme arthritis (LA). However, in contrast to Borrelia-specific antibodies, T cells are consistently recruited in early LD. Furthermore, different T cell subsets are thought to play a key role in developing autoimmune-driven LA in some patients, although underlying mechanisms remain enigmatic. With this FWO-SB project, we will investigate the potential of T cells as a new avenue for diagnosis. Building upon the recent advances in single-cell immune profiling, this project will deliver a novel, integrative approach for characterizing disease-associated T-cell signatures in unprecedented detail, combining T cell phenotype with its receptor specificity information on a single-cell level. We will construct this detailed immune map in patients with acute and autoimmune-driven Lyme, and contextualize it through comparative analysis with various forms of chronic autoimmune arthritis. This novel methodology will allow us to convert complex immune sequencing data into clinically actionable insights and extremely specific biomarkers. This empowers us to address the imperative diagnostic needs in Lyme, and might shed light on the elusive pathogenesis of acute and chronic LA disease states.

Researcher(s)

• Promoter: Ogunjimi Benson
• Co-promoter: Laukens Kris
• Co-promoter: Meysman Pieter
• Fellow: Van Deuren Vincent

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

T-cells are white blood cells that are elicited after exposure to pathogens, either after natural infection or vaccination. Different phenotypes of T-cells exist and these are assumed to behave functionally differently. T-cells recognize specific epitopes from pathogens via so-called T-cell Receptors (TCR) that reside on the T-cell membrane. It remains currently not known how T-cells differentiate on a TCR level. During this 5-year research plan, we will develop highly innovative mathematical and computational models to simulate how unique T-cells, represented by their TCRs, against pathogens evolve as a function of different relevant variables and perturbations. We will first further develop the new ERC cellulo-epidemiology paradigm by combining unique cellular immune responses against pathogens on a population level with mathematical modeling, thereby generating unique and otherwise not obtainable multidimensional T-cell profiles. This population level mathematical model will be an agent-based model, but the T-cell dynamics after perturbation (natural infection or vaccination) will be modeled via different modeling strategies including ordinary differential equation (ODE) based modeling. Our agent-based population model will be parameterized and fitted by in-house cross-sectional T-cell data against a wide set of pathogens from over 400 individuals (sampled again after 1 year). Primary and secondary T-cell response shape modeling will be based on unique in-house data from individuals with known first infections with Chikungunya (natural infection) or Yellow fever (vaccination) and longitudinal data from individuals re-exposed to chickenpox (natural infection), hepatitis b surface antigen (vaccination), measles (vaccination) and poliovirus (vaccination). T-cell phenotyping will be achieved via multiparametric flow cytometry and advanced single cell sequencing technology. The overarching unique and innovative goal of my future research plan is to develop a holistic in silico T-cell dynamics model to quantify how T-cell differentiation and dynamics occur after perturbation (thus either post natural exposure or post-vaccination). This will be accomplished through combining unique (longitudinal) T-cell (receptor) responses against different pathogens after infection and/or vaccination with the use of computational and mathematical modeling to unify the multidimensional cellular profiles across age and time.

Researcher(s)

• Promoter: Ogunjimi Benson
• Fellow: Ogunjimi Benson

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

This PhD project includes the statistical modelling of the results from the EBL2007 clinical trial, which is part of EBOVAC3 (IMI Horizon 2020 project) and aims to investigate the immunogenicity (WP4) of the prophylactic Ebola vaccine in Phase III (developed by Janssen Vaccines & Prevention B.V. in partnership with Bavarian Nordic A/S) in health care providers in the Democratic Republic of Congo (DRC).

Researcher(s)

• Promoter: Hens Niel
• Fellow: Garcia-Fogeda Irene

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

The development process of EQ-HWB took careful consideration of the views of patients, service users and their carers, with regard to how health and social care services and/or caring roles can impact their quality of life (QoL). As a result, theoretically, EQ-HWB has the potential to be used in various populations and thus, is suitable for outcome measurement of interventions across health and social care. Apart from collecting statistical psychometric properties to know whether EQ-HWB can function well in not only patients but also service users and carers, it is equivalently important, if not more, to know how EQ-HWB can be used across different groups of populations. Evidence from a more conceptual point of view is needed to show why EQ-HWB can have a variety of targeting audiences and how such variety can affect the measurement and evaluation of QoL. The overall aim of this study is to explore similarities and differences in perceptions of QoL, as defined by EQ-HWB, among different groups of populations, including patients, carers and the healthy general publics. We propose to use Q-methodology to investigate the subjective constructions of QoL across the groups. We would like to examine whether and to what extent the role/position of an individual can influence how the items of EQ-HWB are interpreted and evaluated.

Researcher(s)

• Promoter: Mao Zhuxin

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

Pandemics have the potential to disrupt our daily lives and to affect every part of society. SARS-CoV-2 causing COVID-19 disease painfully showed how responding too late, in a fragmented mannar and/or with too little coordination across different sectors and countries, led to huge human and economic costs. ESCAPE's main objective is to improve efficiency and scalability of early pandemic response plans by providing evidence-based guidelines, standardised research protocols, retrospective insights, and digital solutions that will support scientists in producing and integrating evidence and inform public health authorities in taking decisions to avert or reduce disease and societal burden. The project will provide knowledge and tools that will enhance Europe's preparedness for a pandemic of pathogen X. These include a science-based blueprint for faster and better decision-making in managing pandemics, tools and frameworks to improve data availability, collection and sharing, as well as advanced analytics and models to understand and project transmission dynamics of pathogen X under candidate response scenarios. ESCAPE will also identify determinants of success and failure in managing pathogen X based on the SARS-CoV-2 pandemic, helping to develop effective response strategies for future pandemics. In addition, the project will contribute to fostering a multi-stakeholder intelligent community allowing improved knowledge sharing and cooperation between policy-makers, the scientific community, the media and the public, ensuring a much more effective response to future pandemics. In the long-term, by improving pandemic preparedness and the effectiveness of response to a pandemic of pathogen X, the project will contribute to reducing health burden and potential negative societal and economic consequences during pandemics, as well as increase the confidence of policy makers and the public in science-based solutions

Researcher(s)

• Promoter: Beutels Philippe

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

This study aims to collect health related quality of life data relevant for infants suffering from Respiratory Syncytial Virus infection in different European countries, using standardised health related quality of life instruments.

Researcher(s)

• Promoter: Beutels Philippe

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

The primary aims of this project are (1) to use mathematical models to predict the impact of next-generation rotavirus vaccines in Malawi and Ghana, (2) to conduct a health economic evaluation to determine whether switching to next-generation rotavirus vaccines is a cost-effective strategy in Malawi and Ghana, and (3) to determine the predicted impact and cost-effectiveness of next-generation rotavirus vaccines across all low- and middle-income countries.

Researcher(s)

• Promoter: Beutels Philippe

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

RSV causes severe disease in the very young and elderly and results in substantial healthcare costs. In the last 4 years, substantial progress has been made in development of products for active and passive immunization against RSV, with 19 products currently in clinical development. In 2017, we were funded by IMI to set up RESCEU project (Grant Agreement number 116019), which is the single largest consortium currently working on RSV and has addressed several of the key evidence gaps to inform the introduction of an RSV vaccine. However, new gaps in evidence have emerged and many key requirements for the introduction of a novel RSV vaccine into national immunisation programmes (not addressed within RESCEU) remain unmet. PROMISE's vision is to seamlessly build on, exploit, and add value to the significant achievements of RESCEU to prepare for the imminent introduction of an RSV vaccine. Expanding the existing RESCEU network to include 5 new partners, PROMISE comprises of 5 distinct but interconnected work packages (WPs). WP 1 will conduct epidemiological and cost-effectiveness analyses marshalling data from systematic reviews; national and regional disease registries; surveillance programmes and linked routine healthcare datasets. WP2 will foster a consensus and develop an operational plan for expanded coordinated RSV surveillance and reporting activities; post-licensure monitoring and evaluation of products for RSV immunization across Europe. WP3 will initiate new prospective studies to address key gaps in existing knowledge (RSV disease severity scores, asthma in school age children) and assemble biobanks for biomarker validation. WP4 will validate temporally and at mucosal level biomarkers that were identified in RESCEU adopting state of the art technologies. WPs 1-4 will develop high-quality, sustainable, robust data collection systems that link closely with public health/ regulatory bodies/health care providers for informing policy and regulatory processes.

Researcher(s)

• Promoter: Beutels Philippe

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project website

Project type(s)

• Research Project

Abstract

Multiple Sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease leading to focal and diffuse damage of myelin sheath and axons in the central nervous system (CNS). Pathophysiologically, the adaptive and innate immune system are involved in the inflammatory process, while mitochondrial dysfunction, oxidative stress and failure of remyelination are the main mechanisms in chronic neurodegeneration. Despite currently available disease modifying treatments (DMTs) that target the immune system, patients continue to accumulate disability leading to progression. Unfortunately, no neuroprotective or remyelinating agents are available as therapy for progressive MS. Hence, drugs to tackle disease progression in MS represent a major unmet need. In this respect, metformin is a very interesting drug to investigate in MS patients as a neuroprotective and remyelinating therapy. Several preclinical studies in animal models of MS have shown that metformin has both anti-inflammatory, neuroprotective and remyelinating properties. A clinical study with metformin in a limited sample of MS patients did not demonstrate significant adverse events. As metformin is available as generic drug and the price is low (0.10 eurocent per tablet), pharmaceutical companies have no interest is sponsoring clinical trials with this agent. However, major gains for patients and society may be reached if metformin proves to be a neuroprotective and remyelinating agent. In this research proposal we aim to provide evidence for the neuroprotective and remyelinating effects of metformin (I) in MS patients (P) via measurement of clinical and MRI outcome measures (O), via a multicentre randomized placebo-controlled (C) clinical trial.

Researcher(s)

• Promoter: Bilcke Joke
• Promoter: Willem Lander

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)
• Primary and interdisciplinary care Antwerp (ELIZA)

Project type(s)

• Research Project

Abstract

In this proposal we focus on challenges regarding infectious diseases such as measles elimination and optimal influenza vaccination and draw motivation from fundamental questions with respect to healthcare prioritisation. Advancements in the fields of epidemic modelling, health economics and multi-agent learning paired with formally-verified guarantees can improve the effectiveness and reliability of the complex decision-making mechanisms needed to answer such questions. This complexity is situated in different aspects: the computational complexity, model structure and the interactions between multiple agents, in combination with multi-criteria objectives. Our consortium establishes a unique combination of leading expertise, which as a team not only will advance each of these fields, but also develops a new, internationally unique, multidisciplinary research line.

Researcher(s)

• Promoter: Beutels Philippe
• Co-promoter: Perez Guillermo Alberto

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

Celluloepidemiology is a term invented to describe an interdisciplinary approach combining unique cellular immune responses against pathogens on a population level with mathematical modeling, thereby generating unique and otherwise not obtainable multidimensional T-cell profiles. CELLULO-EPI will develop and use such a highly innovative model to simulate how T-cells against pathogens evolve in a synthetic population as a function of age, gender, time since infection and other relevant variables. This model will be parameterized and fitted by cross sectional T-cell data against a wide set of pathogens from 500 individuals (sampled again after 1 year), unique data from individuals with known first infections with dengue and measles and longitudinal data from individuals re-exposed to chickenpox and parvovirus B19. The insights of CELLULO-EPI will be pivotal for public health. One important example: Varicella-zoster virus (VZV) causes chickenpox but also shingles after VZV reactivation. Vaccination can prevent chickenpox, but the predicted increase in shingles incidence has blocked chickenpox vaccination in many EU-countries. Indeed, re-exposure to chickenpox is hypothesized to protect against shingles through boosting of T-cells. Unfortunately, none of the available epidemiological or immunological tools allow for adequate validation of the boosting hypothesis. However, CELLULO-EPI will be able to solve this persisting VZV vaccination dilemma. Furthermore, CELLULO-EPI will also redefine infectious disease epidemiology, for example by allowing us to back-calculate the time since last exposure.

Researcher(s)

• Promoter: Ogunjimi Benson

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of autoimmune diseases that mainly affect the joints in children under the age of 16-18 years. It is the most common chronic arthritis in childhood with a prevalence of 16-150 in 100,000 children, in which enthesitis-related JIA (JIA-ERA) represents up to 20% of JIA cases. JIA-ERA has long been characterised by a strong association with HLA-B27, which is a major histocompatibility complex class I on the cell surface that is responsible for presenting antigenic peptides (derived from self and nonself antigens) to T-cells. However, it remains unclear how HLA-B27 contributes to the onset and pathogenesis of JIA-ERA. In cell-mediated autoimmunity, T-cells (including CD4+ and CD8+ T-cells) have been implicated in mediating many aspects of autoimmune inflammation. Among CD4+ T-cells, CD4+CD25+FOXP3+ regulatory T-cells (Tregs), which are crucial in preserving immune homeostasis, are believed to be dysfunctional in autoimmunity. Although Tregs were identified and analysed in different rheumatic diseases, their role is incompletely understood. There are also very few publications available that investigate the heterogeneous phenotypes and functions of T-cells at the inflamed site across different paediatric rheumatic diseases. Stemming from this dilemma, there are two research questions that I want to answer in this proposed study: (1) by which mechanism HLA-B27 confers its effects in JIA-ERA (i.e., molecular mimicry/arthritogenic peptide theory, free heavy chain theory, or protein misfolding theory) and how does HLA-B27 participate distinctly in JIA-ERA compared to other adult or juvenile arthritis; (2) what are the roles of different subsets of synovial T-cells in JIA-ERA pathogenesis and how does the T-cell receptor (TCR) profile of Tregs differ from those of conventional CD4+ and CD8+ T-cells in HLA-B27+ JIA-ERA patients' synovial fluid. To my knowledge, this will be the first (pilot) study that analyses the roles of HLA-B27 and T-cells in different types of JIA and compares JIA with other adult and juvenile arthritis. Modern (paediatric) rheumatology is increasingly evolving in a direction of pathology-specific and patient-specific diagnostics and therapy (i.e., personalised medicine). Better molecular stratification is thus an absolute necessity to improve patient care. A key transforming factor in (paediatric) rheumatology has been the application of sequencing techniques (e.g., microarray, Sanger sequencing, and next-generation sequencing) in assessing the TCR repertoire in blood cells or synovial fluid cells. Characterisation of TCR profiles is rapidly becoming an important complement to conventional immunophenotyping in understanding disease pathogenesis, prognosis, and response to treatment. Considering the research questions and state-of-the-art mentioned above, I believe that studying the TCR repertoire of synovial T-cells in HLA-B27+ patients will provide important knowledge of JIA-ERA.

Researcher(s)

• Promoter: Ha My

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

A substantial number of studies estimated mapping functions between a preference-based measure, such as EQ-5D, and other non-preference-based measures, but few have looked into the concepts being measured by the present measures to check the legitimacy of mapping. Concepts such as health-related quality of life (HRQoL) and mental well-being are vaguely defined in health outcomes research and there is no agreement on their definitions and measurement. A crude analysis of the PubMed citations indicates that EQ-5D is associated with terms such as health status (29%), health-related quality of life (85%), quality of life (81%), well-being (6%), patient-reported outcome (9%), and/or satisfaction (10%), but what does EQ-5D measure? These concepts are not well clarified. In this study, we aim to use a series of statistical methods to explore the constructs of HRQoL and mental well-being, as defined by EQ-5D and GHQ-12, respectively. Specifically, we aim to understand to what extent the items of EQ-5D and GHQ-12 associate/overlap with each other. The second aim is to provide empirical evidence to distinguish the constructs of concepts including health, quality of life, mental well-being and satisfaction, which are all vaguely defined and often used interchangeably. We will use the data collected in the 'Great Corona Study' (GCS) in Belgium. The GCS study included EQ-5D-5L, GHQ-12, overall satisfaction score, the Brief Resilience Scale (BRS) and the 6-item Revised UCLA Loneliness Scale (ULS-6). We will perform a set of statistical analyses, including multidimensional scaling and exploratory factor analysis to attain the research aims.

Researcher(s)

• Promoter: Mao Zhuxin

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

Chikungunya virus (CHIKV) is a reemerging human pathogen that has seen a rapid global spread in the past decade. It is the most wide-spread member of a group of mosquito transmitted, arthritogenic viruses that can leave up to half of the patients with chronic joint pains long after the initial infection. The chronic joint pain is caused by sustained inflammation and bears hallmarks of auto-immune rheumatoid arthritis. However, the antigenic driver of the prolonged joint inflammation, and the relative contribution of auto-reactive immune cells have not been elucidated. Using next-gen T-cell Receptor (TCR) sequencing on peripheral blood CD4 T cells from CHIKV patients that do or do not develop sustained joint pains we will identify the TCR signatures specifically associated with development of chronic disease. These preliminary findings will extend the role of T cells in the etiology of chronic CHIKV to humans, provide a basis for the search for the antigenic drivers of the disease and potentially identify biomarkers for progression to chronic CHIKV.

Researcher(s)

• Promoter: Ogunjimi Benson
• Co-promoter: Laukens Kris
• Co-promoter: Meysman Pieter

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

Current serology-based testing methods to support Lyme disease (LD) diagnosis are critically flawed: they lack sensitivity (25–50%) and specificity for diagnosis in early LD, and are unable to differentiate active from past infections in the burdensome late LD stages such as Lyme arthritis (LA). In contrast to Borrelia-specific antibodies, T cells have been shown to be consistently recruited in early LD. Furthermore, different T cell subsets are thought to play a key role in the development of later postinfectious (autoimmune-driven) LA. With this FWO-SB project, we will investigate the potential of T cells as a new avenue for diagnosis. Building upon the recent advances in single-cell immune profiling, this project will deliver a novel framework for characterizing disease-associated T-cell signatures in unprecedented detail, integrating the T cell phenotype with its receptor specificity on a single-cell level. We will address the critical need for post-analysis tools for such complex datasets by developing novel immunoinformatic workflows, allowing efficient extraction of clinically actionable insights and extremely specific biomarkers. Employing the developed methodology and tools across various types of LD, LA, and other relevant autoimmune-driven arthritides will then empower us in addressing the imperative diagnostic need and in shedding light on the elusive pathogenic mechanisms behind postinfectious LA.

Researcher(s)

• Promoter: Ogunjimi Benson
• Co-promoter: Laukens Kris
• Co-promoter: Meysman Pieter
• Fellow: Van Deuren Vincent

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

High throughput sequencing allows the characterization of the human immune system, but the resulting data cannot simply be translated into clinical insights. We have therefore developed artificial intelligence models that can translate T-cell receptor (TCR) and gene expression data into useful insights about an individual's immune status. For example, we have developed the first online platform to predict the epitopes of TCRs. We have demonstrated its value for predicting and modeling vaccination-induced immune responses.

Researcher(s)

• Promoter: Ogunjimi Benson

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

To date, only a handful of studies have generated cost-effectiveness estimates for Vi-polysaccharide vaccines, and all of these have been based on static modeling approaches. We will conduct cost-effectiveness analyses (CEAs) to assess the costs and effects of new and existing TCV vaccination strategies compared to no vaccination from the health care perspective based on dynamic models. We will build off of CEAs currently being led by Dr. Pitzer (funded by BMGF) by incorporating primary data from sentinel hospitals in the surveillance sites to inform immunization rates and estimates of costs of vaccine administration and disease.

Researcher(s)

• Promoter: Bilcke Joke

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

Mathematical simulation models have become indispensable tools for forecasting and studying the effectiveness of intervention strategies such as lockdowns and screening during the SARS-CoV-2 pandemic. Estimation of key modeling quantities uses the serological footprint of an infection on the host. However, although depending on the type of assay, SARS-CoV-2 antibody titers were frequently not found in young and/or asymptomatic individuals and were shown to wane after a relatively short period, especially in asymptomatic individuals. In contrast, T-cells have been found in different situations – also without antibodies being present - ranging from convalescent asymptomatic to mild SARS-CoV-2 patients and their household members, thereby indicating that T-cells offer more sensitivity to detect past exposure to SARS-CoV-2 than the detection of antibodies can. In this project, we will gather on a population level T-cell and antibody SARS-CoV-2 specific data from different well-described cohorts including 300 individuals (and 200 household members) who have had proven covid-19 infection > 3 months earlier, 100 general practitioners, 100 hospital workers, 500 randomly selected individuals and 75 pre-covid-era PBMC/sera. This data will be used in comparative simulation models and will lead to a reassessment of several key epidemiological estimates such as herd immunity and the reproduction number R that will significantly inform covid-19 related public health interventions.

Researcher(s)

• Promoter: Ogunjimi Benson
• Co-promoter: Beutels Philippe
• Co-promoter: Coenen Samuel
• Co-promoter: Laukens Kris
• Co-promoter: Lion Eva
• Co-promoter: Meysman Pieter
• Co-promoter: Van Damme Pierre

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

In order to suppress or mitigate the COVID-19 – or any similar future - pandemic, both speed and broad population engagement are key. This project aims to collect timely information on behavioural change (voluntary or enforced by government), symptoms, workforce participation and telework, postponed treatment for non-COVID-19 related disease, as well as its psychological and social impact. We do this by setting up a large scale weekly online survey, allowing us to study evolutions over time as well as patterns in the large sets of data obtained (thus far 1 in 6 people in Flanders participated in at least one of the 6 survey waves). We use a great diversity of advanced statistical techniques to analyse the data generated, and share our insights directly with policy makers and the general public. This information directly informs policy making and partly feeds into mathematical models predicting the evolution of the pandemic under various scenarios, and can partly also be used to estimate its economic and social impact. Drawing from this experience, for future COVID-19 waves or other pandemics we aim to set up a lasting framework to obtain quickly reliable information that is representative of the general population. We also want to establish a lasting database, that enables researchers of various disciplines to use as study material in years to come.

Researcher(s)

• Promoter: Beutels Philippe
• Co-promoter: Van Damme Pierre

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

EpiPose aims to provide urgently needed answers about the epidemiological characteristics of 2019-nCoV, the social dynamics of the outbreak, and the related public health preparedness and response to the ongoing epidemic, as well as to assess its economic impact. The consortium consists of 6 partners in 5 countries (BE, NL, UK, CH, IT) who provide complementary expertise in mathematical and statistical modelling of infectious diseases, participatory surveillance systems, living systematic reviews, and health economic analysis and have a strong international public health network. EpiPose aims at a quick delivery of results, according to the following objectives: (1) To collect and share epidemiological data of 2019-nCoV as widely as possible (2) To provide country-specific estimates of key epidemiological parameters (3) To model the expect impact of 2019-nCoV on morbidity and mortality (4) To monitor awareness and behavioural change during the 2019-nCoV epidemic (5) To provide health economic analyses for interventions within the EU (6) To foster the interaction between the scientific community, public health agencies and the public EpiPose aims to make all research data, code, tools and results publicly available and its dissemination plan targets active communication and interaction with policy makers, other scientific groups and the general public. As such, the epidemic intelligence provided by EpiPose will help minimize the 2019-nCoV's public health, economic and social impact.

Researcher(s)

• Promoter: Beutels Philippe

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

Background – Infectious diseases have substantial impact on society and model-based health economic evaluation has acquired prominence for policy making. Stochastic individual-based models, in which each individual is modelled separately, are highly relevant to capture heterogeneities in social contacts patterns and transmission dynamics. Although they are suitable to predict disease burden and medical costs in detail, they are not fully exploited yet due to model complexity and computational burden. Aim – To improve health economic evaluations with stochastic individual-based disease transmission models while accounting for uncertainty. Methods – To advance from a C++ simulator towards a new platform for health economic evaluation, "rStride" in the widely used R software. This open-source package will integrate high-performant transmission modelling and state-of-the-art uncertainty analysis. Expected results – (1) New and improved individual-based modelling methods on demography and transmission dynamics. (2) Insights on the effect of social mixing assumptions on the estimated burden of disease. (3) The integration of stochastic effects from individual-based transmission models within uncertainty analysis in economic evaluations. (4) Long-term model predictions, including household dynamics, to explore between- and within-host dynamics. All methods will be applied to case studies on Respiratory Syncytial Virus (RSV) and Varicella-Zoster Virus (VZV).

Researcher(s)

• Promoter: Beutels Philippe
• Fellow: Willem Lander

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

Deze Franqui chair is occupied by Prof Philippe De Wals, Professor at the Laval University in Quebec, Canada. The subject is immunisation programs. During his stay he will convene a "Class of Excellence", selected from different universities. At the end of his stay there will be a symposium at UAntwerpen, with collaboration of this "Class of Excellence".

Researcher(s)

• Promoter: Beutels Philippe
• Co-promoter: Van Damme Pierre

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

Varicella-zoster virus (VZV) causes chickenpox in children and remains latent in neural ganglia afterwards. VZV can cause encephalitis or cerebellitis during both the acute and subacute phases of chickenpox. After resolution of chickenpox, VZV can reactivate from its latent state and cause herpes zoster. Moreover, VZV reactivation is believed to be able to cause stroke in children. The pathophysiology underlying all of these central nervous system VZV complications remains largely unknown so far. In this project, we aim to deepen our understanding regarding two factors that might cause a genetic predisposition in humans for the development of chickenpox-associated neurological complications. Preliminary data from our lab previously showed that mutations in RNA polymerase III (POL III) cause a defect in VZV sensing (via AT-DNA "recognition") in blood cells and consequently cause a reduced control of VZV proliferation. In this project, we first aim to show that following primary VZV infection, glial cells, which are immune-responsive cells in the central nervous system, recognize VZV and subsequently produce protective cytokines. Moreover, we will assess whether mutations in AT-DNA sensor POL III in children with encephalitis, cerebellitis or stroke/vasculitis due to chickenpox have a defective recognition of VZV and subsequently increased VZV proliferation in central neurons. We will do this by differentiating induced pluripotent stem cells (iPSC) from patients and controls into neurons and glial cells, and subsequently infecting these with VZV. This will lead to a simultaneous analysis of VZV dynamics in neurons and cytokine production by glial cells. Preliminary data from our labs and others have shown that the cellular process called autophagy, important for protein processing, might be involved in cellular VZV dynamics as inhibition of autophagy led to reduced VZV proliferation. In this project, we aim to further address this potential pathogenic route by experimentally inhibiting autophagy in iPSC-derived neurons from healthy controls and measuring the subsequent effects on VZV dynamics. In addition, we noted that 3/9 cerebellitis patients had a mutation in the autophagy-associated gene TBC19DB. In a first exploration, we will assess how autophagy is affected by this mutation and whether this influences VZV proliferation in monocytes from these patients and controls.

Researcher(s)

• Promoter: Ogunjimi Benson
• Co-promoter: Le Blon Debbie
• Fellow: Buyle-Huybrecht Tamariche

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

There are few preventive RSV interventions available and these are generally too expensive for widespread use outside of high-income regions. There are additional RSV preventive interventions under development including maternal RSV vaccines to protect infants as well as monoclonal antibody approaches to be given to infants. PATH has developed an RSV impact and cost effectiveness model for RSV interventions. The purpose of this work is to develop another model for comparison purposes.

Researcher(s)

• Promoter: Beutels Philippe

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

Respiratory syncytial virus (RSV) is not well known outside medical circles, yet most people have probably suffered from it in childhood, as it is the most common cause of severe respiratory illness in infants and children worldwide. The elderly and people with weakened immune systems are also vulnerable to RSV infection. While most people's symptoms are mild, it can result in pneumonia and 3.4 million cases annually require hospitalisation. There is no specific treatment or vaccine for RSV. The goal of the RESCEU project is to gather information on the scale of RSV infection in Europe and its economic impacts. It will then use this information to design best practice guidelines to improve the way RSV cases are monitored in Europe, and to shape future vaccination programmes. The team will also gather and analyse patient samples to identify biological markers associated with severe RSV infection. This information could aid in diagnosis and facilitate the development of new treatments and vaccines.

Researcher(s)

• Promoter: Beutels Philippe
• Co-promoter: Bilcke Joke
• Co-promoter: Hens Niel

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project website

Project type(s)

• Research Project

Abstract

Health expenditure in wealthy countries (eg Belgium) increased much over the last 50 years. Growth in health care resources and their use (more and better diagnostics, medication, hospitals, nurses and physicians) may often have surpassed economic and population growth. Knowing how different ways of making health care available translated into different levels of population health is key to evaluating health system efficiency. We want to study the interdependencies between numerous potential determinants of health and health outcomes at the population level.

Researcher(s)

• Promoter: Beutels Philippe

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

TransMID focuses on the development of novel methods to estimate key epidemiological parameters from both serological and social contact data, with the aim to significantly expand the range of public health questions that can be adequately addressed using such data. Using new statistical and mathematical theory and newly collected as well as readily available serological and social contact data (mainly from Europe), fundamental mathematical and epidemiological challenges as outlined in the following work packages will be addressed: (a) frequency and density dependent mass action relating potential effective contacts to transmission dynamics in (sub)populations of different sizes with an empirical assessment using readily available contact data, (b) behavioural and temporal variations in contact patterns and their impact on the dynamics of infectious diseases, (c) close contact household networks and the assumption of homogeneous mixing within households, (d) estimating parameters from multivariate and serial cross-sectional serological data taking temporal effects and heterogeneity in acquisition into account in combination with the use of social contact data, and (e) finally the design of sero- and social contact surveys with specific focus on serial cross-sectional surveys. TransMID is transdisciplinary in nature with applications on diseases of major public health interest, such as pertussis, cytomegalovirus and measles. Translational methodology is placed at the heart of TransMID resulting in the development of a unifying methodology for other diseases and settings. The development of a toolbox and accompanying software allow easy and effective application of these fundamentally improved techniques on many infectious diseases and in different geographic contexts, which should maximize TransMID's impact on public health in Europe and beyond.

Researcher(s)

• Promoter: Hens Niel

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

BACKGROUND: Dynamic models and sensitivity analysis are valued as crucial to inform decision makers on the cost-effectiveness of interventions against infectious diseases. But currently, sensitivity analyses fail to account for the uncertainty from dynamic models, as such overestimating the confidence in the cost-effectiveness estimate and potentially setting wrong priorities for future research. AIM: To include the uncertainty from transmission-dynamic models in health economic evaluations based on these models. METHODS: We will conduct health economic evaluations of vaccination against rotavirus in Belgium and typhoid in low-income countries, based on existing transmission-dynamic models, and will use probabilistic methods to incorporate the estimated uncertainty from the dynamic models. EXPECTED RESULTS: Identification of the factors that are most influential for (1) the cost- effectiveness of rotavirus vaccination in Belgium when accounting for herd immunity and potential serotype replacement, and (2) the cost-effectiveness of implementing the newly developed typhoid vaccine strategies in low-income countries. (3) Software tool that allows for easy re- assessment of cost-effectiveness and future research priorities when new information becomes available. (4) Recommendations on how to apply different types of sensitivity analysis in the context of health economic evaluations based on dynamic disease transmission models.

Researcher(s)

• Promoter: Beutels Philippe
• Fellow: Bilcke Joke

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

The aim of the project is to develop a suite of advanced, state-of-the-art methodology for epidemiologists and biostatisticians interested in modeling infectious diseases spread from person to person. The key mechanism underlying infectious disease spread is the contacts susceptible people make with infectious people. The individuals in the population can be represented by nodes and the contacts between them as lines connecting the nodes. The collection of nodes and connecting lines is called a contact network. This project aims to collect data on contact networks at home, at school and at work and to develop new statistical methodology that allows for the estimation of key epidemiological parameters such as the basic reproduction number and the generation interval distribution while dealing with complexities as missing data. There are five main objectives: (1) Design and conduct a pilot contact network survey; (2) Develop statistical methodology to estimate the network from egocentric or second generation network data; (3) Augment existing methodology to estimate parameters from observed outbreaks using network theory; (4) Develop methodology to estimate parameters from partially observed outbreaks; (5) Develop an easy-to-use statistical toolbox for epidemiologists interested in the surveillance of epidemics.

Researcher(s)

• Promoter: Hens Niel
• Fellow: Torneri Andrea

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

Synucleinopathies, encompassing diseases like Parkinson's disease and dementia with Lewy bodies, are a group of neurodegenerative disorders characterized by the formation of alpha-synuclein (αSyn) aggregates that are able to propagate in a prion-like manner between cells of the nervous system. However, the exact role of αSyn pathology in the disease progression of these synucleinopathies remains to be elucidated. Moreover, microglia have been pointed to as a major player in synucleinopathy pathophysiology, but how these cells affect αSyn pathology remains unclear. Current in vitro models are limited in their ability to replicate human responses to pathological αSyn with sufficient fidelity. Recently developed (microglia-containing) brain organoids represent a promising new tool to study αSyn pathology in a human-brain like environment. In this study, we will use human brain organoids or 'neurospheroids' (NSPHs) to enhance our understanding of αSyn pathology, focusing on propagation and associated pathophysiological pathways. By using NSPHs with and without microglia (annotated as tri- and bipartite NSPHs), we aim to determine the role of microglia and neuroinflammation in these processes. To this end, pre-formed αSyn fibrils will be added to NSPHs. Staining of NSPHs for pathological αSyn, by phosphorylated αSyn antibody and thioflavin, at different timepoints allows to monitor internalization, accumulation and propagation of αSyn pathology. Altered pathophysiological pathways will be determined by RNA-sequencing and validated at the protein level by means of immunocytochemistry (ICC). In summary, this project will help to identify major alterations associated with αSyn pathology and clarify the role of microglia in a human brain-like context.

Researcher(s)

• Promoter: Van Breedam Elise

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Next Generation Sequencing (NGS) has emerged as a suitable tool to evaluate and characterize the T Cell Receptor (TCR) immune repertoire. This approach paves the way for the use of the TCR repertoire study as a novel complex biomarker to track the exposure of individuals to non-self antigens and to develop new therapeutic strategies by improving our comprehension of the adaptive immune response against infectious agents and cancer antigens. The collaboration between Italy's Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" (IRST) and Belgium's University of Antwerp involves both these fields and aims to identify and characterize specific human TCRs via NGS to develop therapeutic TCR-T cells, exploiting experimental protocols, in silico analysis, and in vitro assays for T cell stimulation with antigens' pools. The first objective is to study the T cell response to mRNA-based COVID vaccines in healthy subjects and lymphoma patients from Emilia Romagna region through RNA samples sequencing and subsequent analysis of TCR specificity against SARS-CoV-2 proteins. The correlation between TCR diversity and strength with the amount of neutralizing antibodies will also be examined in consideration of the predicted HLA context, leading to an actionable SARS-Cov2 bulk TCR-seq database. Genomic instability, which is a common feature in cancer cells, often leads to the generation of chromosomal rearrangements and aneuploidy. Many are the examples today of gene fusions that promote cell transformation in different oncological settings. Those events lead to the unique opportunity to generate neoantigens that could be presented to the immune system in an HLA-restricted manner. Therefore, the second objective is the identification and validation of neoantigens originated from genetic fusion events in cancer patients already available in IRST. Subsequently, experiments will be focused on the identification of antigen-specific T cells and TCRs against neoantigens originating from selected genetic fusion events. To these ends, computational protein reconstruction and prioritization from the already available fusion genes database will be performed to retrieve fusion transcripts in hematological tumors. These peptides will be later synthesized and pooled to stimulate T cells, with subsequent expansion and characterization of the expressed receptors. Before that, a proof-of-concept T cell expansion and following TCR-identification experiments with model protein(s) for a known neoantigen will be set up.

Researcher(s)

• Promoter: Lion Eva
• Co-promoter: Campillo Davó Diana
• Co-promoter: Meysman Pieter

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The research team of prof. Peter Ponsaerts at the Laboratory of Experimental Hematology (University of Antwerp, UA) has established during the past 5 years multiple 2D and 3D murine and human iPSC-derived neuro-immune cell culture models (including neurons, astrocytes, macrophages and microglia), with a specific focus on inflammation, viral infection, stroke and Parkinson's Disease. Having established these models, the research team of prof. Peter Ponsaerts has already implemented standard cytokine profiling, immunocytochemistry (ICC) and bulk RNA-Seq analyses for cell type characterization and cellular responses to inflammation, trauma or infection. Nevertheless, there is an unmet need to advance their experimental toolbox to characterize 2D and 3D neuro-immune cell culture models. The envisaged research sabbatical at the "Mass Spectrometry Lab" of the "Analytical Biochemistry and Proteomics Research Unit" from the "Center for Advanced Studies and Technology (CAST)" at the "University G. d'Annunzio" in Chieti-Pescara in Italy aims at two educational (E) and two scientific (S) action points: (E1) To learn and understand the base principles of high sensitivity proteomics and metabolomics (including metallomics and lipidomics) analyses using state-of-the-art mass spectrometry instruments and methods. (E2) To learn and apply MaxQuant, Perseus, Ingenuity Pathways Analysis (IPA) and MetaboAnalyst software for omics data analysis. (S1) To perform a longitudinal proteomics and metabolomics study of human (h)iPSC-derived bi- and tri-partite neurospheroids during development and maturation. (S2) To perform a proteomics and metabolomics study of mature hiPSC-derived bi- and tri-partite neurospheroids following viral infection, hypoxic/hypoglycemic stress (stroke) and Parkinson's Disease (PD) mimicking conditions. By completion of this research sabbatical, prof. Peter Ponsaerts will not only have gained the necessary bioinformatics skills to analyse proteomics data, but also will be able to integrate novel proteomics and metabolomics data with scRNA-Seq, ICC and electrophysiological analyses performed by his research team at UA, within current and future research projects.

Researcher(s)

• Promoter: Ponsaerts Peter

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The research team of prof. Peter Ponsaerts at the Laboratory of Experimental Hematology (University of Antwerp, UA) has established during the past 5 years multiple 2D and 3D murine and human iPSCderived neuro-immune cell culture models (including neurons, astrocytes, macrophages and microglia), with a specific focus on inflammation, viral infection, stroke and Parkinson's Disease. Having established these models, the research team of prof. Peter Ponsaerts has already implemented standard cytokine profiling, immunocytochemistry (ICC) and bulk RNA-Seq analyses for cell type characterization and cellular responses to inflammation, trauma or infection. Nevertheless, there is an unmet need to advance their experimental toolbox to characterize 2D and 3D neuro-immune cell culture models. The envisaged research sabbatical at the "Mass Spectrometry Lab" of the "Analytical Biochemistry and Proteomics Research Unit" from the "Center for Advanced Studies and Technology (CAST)" at the "University G. d'Annunzio" in Chieti-Pescara in Italy aims at two educational (E) and two scientific (S) action points: (E1) To learn and understand the base principles of high sensitivity proteomics and metabolomics (including metallomics and lipidomics) analyses using state-of-the-art mass spectrometry instruments and methods. (E2) To learn and apply MaxQuant, Perseus, Ingenuity Pathways Analysis (IPA) and MetaboAnalyst software for omics data analysis. (S1) To perform a longitudinal proteomics and metabolomics study of human (h)iPSC-derived bi- and tri-partite neurospheroids during development and maturation. (S2) To perform a proteomics and metabolomics study of mature hiPSC-derived bi- and tri-partite neurospheroids following viral infection, hypoxic/hypoglycemic stress (stroke) and Parkinson's Disease (PD) mimicking conditions. By completion of this research sabbatical, prof. Peter Ponsaerts will not only have gained the necessary bioinformatics skills to analyse proteomics data, but also will be able to integrate novel proteomics and metabolomics data with scRNA-Seq, ICC and electrophysiological analyses performed by his research team at UA, within current and future research projects.

Researcher(s)

• Promoter: Ponsaerts Peter

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Due to the enormous impact of stroke on the patient's quality of life and on society, decades of research resulted in the identification of thousands of candidate neuroprotective drugs. Unfortunately, none have led to an effective therapy to date. This can partially be attributed to the lack of in vitro systems able to accurately recapitulate human ischemic responses. Fortunately, the advent of induced pluripotent stem cell (iPSC)-technology has provided novel tools for generating human-based in vitro brain models, namely neurospheroids. Extending the host laboratories' preceding research efforts to generate bi-partite (neurons + astrocytes) and tri-partite (neurons + astrocytes + microglia) human iPSC-derived neurospheroids, I hypothesize that subjection of mature tri-partite neurospheroids to stroke-like conditions (oxygen/glucose-deprivation), in combination with advanced single cell analysis tools and measurement of electrophysiological network activity, will aid to unravel biologically relevant cellular and molecular events in the context of stroke pathology. In this way, the combined cellular and molecular toolbox for neurospheroid culture, manipulation and analysis will in short term pave the way for novel fundamental studies unravelling new pathways and/or potential targets for neuroprotection or repair, and in long-term novel therapeutic approaches for patients with cerebral ischemia.

Researcher(s)

• Promoter: Ponsaerts Peter
• Fellow: Van Calster Siebe

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

More than 2.8 million people worldwide are living with multiple sclerosis (MS). This disabling disease is caused by an autoimmune reaction directed against myelin proteins. However, the specific myelin epitopes that MS targets are not yet known. This poses an obstacle to the development of antigen-specific therapies. Currently, most therapies for MS are immunomodulatory, and although they alleviate the symptoms of the disease, they also increase the risk of opportunistic infections. Therefore, this project seeks to identify the target antigens involved in MS to pave the way for the development of antigen-specific therapies. For this purpose, we will use human dendritic cells (DCs) loaded with myelin lysate or lysate from Epstein Barr Virus (EBV)-infected cells. The DCs are loaded via phagocytosis, reflecting the in vivo process of antigen-loading of DCs. After antigen loading, the lysate will be processed and presented by the DCs on major histocompatibility complexes (MHC). The epitopes presented will be identified by immunopeptidomics, a recently developed technique using mass spectrometry. The pathogenicity of the identified epitopes will then be studied in an in vivo mouse model, while the presence of T cells specific for these epitopes in the blood of MS patients will be examined with IFN-gamma ELISpot assay.

Researcher(s)

• Promoter: Cools Nathalie

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of certain hematologic cancers. In this immunotherapy, the patient's T-cells are "armoured" ex vivo with a CAR that targets certain antigens on the tumor cell surface. Once administered, the CAR-T-cells will recognize the tumor cells and mediate lysis of the cells However, CAR-T-cell therapy is not yet a breakthrough for acute myeloid leukemia (AML), a highly aggressive blood cancer with dismal prognosis, due to various reasons. One of the reasons is the lack of a suitable CAR-target antigen on the AML cell surface. Another contributing factor is that the T-cells in AML, which are usually taken from peripheral blood, are deemed suboptimal. It is possible that tumor-infiltrating lymphocytes (or TIL) represent a superior cell population, but little research in the CAR therapy field is focused on TIL. To our knowledge, no research has been conducted on the use of TIL for the development of CAR-T cell therapy in AML. The aim of this project is twofold, with the ultimate goal of developing a new CAR-T-cell therapy for AML. Firstly, in this project, a new CAR targeting a promising target antigen that is highly expressed on the AML cell surface will be tested. Secondly, we wish to determine whether bone marrow-derived TIL may be suitable as a source for CAR-based therapy for AML. In a model of AML, we will perform an extensive phenotypic, transcriptional, and functional characterization of anti-AML CAR-engineered TIL compared to conventional peripheral blood lymphocytes.

Researcher(s)

• Promoter: Anguille Sébastien
• Fellow: Katana Zoi

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system for which no cure is available. It is the leading cause of non-traumatic disabling neurological disease in young adults with more than 6.500 people affected in Flanders. Since MS strikes during the primary productive time of one's personal and professional life, it leads to a major physical and socio-economic burden to the patient, family, and society. Therefore, new therapeutic interventions with improved efficacy over existing drugs and good tolerability are needed. As chronic inflammatory processes drive the neurodegeneration, we hypothesize that improved clinical outcome depends on restoring the balance between inflammation and the remaining capacity of neuronal self-renewal. Therefore, cell therapy that specifically targets the damaging immune reactions that cause MS and induce disease-specific tolerance without affecting protective immunity against pathogens and cancer is a promising approach. Recently, a collaborative network of European centers joined efforts to bring antigen-specific therapy for MS to the clinic. Two single-center phase I clinical trials evaluating the use of antigen-specific tolerance-inducing dendritic cells (tolDC) in MS patients were conducted (previously funded by IWT- TBM and H2020). No serious adverse events were observed. Next, we aim to demonstrate efficacy of tolDC treatment in a phase II clinical trial in patients with MS. Coordinated patient and MRI monitoring, including radiological correlates of neurodegeneration, and immunomonitoring will enable us to demonstrate efficacy of tolDC administration and to support future efforts in the field of MS therapy. An effective therapy that lowers morbidity with reduced occurrence of side effects and less frequent hospitalizations will enhance quality of life of patients as well as dramatically reduce economic burden. This would represent a breakthrough for healthcare in MS.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Wens Inez

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Recently, interest has grown in using self-amplifying RNA (saRNA) in vaccines for infectious diseases and cancer. SaRNA is a type of messenger RNA (mRNA) that contains the non-structural proteins of an alphavirus replicase complex that amplifies the original strand of RNA and allows the expression of proteins of interest in the host cell without risk of infection. Compared to conventional mRNA, saRNA-mediated expression of proteins of interest may last for 28 days, while lacks the risks of genomic integration or cell transformation of integrative technologies such as viral vectors, transposons, and CRISPR-based knock-in. Moreover, saRNA vaccines under clinical investigation show that saRNA is safe and elicits robust immune responses. However, this technology has not been explored yet to genetically engineer effector immune cells, such as T cells, ex vivo. Therefore, the START project aims to investigate and optimize saRNA transfection as an innovative and potent technology for genetically engineering T cells with chimeric antigen receptors (CARs) and T-cell receptors (TCR) against different hematological and solid cancer antigens, with a thorough evaluation of antitumor activity, T cell fitness and potential transcriptomic and cell metabolic changes that could be related to saRNA replication activity. The START project will provide the basis for the future generation of non-integrative and long-lasting CAR-T and TCR-T cell therapies for hematological and solid malignancies.

Researcher(s)

• Promoter: Lion Eva
• Fellow: Campillo Davó Diana

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The emergence of immunotherapy has improved cancer treatment in many different ways. One of the specific approaches is T-cell receptor (TCR)-T-cell therapy, in which potent TCRs are introduced into patient T cells in the laboratory, after which they can specifically destroy unwanted cells in the body. Although this therapy shows promising results, identification of potent TCRs remains a major hurdle. Due to the immense diversity of TCR repertoires, it is challenging to efficiently detect tumor-reactive T cells in the blood. In addition, TCRs are antigen-specific, meaning that different TCRs are required for different (sub)cancer types. The aim of project PrioriTCR is to develop an immunoinformatics platform that simplifies and accelerates the identification of potent TCRs. This proof-of-concept project is designed for the Wilms' Tumor 1 (WT1) antigen, which is overexpressed in a variety of solid tumors and blood cancers. WT1 is considered a virtually universal cancer marker, promising to target with specific immunotherapy. By combining limited laboratory experiments with blood samples from cancer patients with artificial intelligence, this project will result in the identification of new candidate potent WT1-specific TCRs for development of next-generation T-cell therapies. The developed computer models can be further extended for TCRs against other cancer markers.

Researcher(s)

• Promoter: Lion Eva
• Co-promoter: Laukens Kris
• Co-promoter: Meysman Pieter

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Recently, interest has grown in using RNA in vaccines for infectious diseases and cancer. In this project, we will investigate a new type of messenger RNA (mRNA) for genetic engineering of T cells with chimeric antigen receptors (CARs) and T cell receptors (TCRs) against hematological and solid cancers. This novel mRNA allows prolonged expression of the protein of interest compared to conventional mRNA without the risks of insertional mutagenesis present in integrating engineering technologies such as viral transduction. We will conduct an in-depth analysis of T cell fitness after RNA engineering and thoroughly evaluate the antitumor activity of the RNA-engineered CAR-T and TCR-T cells. This project will provide the basis for the future generation of safer and more durable cellular therapies for hematological and solid cancers.

Researcher(s)

• Promoter: Campillo Davó Diana

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Neuromyelitis Optica Spectrum Disorders (NMOSD) and Myelin Oligodendrocyte Glycoprotein Antibody Associated Disease (MOGAD) are rare autoimmune diseases of the central nervous system (CNS) that are distinct from multiple sclerosis (MS), a more prevalent CNS autoimmune disease. Even though there is evidence for a key role of T cells in the pathogenesis of NMOSD and MOGAD, the focus of research has been directed more towards unravelling the role of autoantibodies. Detection of antigen-specific T cells in the peripheral blood of people with aquaporine-4 positive NMOSD and even more so in MOGAD, has been challenging so far. Identification and functional characterization of antigen-specific autoreactive T cells in the peripheral blood is a necessary step to demonstrate and strengthen the evidence for the pivotal role of T cells in the pathogenesis of NMOSD and MOGAD and may pave the way towards future development of antigen-specific T cell modulatory treatments.

Researcher(s)

• Promoter: Willekens Barbara

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project website

Project type(s)

• Research Project

Abstract

Multiple myeloma is a rare form of white blood cell cancer of the bone marrow. While there is no cure, multiple myeloma can be managed successfully in many patients for years because of the growing availability of new drugs. Despite these advances, most current treatment strategies follow a one-size-fits-all approach and novel techniques to select patients for specific therapies are needed, especially considering the potential toxicity and cost of emerging immunotherapies (like CAR-based cellular therapies). Moreover, pockets of myeloma cells can exist within a patient with different sensitivity for a specific treatment, and single-site bone marrow biopsy may be less reliable to identify heterogeneous disease. Positron emission tomography (PET) provides a powerful platform to characterize tumors non-invasively by modifying and radio-labeling antibodies to image the tumor phenotype. In this preclinical project, we will develop, validate, and assess the predictive potential of a new antibody-based PET tracer to assess BCMA, a protein that is highly and selectively expressed on myeloma cells, offering our radiopharmaceutical unique specificity. Finally, a mouse model expressing human characteristics will be used to assess our tracer in a clinically relevant setting using CAR-based cell therapy. If successful, our tracer will help physicians select patients who can benefit from CAR therapy and avoid risking the severe side-effects in patients with a low likelihood of response.

Researcher(s)

• Promoter: Anguille Sébastien
• Co-promoter: Elvas Filipe
• Co-promoter: Van den Wyngaert Tim

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The traditional process of designing and developing vaccines has been challenged dramatically by the COVID-19 pandemic, with the adoption of mRNA-based vaccines and a reduction of lengthy development pipelines from 10-15 years to 1-1.5 years. This creates a push for further innovation in vaccine development, in particular for diseases with a high unmet need. As an example, mortality due to rabies (a lyssavirus) remains unacceptably high. Although safe, effective vaccines are available for human and animal use, human vaccines are too expensive and generally inaccessible for widespread use in regions where the risk of bites from rabid animals is highest. mRNA approaches offer an opportunity to provide affordable vaccines with the possibility of manufacturing in low and middle income countries, with optimised design affording broader protection. The aim of such an approach would be to drive down cost and broaden supply and equity of access. Novel in silico approaches such as those analysing the T cell receptor response may permit insights into the immune response elicited by rabies vaccines, aid understanding of the mode of action and guide future use. The objective of the current project is to investigate if detailed analysis of the T-cell receptor response can be valuable to inform vaccine design and improve the vaccine development process, using a rabies mRNA vaccine as a proof-of-concept. We will combine in vitro (UAntwerp) and in silico (ImmuneWatch) techniques to gain insights into the T cell response against a range of experimental rabies mRNA vaccine constructs (Quantoom). The project is a public-private partnership aiming to explore novel approaches in vaccine development and to prepare future collaborations between the project partners.

Researcher(s)

• Promoter: Lion Eva
• Co-promoter: Ogunjimi Benson

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

There is a clear unmet need for innovative treatments that can suppress ongoing inflammatory disease activity in treatment refractory RRMS patients. The grant of the Belgian Charcot Foundation enables us to start developing CD19 CAR T cells for the use in MS and related autoimmune diseases that are driven by pathogenic B cells. While this project is focused on laboratory research, we are committed to paving the road towards a first-in-man clinical trial in the future.

Researcher(s)

• Promoter: Willekens Barbara
• Co-promoter: Cools Nathalie

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project website

Project type(s)

• Research Project

Abstract

MS is a chronic auto-immune disorder of the central nervous system (CNS) and the leading cause of non-traumatic disabling disease in young adults. Although the exact cause of MS remains to be elucidated, it is currently accepted that both genetic and environmental factors affect complex immunological responses, both in the periphery and the CNS. To date, there is still no cure for MS, but several immune-modifying and/or -suppressive treatments, especially targeting the peripheral immune system, have been developed over time. However, these have varying efficacy, have limited long-term effectiveness, and sometimes life-threatening side effects, thereby underscoring the urgent need for novel therapeutic approaches to be developed and evaluated. Tolerogenic dendritic cells (tolDCs) are professional antigen-presenting cells with immunosuppressive properties, priming the immune system into a tolerogenic or unresponsive state against various (self)antigens. TolDCs are essential in maintenance of central and peripheral tolerance through induction of T cell clonal deletion, T cell anergy, generation and activation of regulatory T-cells (Tregs), as well as the direct modulation of pro-inflammatory environments. For that reason, tolDCs show considerable promise as candidates for specific cellular therapy for treatment of allergic diseases, autoimmune diseases or transplant rejections. In this context, the Laboratory of Experimental Hematology (LEH, Cools' team) recently recruited nine patients for a phase I clinical trial evaluating the potential safety and feasibility of tolDCs for the treatment of multiple sclerosis (MS) (NCT02618902). While no serious adverse events are observed in all treated patients, much remains to be understood about the exact molecular and cellular interactions these therapeutic cells provoke in vivo. Accumulating evidence shows that extracellular vesicles (EVs) secreted by immune cells play a key role in intercellular communication. In this project, we aim to determine the immune-regulatory mechanism by tolDCs, hypothesising that it would be mediated by EVs and their immunosuppressive cargo. To achieve this goal, we will apply an unbiased multi-omics approach, both in vitro and in vivo, to unravel the therapeutic potential of tolDC-derived EVs. We hereby anticipate that our findings will lead to ground-breaking insights on current understanding of EVs in immune-regulatory therapy and ultimately will lead to the development of a novel (non-cellular) off-the-shelf therapeutic compound to be evaluated in patients suffering from detrimental auto-immune disorders, including MS. This highly innovative application addresses the use of tolDC-derived EVs as disease-modifying treatment in MS and is expected to provide new insights into how immune tolerance is initiated following interaction of key immune-regulatory cargo of the EVs with peripheral and CNS immune cells. With this project, we present a clinically relevant project relying on inventive fundamental research with a high translational value and valorization potential. The integrative multiomics analysis will give a better insight in the molecular pathways involved in the induction of tolerance and immunoregulation by tolDCs. Furthermore, this project could lead to the development of a cell-free therapy based on tolDC-EV for the treatment of MS, which can surpass drawbacks associated with cell therapy. In addition, the possibility of allogenic exosome therapy would result in a more positive cost-benefit ratio since an "off-the-shelf" product is less expensive than an individualized cell therapy. Hence, the study proposed here is merely the beginning of numerous possible new research questions as well as clinical translation.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Ponsaerts Peter

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Perinatal tissues encompass a large and diverse cell/tissue family obtained from term pregnancies. Perinatal derivatives (PnDs) include amniotic membrane, chorion, Wharton's jelly, amniotic fluid, and the cells isolated from these tissues, as well as the factors that these cells release. PnD have drawn much attention due to their immune-modulatory and tissue-protecting properties, making them attractive candidates in regenerative medicine. Focussing on neuro-protection, we will here investigate whether different types of PnDs are able to inferfere with inflammation-associated neuro-degenerative processes in murine induced pluripotent stem cell (iPSC)-derived neurospheroids. Neurospheroids cultured from iPSC represent an important research tool to study neuron-astrocyte interactions, during development, homeostasis and stress. Hereto, we developed a 5-week old murine iPSC-derived neurospheroid model containing mature neurons and astrocytes in order to evaluate the therapeutic potential of several neuro-protective/modulating compounds in vitro preceding animal experiments. Following development and characterization of this new murine iPSC-derived neurospheroid model, its sensitivity to immune signal-induced stress (a.o. stimulation with IL1b, TNF and/or LPS) has been demonstrated by monitoring astrocyte activation (a.o. production of IL6 and CXCL10). In this new project in collaboration with the 'Universita Cattolica del Sacre Cuore' (Rome, Prof. Ornella Parolini) and the 'Centro di Ricerca E. Menni' (Brescia, Dr. Antonietta Silini), we will now investigate the neuro-protective/modulating activity different PnDs on astrocyte activation in murine iPSC-derived neurospheroids. These studies will then allow to preselect the most potential PnDs for subsequent animal studies and/or human clinical trials in the field of neuro-degenerative disease.

Researcher(s)

• Promoter: Ponsaerts Peter

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Multiple Sclerosis is a complex neurodegenerative disease of the central nervous system (CNS), currently affecting almost 15 000 people in Belgium. To date, there is still no cure for MS, but several immune-modifying treatments have been developed. The use of tolerogenic dendritic cells (tolDC) for the treatment of MS is currently being investigated. These tolDC can modulate the immune response and (re)establish self-tolerance. However, their exact working mechanism has not been fully elucidated yet. In this project, we hypothesize that tolDC modulate the auto-reactive response via extracellular vesicles (EV). EV are nanosized membrane vesicles that are released by almost every cell type and have been reported to be involved in immune regulation. In particular, the cargo carried by these EV can influence the immune response. Indeed, the cargo compromising of functionally active compounds such as RNAs, lipids, metabolites, and proteins can alter the phenotypic and functional properties of the recipient cells. Hence, we anticipate a role of immunomodulatory cargo-containing EVs in the mode-of-action of tolDC. For this, we aim to explore the immunosuppressive properties of tolDC-derived EV and their capacity to establish tolerance. This research would contribute to a better understanding of the working mechanism of tolDC. In addition, results could lead to the development of a cell-free therapy for MS surpassing the drawbacks associated with cell therapy.

Researcher(s)

• Promoter: Cools Nathalie
• Fellow: Van Delen Mats

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Hematologic malignancies are cancers that primarily affect the blood, bone marrow and lymph nodes. Among the different subtypes, B-cell non-Hodgkin lymphoma (B-NHL) and Acute Myeloid Leukemia (AML) are the most prevalent indications. Common to both indications, alterations in the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway are frequently observed, leading to constitutive activation and oncogenic signalling. Known key effectors within the pathway such as Bruton's tyrosine kinase (BTK), interleukin-1 receptor associated kinases (IRAKs), Myeloid differentiation primary response 88 (MYD88), and Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) represent promising therapeutic targets for these indications and have been at the center of significant drug discovery efforts. In order to tackle common limitations associated to canonical small molecule inhibitors (SMI) (e.g., resistance mutations, lack of response due to scaffolding functions, …), this project is aimed at exploring the therapeutic potential of selective target degradation through PROteolysis-TArgeting Chimera (PROTAC). PROTAC represents an innovative protein degradation technology able to induce protein degradation by taking advantage of the ubiquitin proteasome pathway. The goal of the project is to provide a better understanding of the therapeutic potential of PROTACs specific for BTK, IRAK1 and IRAK4 in comparison to their respective SMI counterparts. To this end, we will evaluate the molecular and functional consequence of target degradation or inhibition in relevant models of AML and B-NHL as well as reflect the work on AML primary patient material. In addition, potential synergistic activity between PROTACs and clinically relevant SOC/SMIs options will be evaluated. Last, potential on-target/off-tumor activity in immune cell sub-types in which the NF-kB pathway is known to play a role (e.g., T-cells) will be evaluated.

Researcher(s)

• Promoter: Lion Eva
• Co-promoter: Anguille Sébastien
• Fellow: Suls Toon

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Parkinson's Disease (PD) is a neurodegenerative disease primarily linked to ageing affecting the psychomotor functions. An impairment in the activity of dopaminergic neurons (aggregation and intracellular accumulation of alfa-synuclein), is at the basis of this functional loss. Current therapies do not revert the PD progression but stand on the relief of the symptoms. Importantly, the efficacy of new therapeutic approaches is hampered by the lack of in vitro models that mimic the PD's hallmarks. Moreover, the effectiveness of therapeutic approaches is hampered by the low ability of the drugs to cross the blood- brain barrier (BBB). RePark will develop an in vitro PD model that combines a mimic of the BBB, the brain's extracellular matrix (ECM) and brain cells. With this system it will be possible to overcome the disadvantages of using animal models and to recapitulate in vitro the cellular characteristics of PD, as well as to assess the delivery and efficacy of new therapeutic drugs.

Researcher(s)

• Promoter: Ponsaerts Peter

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

In this application, we request financing for three benchtop CERO 3D Cell Culture Bioreactor units for the culture of 3D cell cultures, including spheroids and organoids, that are increasingly being used in biomedical research. Currently, 3D organoids and spheroids are cultured in traditional cell culture plates under static or shaking (using orbital shaker) conditions in a standard CO2 cell culture incubator, which is suboptimal for long-term and large-scale culture of spheroids and organoids. A bioreactor system would take organoid and spheroid culture at the campus to a next level in terms of quality (improved viability, maturation and homogeneity) as well as quantity. Each CERO 3D Cell culture bioreactor unit can maintain four 50 mL organoid cultures, including monitoring and control of temperature, pH and carbon dioxide levels. In total, the envisaged bioreactor infrastructure will be able to accommodate twelve simultaneous organoid cultures under highly controlled conditions. The envisaged CERO 3D Bioreactor units will be applied for multiple research domains at the University of Antwerp, and more specifically for upscaled culture of stem cell-derived spheroids and organoids, tumoroids derived from primary tumour material of patients, stem cell-derived cardiomyocytes, stem cell-derived cartilage tissue and intestinal organoids. Furthermore, based on our own experience in upscaled organoid culture, the instalment of bioreactor units has become an urgent need to progress towards future valorisation activities.

Researcher(s)

• Promoter: Ponsaerts Peter
• Co-promoter: Alaerts Maaike
• Co-promoter: Lardon Filip
• Co-promoter: Verstraeten Aline

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Flow cytometry is a widely used technique that allows the simultaneous and multi-parameter analysis of physical and biochemical characteristics of a population of living cells or particles in a heterogenous sample. The Laboratory of Experimental Hematology (LEH) has 20+ years of demonstrable experience in flow cytometry (200+ published manuscripts), as well as experience in guidance and support of both internal and external research groups with flow cytometric experiments (30+ joint manuscripts). With this application, we now aim to maintain and expand a flow cytometry and cell sorting core facility at the AUHA. The ambition of LEH is to make basic and advanced flow cytometry available for all active and prospective users at the AUHA in order: (i) to leverage qualitative cell biological and (pre)clinical cellular research, (ii) to provide qualitative education covering flow cytometry and its applications over multiple faculties (FGGW, FBD and FWET), and (iii) to provide external service using flow cytometry as a basis, both intellectually as well as practically.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Anguille Sébastien
• Co-promoter: Lion Eva
• Co-promoter: Ponsaerts Peter

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Most CAR-T cell therapies for treatment of multiple myeloma (MM) are directed towards BCMA, a target antigen that is highly expressed on malignant plasma cells. It has become evident that the extracellular BCMA-binding domain of a CAR, derived from a monoclonal antibody (mAb), is an important determinant of clinical efficacy of anti-BCMA CAR-T cell therapies. In this project, we want to further investigate and compare anti-BCMA mAbs from different animal species for their competence for incorporation in CAR-T cell therapies against MM. In addition, most CAR-T cells get their genetic material delivered via viral transduction or transposons. A major disadvantage of viral loading methods are the need for highly specialized infrastructure and the long time needed for production. The speed up the production process, make it safer and to counteract virus-mediated insertion of DNA in the genome, we want to use episomal vectors. These vectors exist extrachromosomal, yet are duplicated and thus passed along to daughter cells. Next, we want to turn on/off specific CARs by (de)methylating the genes, thereby regulating transcription. It also enables speeding up and optimization of the production process by incorporating different CARs in a single T-cell, whereby only the CAR of choice is switched on. This could be incorporated into allogenic cell therapy in which different CARs are present in an off-the-shelf allogenic T-cell/NK-cell.

Researcher(s)

• Promoter: Anguille Sébastien
• Fellow: Shaw Philip

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Acute myeloid leukemia (AML) is one of the most common leukemias in adults with a 5‐year overall survival rate of only 30%. Despite therapeutic advances in the last decade, novel adoptive T-cell immunotherapies using anti-tumor chimeric antigen receptors (CARs) and T-cell receptors (TCRs) are not fully developed for AML. Moreover, expression of immunosuppressive immune checkpoints (IICPs) hinder the success of these T-cell therapies. To address this issue, the aim of this project is to develop an innovative multi-epitope Wilms' tumor 1 (WT1)-specific TCR, CD200-specific non-signaling chimeric antigen receptor (NSCAR) and IICP-disrupted (mulTplex)-engineered adoptive T-cell therapy for AML. We will combine TCRs with different human leukocyte antigen (HLA) restrictions and specificities against diverse epitopes of WT1, a key intracellular antigen, in a multi-epitope strategy. To avoid the interaction between native and introduced TCRs, native TCRs will be disrupted by CRISPR-Cas9 technology. The NSCAR, which lacks the typical CAR's signaling domain, will act as an "anchor" for the T cells by locking onto AML cells through CD200, a novel extracellular AML antigen, and without triggering T-cell activation. By doing so, we expect to improve TCR-mediated anti-AML cytotoxic capacity of mulTplex-engineered T cells. To further harness the anti-leukemic activity of engineered T cells, AML-associated IICPs will also be disrupted using CRISPR-Cas9 methods. Both in vitro and in vivo evaluation of mulTplex-engineered T cells will ensure translation of our innovative combinatorial approach into clinical studies.

Researcher(s)

• Promoter: Lion Eva
• Fellow: Flumens Donovan

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment modality for patients with relapsed/refractory (r/r) CD19+ B-cell hematological malignancies, such as acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL). The prognosis of patients in whom the disease is not under control or has relapsed after HSCT, is particularly grim. For these patients, the therapeutic options are limited. One of the few available salvage strategies involves the use of donor lymphocyte infusions (DLI). The mechanism of action of DLI relies on the administration of immune effector cells, predominantly T cells, from the stem cell donor, with the ultimate goal to elicit a "graft-versus-leukemia" or "graft-versus-tumor" effect. Unfortunately, DLI have only modest clinical activity and can evoke or exacerbate serious transplant-related side effects such as "graft-versus-host" disease. CD19-targeted chimeric antigen receptor (CAR)-T cell therapy offers new hope for patients with r/r B-cell hematological malignancies. Here, T-cells derived from the patient (autologous) are genetically modified to express a CD19 CAR, a synthetic receptor enabling binding of the cells to the CD19-expressing target cells. Upon engagement, the CAR will trigger activation of the T cells which will then become cytotoxic towards the target cells. In this project, DLI products will be loaded with an in-house developed and optimized CD19 CAR. By using allogeneic cells derived from healthy donors as source for CAR-T cell manufacturing, which are usually "fitter" than autologous, patient-derived T cells, we aim to enhance the anti-tumoral activity of the CAR-T cells.

Researcher(s)

• Promoter: Anguille Sébastien
• Fellow: De Laere Maxime
• Fellow: Krekelbergh Laurens
• Fellow: Krekelbergh Laurens

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Confidential .

Researcher(s)

• Promoter: Lion Eva
• Co-promoter: Anguille Sébastien
• Co-promoter: Berneman Zwi

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Varicella zoster virus (VZV) is a member of the herpesvirus family and is a highly successful and ubiquitous human pathogen. Both in children and in adults, varicella-related complications may lead to hospitalisation. While in children direct neurological complications may occur following primary infection (varicella), in adults vasculitis and neurological complications are not uncommon following reactivation of latent VZV (herpes zoster). With a clear link between VZV and neuropathology, it is inevitable that the immune system of the central nervous system (CNS) will be challenged by VZV. However, to date little is known about how astrocytes and microglia behave upon encounter of VZV in the CNS. In this project, we will address this question using an established human in vitro model of axonal infection of human induced pluripotent stem cell (hiPSC)-derived CNS neurons with fluorescent reporter VZV stains. Using this model, we will first longitudinal monitor how hiPSC-derived astrocytes and microglia influence the processes of VZV infection, latency and reactivation. Next, using iPSC models derived from VZV patients with mutations in POLRIII, we will investigate whether immune compromised astrocytes and/or microglia can control neuronal VZV infection. Altogether, these studies will help us understanding innate immune control of VZV in the CNS, and will allow - beyond the scope of this project – to develop novel strategies to prevent VZV spreading in the CNS.

Researcher(s)

• Promoter: Ponsaerts Peter
• Co-promoter: Delputte Peter
• Co-promoter: Ogunjimi Benson

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Pluripotent stem cell (PSC) technology is increasingly gaining interest for modelling diseases and developing precision therapeutics. However, the immaturity and heterogeneity of PSC-derived cell populations impinge on the reproducibility and preclude their use for comparative and diagnostic analyses. Recognizing these caveats for their own human induced (hi)PSC-based research, the Laboratories of Experimental Hematology, Cardiogenetics and Cell Biology and Histology have teamed up to develop a pipeline that enables accurate phenotypic staging of hiPSC-derived cell culture models. Specifically, to create mature and standardized 2D and 3D-models for cardiomyocyte cultures and brain organoids, our consortium proposes to optimize the culture conditions and refine the interrogation methods. Longitudinal follow-up and validation of functional activity in the differentiation products will be achieved by means of high-throughput multi-electrode array recordings and live cell calcium and voltage imaging. In parallel, cellular heterogeneity will be mapped with quantitative immunofluorescence and transcriptome analyses. The correlation of functional and molecular readouts will allow establishing a biomarker panel for mature hiPSC-derived cardiomyocyte models and brain organoids. Thus, with this work, we intend to develop more reproducible models and to allow selecting only those with the highest functional maturity, a prerequisite for our future stem cell research aimed at studying and treating neuro-inflammatory and cardiogenetic disorders.

Researcher(s)

• Promoter: Ponsaerts Peter
• Co-promoter: De Vos Winnok
• Co-promoter: Loeys Bart

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Chimeric antigen receptor (CAR)-T cell therapy has demonstrated unprecedented clinical activity in patients with hematological diseases, but a large proportion of them will ultimately relapse. Further optimization of this new treatment modality is therefore required to unlock its full therapeutic potential. In this project, in addition to using readily available cell line models, we will use our mRNA electroporation technology for CAR loading of immune cells. This will provide a rapid and efficient way to explore new research paths that can lead to optimized CAR-based cellular therapies for hematological diseases. Will assess the value of a multi-targeted approach incorporating two established CAR targets (CD19 and B-cell maturation antigen) and the novel CAR candidate CD200. Next, the hinge and co-stimulatory domains in the CAR structures will be sequentially modified, comparing conventional hinge and co-stimulatory domains with our recently discovered 4-1BB-hinge and CD26 co-stimulatory domains. Exhaustion will be prevented by introducing programmed death (PD-1) silencing RNA in the CAR-modified cells to reduce PD-1-mediated co-inhibitory signaling. Finally, positive findings will be translated from our cell line models to conventional T cells, NK cells and gdT cells.

Researcher(s)

• Promoter: Anguille Sébastien
• Co-promoter: Lion Eva
• Fellow: Roex Gils

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS), characterized by inflammatory attacks against the myelin sheath. Today, over 10 disease-modifying therapies are approved, predominantly focusing on immunomodulation. However, remyelination remains a major unmet clinical need in (progressive) MS therapy. Today, efforts are made to unravel de- and remyelinating mechanisms. Therefore, brain-derived neurotrophic factor (BDNF) seems an interesting protein, as it promotes neuroprotection and (re)myelination. Interestingly, BDNF levels are reported to be reduced in MS. While neurons are the principal source of BDNF in the CNS, key-immune cells can also secrete BDNF, suggesting that BDNF mediates the cross-talk between the immune- and nervous system. Recently, a growing body of research underscoring the key role of regulatory T cells (Treg) in MS, has emerged. Interestingly, a novel pro-regenerative function of Treg was revealed, mediated by the secretion of pro-myelinating factors. Nevertheless, the relation between immune cell-mediated BDNF expression and its accompanying effects in the CNS, such as remyelination, remains elusive in MS. Therefore, we aim to investigate the influence of immune cell-induced BDNF expression on remyelination using state-of-the-art techniques and patient samples. Our findings may result in the development of novel strategies to improve remyelination, predominantly focussing on progressive MS treatment.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Wens Inez
• Fellow: El Ouaamari Yousra

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Based on the strong need for more targeted, tolerable and durable treatment strategies that could postpone or even prevent recurrence of disease in the most common adult malignant brain tumor, we embarked on a phase I/II clinical trial assessing frontline treatment with autologous dendritic cell (DC) vaccines loaded with glioblastoma-associated tumor antigen Wilms' tumor 1 in conjunction with conventional chemoradiation following surgery in adults with glioblastoma multiforme (GBM; NCT02649582). Childhood high-grade glioma (HGG, including GBM) and diffuse intrinsic pontine glioma (DIPG) are rare aggressive brain tumors. In the absence of a standard of care, treatment is mostly adapted from adult schedules, resulting in 5-year survival rates of less than 5% and 1% after diagnosis, respectively. With limited advanced investigational treatment options for this vulnerable patient population, we strive to extend our clinical study to the pediatric application. Ultimately working towards the clinical valorization of an adjuvant DC-based immunotherapy approach, health care evaluation is warranted. To this extent, we will include collection of patient-reported outcome on how the study therapy is experienced throughout time in the response evaluation of all study patients. As the search for biomarkers is gaining momentum in the rapidly evolving cancer immunotherapy landscape, we are also continuously expanding the screening assays on clinical patient material. The present project proposal is designed to allow completion of the intended adult GBM patient recruitment number and to extend the trial, innovating on the pediatric application of DC vaccination, health care evaluation and emerging therapeutic biomarker research. Within the context of hard-to-treat brain tumors, this study and its specific design will add a new dimension to our translational and clinical DC vaccine programs by investigating whether DC vaccination can be combined with first-line chemoradiation treatment of adult GBM and childhood HGG and DIPG patients and whether this combination leads to tumor-specific immune responses and improved survival. Exploration of patient-reported outcomes will help to improve symptom management, functional status and overall quality of life and will provide necessary information for future clinical valorization of this type of personalized medicine. In depth research on clinically valuable biomarkers will allow us to make a significant contribution to the broader (immunotherapy-oriented) scientific community.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: De Praeter Mania
• Co-promoter: Lion Eva
• Co-promoter: Norga Koenraad
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Cell therapy is an active area of immunological research and represents a highly innovative and rapidly expanding sector of pharmaceutical industry. The INsTRuCT Consortium answers an unmet need in the field for postdoctoral researchers experienced in scientifically excellent research and cell therapy development. INsTRuCT draws upon complementary expertise of its academic and industrial partners to offer a unique research and training programme. INsTRuCT proposes 15 distinctive research projects based at European companies or universities recognized for their scientific achievements and innovation. INsTRuCT is structured to promote interdisciplinary and intersectoral cooperation between partners, thereby accelerating pharmaceutical development and clinical application of novel myeloid regulatory cell (MRC)-based therapies. INsTRuCT is a primarily research-based training programme, which will be complemented by theoretical and practical training opportunities. INsTRuCT will encourage a translational view of research, which will be reinforced by intersectoral secondments. Teaching transferrable and communication skills is a high priority for INsTRuCT. ESR will gain a comprehensive overview of the drug development process in Europe as it applies to cell-based therapies; hence, INsTRuCT's graduates will be fitted for future roles as innovative leaders in the field. INsTRuCT will strengthen interactions between cooperating research groups at junior and senior levels, thereby promoting dissemination of standardized research approaches and data-sharing. Overall, INsTRuCT constitutes an original research and training concept that responds to the specific needs of a growing sector for postdoctoral scientists trained in Basic Immunology and cell therapy development. Consequently, INsTRuCT has a very high impact potential, both in terms of its scientific and technical advancements, and its future contribution to innovation and economic development within the European Union.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Berneman Zwi

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Acute myeloid leukemia (AML) and multiple myeloma (MM) are two types of blood cancers with a high unmet therapeutic need. The knowledge that cells of our immune system can recognize and kill cancer cells has laid the foundation for immune effector cell (IEC) therapy. This involves the infusion of immune cells that are "armored" outside the body with a T-cell receptor (TCR) or a chimeric antigen receptor (CAR). Such TCR- or CAR-loaded immune cells can execute a targeted attack against cancer cells. The aim of the present project is to improve the therapeutic efficacy of IEC therapy for AML and MM, while reducing the risk of side effects and costs of treatment. More specifically, immune cells will be weaponed with AML-directed TCRs or MM-directed CARs via a technique called electroporation. This involves the application of an electrical pulse to the cells, making temporary holes in their surface and enabling their loading with the TCR or CAR. When compared to the current IEC therapies, this novel procedure will allow for the generation of IECs with reduced costs, improved safety profile and enhanced anti-tumor activity. It is therefore expected that this research project will make an important contribution to the development of the next-generation IEC products for AML and MM.

Researcher(s)

• Promoter: Van Tendeloo Vigor
• Co-promoter: Berneman Zwi
• Fellow: Anguille Sébastien

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Improvement of first-line treatment for cancer patients with a high tumor recurrence rate and low effective treatment options, such as pancreatic cancer (PC), is warranted. Pancreatic cancer is a devastating disease with a 5-year survival rate below 5%, depending on the specific stage of disease when it is diagnosed, rendering it the 4th most common cause of cancer-related death worldwide. Even those who are eligible for curative-intent resection and conventional adjuvant treatment will nearly all die of their disease due to the high tendency towards recurrence. Adjuvant treatment with gemcitabine after resection of PC decreases recurrence rate, but the disease-free survival of these patients stays dismal with a 5-year survival rate below 21%, underscoring the need for new adjuvant regimens. The combination of gemcitabine with immunotherapy might improve outcome as suggested by some studies, but available data is so far limited to a few early-phase uncontrolled clinical trials. Interleukin (IL)-15-transpresenting dendritic cells (DCs) are a promising armament for immunotherapy of PC. Complementary to current treatments, DCs as quintessential antigen-presenting cells of the immune system can activate the antitumor immune system to attack pancreatic cancer cells. Preclinical data demonstrate the therapeutic potential of these innovative IL-15-transpresenting DCs evidenced by superior activation of the antitumor immune system to attack cancer cells. Since this will be the first-in-human use of IL-15-transpresenting DCs, the objectives are to test the safety, feasibility and immunopotency in patients with refractory solid tumors, the prototypic cancer patient population for phase I trials. This phase I clinical study is pivotal for future testing of this promising IL-15-transpresenting DC vaccine as adjuvant therapy to current anticancer regimens aiming to improve the standard of care of cancer patients with a high unmet medical need.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Lion Eva
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The ultimate goal of this research project is to develop a clinically safe and regenerative cell-based vaccine for the treatment of (progressive) multiple sclerosis (MS), since remyelination remains a major unmet need. We recently succesfully developed "designer" Tregs that are engineered to express high levels of BDNF. Here, we are ready to assess the remyelinating capacity of these transgenic Tregs, hypothesizing that these Tregs will excel in their pro-regenerative properties, driving oligodendrocyte differentiation and remyelination, beyond immunomodulation. This would represent a breakthrough for MS healthcare.

Researcher(s)

• Promoter: Wens Inez

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Chimeric antigen receptor (CAR)-T-cell therapy has achieved remarkable clinical response rates in relapsed/refractory B-cell malignancies. Unfortunately, the frequency of relapse remains high as a result of decreased cellular fitness, poor anti-tumor activity or a lack of persistence of the CAR-T-cell product. While the CAR architecture is a foundational driver of CAR-T-cell responses, its design is poorly understood, in particular for the structural hinge domain. Current hypothesis-driven workflows are low in throughput, expensive and laborious, and complicate pattern recognition. This project aims to define CAR hinge domain design rules by studying the relationship between hinge properties and CAR-T-cell responses in the context of hematological malignancies. We employ high-throughput cellular assays to phenotypically and functionally evaluate a large library of novel hinge domain candidates. A machine learning algorithm will be trained to correlate hinge domain characteristics with the obtained cellular outputs. We anticipate to create an algorithm that is capable of predicting superior hinge domains from a naïve set of candidates against a multitude of target antigens. We envision that in the future this model can be further trained to include other CAR domains and domain combinations to assist in further personalization of CAR-T-cell therapy.

Researcher(s)

• Promoter: Lion Eva

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Neurospheroids cultured from induced pluripotent stem cells (iPSC) represent an important research tool to study neuron-astrocyte interactions, during development, homeostasis and stress. In course of the EU MSCA ITN PMSMatTrain project, the UAntwerp partner developed a 5-week old murine iPSC-derived neurospheroid model containing mature neurons and astrocytes in order to evaluate the therapeutic potential of several neuro-protective/modulating compounds in vitro preceding animal experiments. Following development and characterization of this new murine iPSC-derived neurospheroid model, its sensitivity to immune signal-induced stress (a.o. stimulation with IL1b, TNF and/or LPS) has been demonstrated by monitoring astrocyte activation (a.o. production of IL6 and CXCL10). This SEP grant will be applied to support the 4th PhD year of Julia Di Stefano in which the candidate will investigate the neuro-protective/modulating activity of APRIL (delivered by means of AAV vectors) and placenta stem cell-derived factors (delivered by means of extracellular vesicles) on astrocyte activation in murine iPSC-derived neurospheroids. Finally, it is expected that the technology developed here will become an important additional tool in (i) fundamental research to study neuro-development and functioning, as well as (ii) to preselect interesting therapeutic molecules before proceeding to animal studies and/or human clinical trials.

Researcher(s)

• Promoter: Ponsaerts Peter
• Fellow: Di Stefano Julia

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Chimeric antigen receptor (CAR)-T cell therapy is an innovative form of cellular immunotherapy that utilizes T-lymphocytes that are genetically engineered to express a CAR. While initial response rates are often outstanding, the majority of patients suffers from a relapse which is often cause by a lack of sustained effector functionality or persistence of the CAR-T cells. The importance of the CAR architecture to therapeutic outcome is becoming increasingly clear. However, it is unlikely that the full potential of CAR-T-cell therapy will be reached by using a combination of domains derived from only a small subset of immune-related proteins, as is the case today. The main reason behind this limited selection of building blocks is the use of slow and labor-intensive low-throughput methods for the evaluation of novel candidate domains. Only few groups, such as the Birnbaum lab, have developed a high-throughput workflow for the functional evaluation of up to 1 million CAR designs. While those workflows provide invaluable information novel costimulatory domain combinations, it has never been applied to other structural domains of CARs. The aim of this research stay at the Birnbaum lab is to acquire the practical know-how on CAR combinatorial library construction and a high-throughput CAR screening workflow. By applying this knowledge directly under the supervision of the host group, we will attempt to decipher the design language of severely understudied CAR components by screening a sizeable library of potentially valuable CAR domains.

Researcher(s)

• Promoter: Anguille Sébastien

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Recently, there has been growing interest in the use of self-amplifying mRNA (saRNA) in therapeutic vaccines for infectious diseases and cancer. SaRNA is a type of messenger RNA (mRNA) that contains the non-structural proteins (nsP1-4) of an alphavirus replicase that copies the original strand of mRNA upon delivery into the cell. The nsP1-4 replicon is followed by a subgenomic promoter and the sequence of a gene of interest, allowing the expression of proteins of interest in the host cell. The self-replicating property means that proteins of interest encoded in the transfected saRNA will be expressed for a longer period of time compared to conventional mRNA. However, since there is no integration into the genome of the host cell, insertional mutagenesis is prevented. Thus, saRNA-based strategies combine the best of stable viral- or non-viral-based and transient mRNA-based engineering strategies. SaRNA is usually delivered in vivo as "naked" saRNA with or without intradermal electroporation or formulated into nanoparticle vaccines, with which expression of the protein of interest may last for 28 days. However, the exploitation of this technology for ex vivo modification of T cells in a therapeutic product has never been explored thus far. The primary objective of the Replic-ON project is to explore saRNA transfection as an innovative technology for genetically engineering immune cells in the context of the development of cell-based therapies. If successful, this project will provide groundbreaking data for the further development of ex vivo saRNA transfection technology as an amenable approach for T-cell genetic engineering in larger fundamental research project applications. We expect that this project will be the cornerstone for the much-needed development of more efficient and long-lasting non-integrating cellular immunotherapies while straddling the boundary between short-lived conventional mRNA technologies and integrating technologies such as viral transduction. Finally, this pioneering research would consolidate our leadership on ex vivo saRNA-based cellular therapies within the research community.

Researcher(s)

• Promoter: Campillo Davó Diana

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

While first generation tolDC-based therapies have shown considerable clinical promise, a better understanding of tolDC immunobiology will open many possibilities for enhancing or redirecting their therapeutic activities. In this project, we aim to investigate mechanisms linking metabolic activity of tolDC to their functional polarization. We hypothesize that tolDC-derived EV have the potential to regulate tolerance-inducing molecular pathways. We aim to identify metabolites involved in the mode-of-action of tolDC immunoregulation. For this, the following objectives have been set forth: (1) To purify tolDC-derived EV from MS patients and healthy controls and to assess their immunoregulatory function using in vitro systems (2) To identify key metabolomic and lipidomic biomarkers in patients and healthy control tolDC-derived EV using omics analysis (3) To engineer and validate the key factors in tolerance induction and therapeutic repair in tolDC-derived EV (4) To investigate the therapeutic effectiveness of immunometabolite-containing EV in vivo In summary, this research project will contribute to a better understanding of the mode-of-action of vitD3-treated tolDC, focusing on EV and metabolite/bioactive lipid components. We envisage that our results will provide proof of the immunoregulatory capacities of EV and provide new insights in the use of EV or modified form for the treatment of MS.

Researcher(s)

• Promoter: Cools Nathalie

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Chimeric antigen receptor (CAR)-T cell therapy has demonstrated unprecedented clinical activity in patients with hematological diseases, but a large proportion of them will ultimately relapse. Further optimization of this new treatment modality is therefore required to unlock its full therapeutic potential. In this project, in addition to using readily available cell line models, we will use our mRNA electroporation technology for CAR loading of immune cells. This will provide a rapid and efficient way to explore new research paths that can lead to optimized CAR-based cellular therapies for hematological diseases. Will assess the value of a multi-targeted approach incorporating two established CAR targets (CD19 and B-cell maturation antigen) and the novel CAR candidate CD200. Next, the hinge and co-stimulatory domains in the CAR structures will be sequentially modified, comparing conventional hinge and co-stimulatory domains with our recently discovered 4-1BB-hinge and CD26 co-stimulatory domains. Exhaustion will be prevented by introducing programmed death (PD-1) silencing RNA in the CAR-modified cells to reduce PD-1-mediated co-inhibitory signaling. Finally, positive findings will be translated from our cell line models to conventional T cells, NK cells and gdT cells.

Researcher(s)

• Promoter: Roex Gils

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Genetic engineering of lymphocytes for adoptive cell transfer has marked a turning point in personalized immunotherapy, especially in the treatment of cancer. Adoptive T-cell immunotherapies using antitumor chimeric antigen receptors (CARs) and T-cell receptors (TCRs) have, however, not met expectations yet for the majority of malignancies, including acute myeloid leukemia (AML). Moreover, expression of immunosuppressive immune checkpoints (IICPs) hinders the success of these therapies. To address the shortcomings of current T-cell therapies, the aim of this research project is to develop an innovative combinatorial and genetically engineered adoptive T-cell therapy focusing on AML as a disease model. In this project four important issues will be covered. First, cancer cells capitalize on processes such as downregulating peptide-major histocompatibility complex (pMHC) ligands to lower their immunogenicity and, by doing so, evade immune detection. Second, TCRs that target tumor self-antigens are scarce and usually have low affinities, having difficulties in binding target tumor antigens. Finding ways to improve interaction between pMHC ligands and low affinity TCRs, such as those that target self-antigens, would improve the chance of success in TCR-engineered T-cell therapies. Third, adoptive T-cell therapies are confronted with immunosuppressive environments that hinder their efficacy via engagement of IICPs, such as PD-1, TIM-3, or LAG-3. Determining the most relevant IICPs is key for developing effective adoptive T-cell therapies. Fourth, these therapies must be tumor-specific and efficacious once translated into a clinical setting. Taken together, combinatorial and flexible approaches for TCR-engineering will mark the next-generation of T-cell immunotherapies, by addressing (a) improved interaction between T cells and cancer cells, (b) immune evasion through IICPs, (c) cost-effectiveness of an all-in-one therapy, and (d) safety using RNA-based methods. In summary, improved adoptive T-cell therapies that overcome CAR and TCR challenges as well as the immunosuppressive environment that hinders antileukemic T-cell action will facilitate innovative solutions for cancer treatment.

Researcher(s)

• Promoter: Lion Eva
• Co-promoter: Anguille Sébastien
• Fellow: Flumens Donovan

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project website

Project type(s)

• Research Project

Abstract

Acute myeloid leukemia (AML) is a rare type of cancer that predominantly affects people in the third age. The 5‐year overall survival rate of AML patients is only 30%, a figure that has not substantially changed despite enormous therapeutic advances in the last decade. Novel immunotherapies, such as T-cell receptor (TCR) T-cell and chimeric antigen receptor (CAR) T-cell therapies, are difficult to adopt in the context of AML. This is because most AML-related antigens are intracellular self-antigens that are expressed on the AML cell surface as peptides via major histocompatibility complexes (MHC); TCRs specific for these self-antigens are difficult to obtain since self-reactive T cells undergo thymic negative selection. In contrast to CD19 which is a very suitable extracellular target antigen for CAR-T cell therapy in acute lymphoblastic leukemia (ALL), the very few extracellular antigens expressed on AML cells that can serve as targets for CAR-T cell-based therapies, such as CD33 and CD123, are also expressed on normal hematopoietic stem/progenitor cells entailing a risk of intolerable myeloablation. The aim of this innovative project is to combine the best of two worlds, namely to redirect T-cells towards the key intracellular AML antigen Wilms' tumor protein 1 (WT1) using WT1-specific TCRs, combined with an innovative non-signaling CAR (NSCAR) towards a novel candidate extracellular AML antigen.

Researcher(s)

• Promoter: Lion Eva
• Co-promoter: Anguille Sébastien
• Co-promoter: Campillo Davó Diana

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Acute myeloid leukemia (AML) is a rare type of cancer that predominantly affects people in the third age. The 5‐year overall survival rate of AML patients is only 30%, a figure that has not substantially changed despite enormous therapeutic advances in the last decade. Novel immunotherapies, such as T-cell receptor (TCR) T-cell and chimeric antigen receptor (CAR) T-cell therapies, are difficult to adopt in the context of AML. This is because most AML-related antigens are intracellular self-antigens that are expressed on the AML cell surface as peptides via major histocompatibility complexes (MHC); TCRs specific for these self-antigens are difficult to obtain since self-reactive T cells undergo thymic negative selection. In contrast to CD19 which is a very suitable extracellular target antigen for CAR-T cell therapy in acute lymphoblastic leukemia (ALL), the very few extracellular antigens expressed on AML cells that can serve as targets for CAR-T cell-based therapies, such as CD33 and CD123, are also expressed on normal hematopoietic stem/progenitor cells entailing a risk of intolerable myeloablation. The aim of this innovative project is to combine the best of two worlds, namely to redirect T-cells towards the key intracellular AML antigen Wilms' tumor protein 1 (WT1) using WT1-specific TCRs, combined with an innovative non-signaling CAR (NSCAR) towards a novel candidate extracellular AML antigen.

Researcher(s)

• Promoter: Lion Eva
• Co-promoter: Campillo Davó Diana

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

COVID-19 is a disease caused by an infectious outbreak of SARS-CoV-2. This viral SARS-CoV-2 infection can present itself in a broad spectrum of clinical features, ranging from asymptomatic, sensation of a mild cold or flu to severe bilateral pneumonia and death. Cancer patients are at high risk to develop serious illness after infection with SARS-CoV-2. Therefore, it is of high importance to protect these patients by following hygiene measurements and social distancing. But, as indicated by the guidelines of the Belgian and European Society for Medical Oncology, it is also important to vaccinate cancer patients. Although, not many studies that elevated the vaccine efficacy of COVID-19 vaccines in cancer patients have been performed. Due to the cancer or the treatment, it could be possible that the efficacy of the vaccines is lower in cancer patients or that they develop more side effects as a result of vaccination. To investigate this, we will monitor the reaction of the immune system of current and ex oncological and haematological patients on the different COVID-19 vaccines (Pfizer, Moderna, AstraZeneca, Janssen Pharmaceutica). The adverse effects as a reaction on vaccination will be investigated in this population as well. Clinical data of the patients will be collected and a blood drawn will be performed at different time points: before vaccination and 4, 6 and 12 months after receiving the first vaccination dose. The primary endpoint of the study is the quantification of different anti SARS-CoV-2 specific IgG antibodies per study cohort at 4 months after the first vaccination. The secondary endpoints of the study are to measure the SARS-Cov-2 specific T cell response and to investigate the evolution and duration of the cellular immune response after vaccination in the patient cohort. Another secondary endpoint is to analyse the titers of neutralizing antibodies both 4,6 and 12 months after receiving the first vaccination dose. Furthermore, it is aimed to investigate the efficacy of the immune response in the patient cohort for each different vaccine. This will be assessed by the SARS-CoV-2 infection rate based on information collected through questionnaires on incidence of (PCR-confirmed or chest CT scan confirmed) SARS-CoV-2 infection within a time frame of 12 months after the start of the study. At last, we will investigate the safety of the different COVID-19 vaccines that are commercially available in Belgium. Safety will be reported in terms of incidence and severity of adverse effects (AEs) using a questionnaire. Patients will be asked to report their adverse events over a period of 3 days after the vaccination day. This research project will provide knowledge on how the immune reaction after vaccination develops in cancer patients and patients with oncological or haematological history. The team of prof Lion of the Laboratory of Experimental Hematology, focusses on the SARS-Cov-2 specific cellular immunity research.

Researcher(s)

• Promoter: Lion Eva

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The general goal of this research project is to develop a clinically safe cell-based vaccine for the treatment of (progressive) MS, based on BDNF-expressing Tregs. By using state-of-the art techniques, we will develop "designer" Tregs that are engineered to express high levels of BDNF. We hypothesize that these Tregs will excel in their pro-regenerative properties, driving oligodendrocyte differentiation and remyelination, beyond immunomodulation with the aim to induce remyelination in MS.

Researcher(s)

• Promoter: Wens Inez
• Co-promoter: Cools Nathalie

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The field of chimeric antigen receptor (CAR)-T-cell immunotherapy has evolved tremendously over the past decades. One of the milestones in CAR development was the incorporation of co-stimulatory domains, providing the necessary signaling to trigger full T-cell activation. Given their improved performance, these so-called second-generation CAR-T cells equiped with CD28- or 4-1BB -based intracellular domains dominate the clinical trial landscape. For multiple myeloma, the second most common type of blood cancer, early-phase clinical trials with B-cell maturation antigen (BCMA)-targeted CAR-T cells have demonstrated promising results, but relapses are frequently observed. Therefore, a great deal of research attention is currently being paid at improving the efficacy of the CAR-T cells. In the proposed project, we want to evaluate the potential of CD26 as a co-stimulatory domain in BCMA-targeted CARs. CD26 has been shown to improve persistence and anti-tumor activity of T cells, and is associated with a memory phenotype. In addition, the impact of the hinge domain on CAR-T-cell efficacy has been poorly studied, although the hinge domain has been shown to be important for antigen recognition. Therefore, we developed a novel 4-1BB-based hinge in collaboration with colleagues at Fudan University, Shanghai, China. This new hinge was already validated in the context of anti-HER-2, -GPC3 and -CD19 CAR-T cells, and will be further evaluated here in multiple myeloma.

Researcher(s)

• Promoter: Anguille Sébastien

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Can the bioinformatics R package FlowSOM – for high-dimensional single-cell flow cytometry datasets – assist research on dendritic cell-mediated immune cell activation? The primary objective of this Small Project is to evaluate the R package FlowSOM for the analysis of high-dimensional flow cytometry data and to explore its use in the preclinical and clinical evaluation of immunogenicity of next-generation anticancer dendritic cell vaccine candidates that are currently under investigation at the Laboratory of Experimental Hematology (UAntwerp) and the Center for Cell Therapy and Regenerative Medicine (Antwerp University Hospital). With increasing dimensionality of biological data and technical advances, manual flow cytometry data analysis will become inadequate. Applying bioinformatics, automated and unbiased comparisons between in vitro/ex vivo-stimulated immune effector cells with novel dendritic cell vaccine candidates will assist further development of potent dendritic cell preparations with the most superior immune-stimulating capacities and will be essential in unraveling therapy responsive immune profiles in longitudinal studies. FlowSOM is a powerful algorithm that builds self-organizing maps (SOMs) to provide an overview of marker expression on all cells and reveal cell subsets that could be overlooked with manual gating. Ultimately, our aim is to develop an advanced immune profiling platform for evaluation of preclinical and clinical dendritic cell-mediated immune responses.

Researcher(s)

• Promoter: Lion Eva

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Cell therapy is one of the most promising future clinical options in the medical arsenal for the treatment of patients suffering from serious conditions where unmet medical needs exist. Breakthroughs in cell and molecular biology have enabled the development of cell-based vaccines, and to date cell therapies are being evaluated in the first clinical trials aiming to treat autoimmune diseases, including multiple sclerosis (MS). Although the therapeutic landscape of MS is constantly evolving, none of the currently available treatments results in a permanent stabilization of the disease, and most of them indiscriminately suppress the immune system. In this perspective, immune-modulatory cell therapy has the potential to target underlying disease mechanisms in a more specific way. In particular, regulatory T cells (Tregs) offer the opportunity to target cells that are potentially involved in the induction and progression of the disease. In current proposal, we aim to develop TCR-engineered Tregs to enforce their interaction with cells that are key in the disease pathogenesis. In doing so, we ultimately aim to control autoimmunity.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Wens Inez

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Whereas antigen-specific activation of autoreactive T-cells is considered essential in the initiation and maintenance of MS, how to identify the broad repertoire of unique receptors expressed by these autoreactive T-cells from blood remains unclear. Nonetheless, with improved T-cell receptor (TCR)-sequencing technological development, efforts in identifying immune T-cell signatures in blood, CSF and brain lesions of MS patients have been initiated. Although accurately evaluating TCR clonal expansion using high throughput sequencing in bulk DNA/RNA has been challenging, single-cell sequencing allows to establish TCR repertoires of autoreactive T-cells on a cell-by-cell basis, obtain full-length V(D)J sequences, pair α and β sequences and combine TCR with 5' transcriptome sequencing in the same cells, and this for 1000s of cells. The combined expertise of our interuniversity team in immunology and characterization of autoreactive T-cells (N. Cools, U Antwerp) on the one hand and in genetics and single-cell sequencing (A. Goris, KU Leuven) on the other makes it now feasible, timely and innovative to investigate the pathogenic characteristics of autoreactive T-cells in MS. For this, the following three aims have been set forth: 1. What is the TCR repertoire of autoreactive T-cells in MS? 2. What are the transcriptional characteristics of autoreactive T-cells? 3. Can the autoreactive T-cell clonotype repertoire be used as a correlate for therapy responsiveness?

Researcher(s)

• Promoter: Cools Nathalie

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

In Belgium, two patients receive the diagnosis of multiple myeloma (MM) each day. Despite considerable therapeutic advances over the past decades, MM remains incurable. Drug resistance often leads to refractory disease and relapses. Therefore, there is an urgent need for novel treatment methods for MM. Immunotherapy has become an important asset in the treatment of various cancers, including MM. Chimeric antigen receptor (CAR)-T cell therapy has attracted much attention in recent years, most notably in B cell malignancies (BCMA). CAR-T cells are T lymphocytes that are genetically modified, predominantly by lentiviral or retroviral transduction, to express a CAR that can recognize virtually any surface epitope expressed on a cell. Results of early-phase clinical trials in MM, mainly targeted towards B cell maturation antigen, were promising with high clinical response rates, including complete responses. Unfortunately, responses are usually temporary and relapses have been described due to loss of BCMA expression following CAR-T therapy. In addition, serious adverse events that usually require hospitalization such as cytokine release syndrome are frequently reported. Hence, there is a general consensus that CAR-T cell-based immunotherapy can only become a "viable" therapeutic option in the future if these 3 challenges are adequately addressed: improving efficacy (challenge 1) while reducing toxicity (challenge 2) and costs (challenge 3). The general objective of this project is to develop a next-generation CAR-T cell treatment for multiple myeloma (MM). The hypothesis of this study is that targeting multiple antigens will broaden the anti-tumor immune response and, thus, enhance efficacy of the treatment by reducing the chance of immune escape. Incorporation of immune checkpoint downregulation and enhancement of their co-stimulatory and migratory function can potentially further augment the anti-tumoral properties of the CAR-T cells. Considering potential adverse events, we envisage mRNA electroporation and the use of gamma/delta (γδ) T cells as improvements to the safety and overall costs of CAR-T cell therapy. In summary, we envision a more effective, safer and economically viable CAR-T cell therapy.

Researcher(s)

• Promoter: Van Tendeloo Vigor

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Multiple myeloma (MM) is an malignancy that remains incurable to date. Chimeric antigen receptor (CAR)-T cell therapy has obtained impressive clinical results in leukemia and lymphoma, and is gaining momentum in MM as well. This project aims to tackle shortcomings in efficacy and safety in current CAR-T cell therapies by targeting multiple MM antigens, reducing T cell exhaustion and exploring alternative T cell subsets. Importantly, transient T cell modification ensures patient safety, reduces manufacturing costs significantly and can serve as an early-phase testing platform for clinical translation of novel CAR-T cell therapies.

Researcher(s)

• Promoter: Van Tendeloo Vigor

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The therapeutic landscape of MS is constantly evolving, and one could pose the question if we still have unmet needs for the treatment of MS? Nevertheless, despite the availability of improved therapies and the significant advances in the understanding of what triggers disease, patients continue to experience relapses and, in some cases, are exposed to potential life-threatening side-effects. Hence, current challenge is to balance the need to modify the underlying disease pathogenesis and the long-term risks. In this perspective, immunemodulatory cell therapy has brought a new hope for a wide spectrum of diseases. Tregs offer the opportunity to target cells that are potentially involved in the disease progress. Nevertheless, whether Tregs act in an antigen-specific manner remains elusive. Hence, despite the potential that Treg therapy holds, 2 there are still some challenges, not in the least to direct the interaction of Tregs with key disease-associated immune cells in an antigen-specific manner. To address these, the following objectives have been set forth in current project proposal: Our first objective is to select antigen-specific effector T cells by means of tetramer analysis, thereby identifying and cloning a myelin-recognizing TCR. Secondly, we will optimize a clinically safe mRNA electroporation protocol to induce expression of mRNA encoding the TCR in freshly-isolated and expanded Tregs from MS patients. Thirdly, we ensure the stability of the phenotype and suppressive function of TCR-engineered Tregs. In doing so, we will deliver in vitro proof-of-concept of the safety of the approach which is especially important when administering the cells in an inflammatory disease-driven microenvironment. Finally, we will investigate if TCR-transgenic Tregs can modulate ongoing disease processes by investigating their effect on the phenotype and function of DCs from healthy volunteers and MS patients. Ultimately, we envisage that this will foster a durable clinical application of this technology without the risk for general immunosuppression.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Wens Inez
• Fellow: Janssens Ibo

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Improvement of frontline treatment for cancer patients with a high tumor recurrence rate and low effective treatment options is warranted. Dendritic cell (DC) vaccination is in this context a promising immunotherapeutic armament. Complementary to current treatments, DCs as quintessential antigen-presenting cells of the immune system, can activate the antitumor immune system to attack cancer cells. We previously established novel monocyte-derived DC generation protocols integrating the pleiotropic immune regulator interleukin (IL)-15 while downmodulating ligands for the inhibitory checkpoint programmed death (PD)-1. Our preclinical data demonstrate high therapeutic potential of these designer DCs, evidenced by superior immunogenic capacities. Further extending our DC immunotherapy program, this project is designed to enable the first-in-human clinical application of our novel designer DC vaccines, allowing development of clinical-grade production processes, human in vivo safety and feasibility testing and design of next-level combinatorial therapy approaches for cancer patients with a high unmet medical need.

Researcher(s)

• Promoter: Lion Eva

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Acute myeloid leukemia (AML) is an agressive type of blood cancer that still carries a dreadful prognosis. Even with treatment, only one out of 4 patients with AML will be alive 5 years after the diagnosis. This explains the urgent need for novel therapies. It is well known that our own immune system can fight cancer, laying the foundation for the development of immune-based therapies for cancer. One type of immunotherapy that has attracted much recent interest is T-cell therapy. Such therapy is based on the intrinsic ability of T cells - an important part of our immune system - to recognize and kill cancer cells. They do so via T-cell receptors, which are expressed on their cell surface. These T-cell receptors recognize certain substances, called antigens, that are presented by the cancer cells. In the context of AML, one antigen that serves as an attractive T-cell target is the Wilms' tumor protein 1 (WT1). In this research project, we will try to "weaponise" T cells to attack leukemia cells by genetically enforcing the expression of T-cell receptors against WT1. The ultimate goal is to exploit these anti-leukemia "killer" T cells for therapeutic purposes and to fulfill the unmet therapeutic need in AML.

Researcher(s)

• Promoter: Anguille Sébastien

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The host's laboratory's promising results of IL13 treatment in a mouse model for MS, encourage us to further investigate this potential therapeutic strategy in a human setup. Therefore, we propose to develop a human in vitro demyelination model to study the effect of IL13-induced M2 macrophages and microglia. We will do so by (I) differentiating hiPSC towards oligodendrocytes; (II) evaluating the myelinating potential by oligodendrocyte-neuron co-culture; (III) optimizing a toxin-induced demyelination procedure; and (IV) evaluating the effect of macrophage/microglia addition with or without IL13 stimulation.

Researcher(s)

• Promoter: Le Blon Debbie
• Co-promoter: Ponsaerts Peter

Research team(s)

• Center for Oncological Research (CORE)
• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system in which the body 's own immune system attacks the myelin sheath. This leads to disruption in signaling in the brain and spinal cord and to loss of brain tissue. MS is the most common cause of non-traumatic disability in young adults. To date, many aspecific immunomodulatory and general immunosuppressive treatments are used to slow down the disease course, but these treatments have several side effects, ranging from mild to severe and life-threatening issues, including other autoimmune diseases and infections. Thus, there remains an unmet need for specific treatments with a good safety profile. Restoring antigen specific tolerance is an interesting approach to tackle these problems. Theoretically, a limited number of vaccinations with tolerogenic dendritic cells (tolDC) could reeducate the patient's own immune system in the longterm. Based on our previous research in the laboratory on MS and clinical studies in other autoimmune diseases we are ready to bring tolDC treatment to MS patients. The aim of this project is to assess safety and feasibility of autologous myelin-peptide-loaded tolDC in active MS patients, who will receive 6 vaccinations in a phase I clinical trial. Safety will be evaluated by recording of adverse events. Feasibility will be determined by successful production of tolDC. Positive results can lead to clinical trials evaluating efficacy.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Cras Patrick
• Fellow: Willekens Barbara

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Neuroinflammation occurs in all central nervous system (CNS) pathologies and can be defined as the activation of local and peripheral infiltrating immune cells, with the key players being brain-resident microglia and blood-borne infiltrating macrophages. While growing evidence ascribes different roles to microglia and macrophages in neuro-inflammation, the main interest in both phagocytes, with regard to therapeutic strategies, is their ability to obtain different activation states, ranging from pro-inflammatory (M1) to anti-inflammatory (M2) activation. These new revelations led to many studies nowadays, which are investigating immune modulation as a potential therapeutic strategy to treat CNS pathologies. However, since existing pre-clinical models for the study of neuro-inflammation are based on either human cell lines or rodent models, this new and potential therapeutic strategy creates the need for more reliable pre-clinical models for human neuro-immune research. Therefore, with this project, we aim to develop an in vitro assay to study and modulate activation states in human neuro-inflammation by using human induced pluripotent stem cell (hiPSC)-derived microglia and macrophages. For this, we will introduce and validate in vitro differentiation protocols for hiPSC-derived microglia and macrophages. Phenotypical characterization will be performed by using known markers for immunocytochemistry and flow cytometry. Next, functional analyses of the developed hiPSC-derived microglia and macrophages will include (i) migration assays for chemokines CX3CL1 and CCL2, known to attract, respectively, microglia and macrophages; (ii) phagocytosis assays; and (iii) M1-M2 priming experiments, determining the polarising capacity of both microglia and macrophages by flow cytometry and ELISA. With this research project, our main aim is to meet the urgent need for novel in vitro human neuro-inflammation models, but with a successful outcome, we will also achieve a major step forward towards less animal testing.

Researcher(s)

• Promoter: Le Blon Debbie

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system (CNS) for which no cure is currently available. It is the leading cause of non-traumatic disabling neurological disease in young adults with more than 500,000 people affected in Europe. Since MS strikes during the primary productive time of one's personal and professional life, it leads to a major physical and socio-economic burden to the patient, family and society. Therefore, new therapeutic interventions with improved efficacy over existing drugs and good tolerability are warranted. As chronic inflammatory processes drive the neurodegeneration, we hypothesize that improved clinical outcome depends on restoring the balance between inflammation and the remaining capacity of neuronal self-renewal. In this perspective, cell therapy that specifically targets the damaging immune reactions that cause MS and induce disease-specific tolerance without affecting protective immunity against pathogens and cancer is a promising approach. Recently, we set-up a collaborative network of European centers working in cell therapy (COST Action BM1305). From this, centers from four different EU countries with two additional partners now aim to take the next step and join efforts to bring antigen-specific therapy for MS to the clinic. Our objectives are to evaluate safety, clinical practicality and demonstrate first proof-of-principle of therapeutic efficacy of antigen-specific tolerance-inducing dendritic cells (tolDC) in MS patients in two single-center clinical trials while comparing different modes of tolDC administration. Coordinated patient monitoring and centralized MRI monitoring, including radiological correlates of neurodegeneration, and immunomonitoring will enable us to directly compare results between trials and enable consented biobanking, data safeguarding and accessibility to support future efforts in the field of MS therapy. Antigen-specific cell therapy has the potential to provide this chronic inflammatory disease with a personalized and effective treatment option and therefore fits within current program. An effective therapy that lowers morbidity by uniting efficacy with reduced occurrence of side effects and less frequent hospitalizations will enhance quality of life of patients as well as dramatically reduce economic burden. This would represent a breakthrough for healthcare in MS.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Hens Niel

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Developing novel neuroprotective and/or immune-modulating therapeutic strategies for almost every neurological disease or trauma requires, both for academia and pharmaceutical industry, the existence of robust in vitro cell culture models to mimic disease-associated pathological events. Unfortunately, a complex interplay between multiple central nervous system (CNS) cell types and multiple cell types from the body's peripheral immune system, cannot be easily recapitulated by currently used 2-dimensional (2D) co-culture assays. It is exactly therefore that successful pre-clinical experimental efficacy has proved to be very difficult to translate into clinical benefit, and as a consequence there is an increasing gap in knowledge and progress between bench and bed side. One highly promising novel approach to improve the predictive power of in vitro human neuro-immune research consists in developing modular 3D brain organoids that resemble brain tissue at the structural, cellular and functional level. Within this project we aim to develop and optimize a new method for generating isogenic 3D brain organoids, comprising human pluripotent stem cell (hPSC)-derived neurons, astrocytes and microglia. Furthermore, hPSC-derived astrocytes and endothelial cells will be used to create a blood-brain-barrier model for physical separation of hPSC-derived macrophages from the generated human 3D brain organoids. Together, this integrated cell system will represent a powerful new 3D human neuro-immune cell culture paradigm. Within this multidisciplinary IOF-SBO project, the methodological approach to generate 3D brain organoids, combined with the experience in the field of clinical research and the availability of patient samples, is truly unique and will - in first instance - highly contribute to the field of in vitro cerebrovascular disease modelling and treatment validation. Furthermore, our aims to install an integrated 3D brain organoid technology platform at the University of Antwerp, will - given the current scientific and economic interests – allow for both short-term and long-term valorisation of our combined efforts, with both intellectual (PhD-theses, A1 publications) as well as financial (contract research) revenues.

Researcher(s)

• Promoter: Ponsaerts Peter
• Co-promoter: De Vos Winnok
• Co-promoter: Jorens Philippe
• Co-promoter: Timmermans Jean-Pierre
• Co-promoter: Wouters An

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The extraordinary specificity of T lymphocytes for their antigen turns them into highly attractive and targeted immunotherapeutics. However, the scarcity of tumor-reactive T cells in cancer patients and the difficulty of their expansion in sufficient numbers for adoptive immunotherapy are substantial hurdles to broaden their clinical application. Transient introduction of a T cell receptor (TCR) specific for a pre-defined tumor-associated antigen by means of RNA-engineering into unselected bulk T cells would instantaneously confer redirected anti-tumor specificity to a large number of effector T cells for adoptive immune therapy with a built-in safety switch. This research project aims to investigate the generation, in vitro validation and preclinical testing of a set of Wilms' tumor 1 (WT1)-specific TCRs derived from leukemia patients that responded successfully to a therapeutic WT1 vaccine. On the short term, we are confident that this research project will provide a sound basis for exploratory and translational phase I trials using WT1-specific TCR mRNA-engineered T cells to study the safety (on- & off-target off-tumor effects) and feasibility of adoptive T cell therapy in patients with WT1-positive hematological malignancies. On the long term, adoptive T cell therapy using redirected T cells is poised to become a new treatment paradigm for both hematological and solid cancer patients at risk of relapse, if needed in combination with other antitumor therapies.

Researcher(s)

• Promoter: Van Tendeloo Vigor
• Co-promoter: Berneman Zwi

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Worldwide, spinal cord injuries (SCI) are a major cause of morbidity, mortality and reduced quality of life. Until now no regenerative therapy for SCI is available and standard care of SCI patients includes primarily the administration of immunosuppressant drugs and rehabilitation. Thus, new therapeutic strategies are desperately needed. After SCI, pro-inflammatory macrophages dominate the spinal cord and exert detrimental effects by secreting multiple pro-inflammatory factors, by stimulating the formation of the inhibitory fibrotic scar, and by attacking dystrophic axons. Previously, the applicants demonstrated that the implantation of IL-13-expressing mesenchymal stem cells or macrophages induces 'antiinflammatory' arginase-1 (Arg-1)-positive macrophages/microglia in the injured spinal cord, leading to improved functional recovery. Therefore, we investigate here whether high Arg-1 production by macrophages with a stable alternative activation leads to the suppression of pro-inflammatory macrophages/microglia after SCI via arginine depletion. In addition, for translation to the human situation, we will investigate whether Arg1-overexpressing human macrophages exert neuroprotective effects in an in vitro multicellular co-culture model of human stem cell-derived corticospinal-like motor neurons, astrocytes and microglia. Thus, in this project, we aim to analyse one key mechanism of how anti-inflammatory macrophages improve functional recovery after SCI.

Researcher(s)

• Promoter: Ponsaerts Peter

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Due to the current understanding that multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), where mononuclear cell infiltration in brain and spinal cord is a major contributor to demyelination, gliosis, axonal loss and eventually loss of neuronal function, we investigated over the past 6 years whether local modulation of CNS lesions with the immune-modulating cytokine interleukin (IL)13 might ameliorate detrimental disease progression. While our pre-clinical studies in the cuprizone (CPZ)-induced CNS inflammation/demyelination mouse model for human MS have demonstrated proof-of-principle for this approach, currently we do not know whether human microglia and macrophages are equally well susceptible to IL13-mediated immunomodulation in the pro-inflammatory MS environment. Using advanced human induced pluripotent stem cell (hiPSC) derived 3D cell culture models, we aim to provide further pre-clinical rationale for the use of IL13 as an additional treatment approach in advanced stage MS.

Researcher(s)

• Promoter: Ponsaerts Peter
• Co-promoter: Le Blon Debbie

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Development of three-dimensional (3D) in vitro cell culture models for human neuro-immunological research is currently a hot topic in medical cell biology research. Although multiple protocols have been described for generating human 3D brain organoids starting from pluripotent stem cells, current models display several limitations, including the lack of extracellular matrix (ECM), the absence of multiple types of immune cells and a functional blood-brain-barrier (BBB). With this project we aim to develop and optimize a new method for generating 3D neuro-immune cell culture models to study and modulate human neuro-inflammatory responses. For this, isogenic 3D cell cultures comprising human embryonic stem cell (hESC)-derived neurons, astrocytes and microglia will be established on decellularized mouse brain sections in order to provide growth and organizational support by original brain ECM proteins. In addition, hESC-derived astrocytes and endothelial cells will be used to create a BBB model for physical separation of hESC-derived macrophages. Further inclusion of genetic engineering strategies, to allow for real time bioluminescence imaging and (live cell) confocal microscopy, will be applied to ensure profound validation and high throughput screening applications. Once established, we will use this technology to further extend our research efforts to optimize therapeutic strategies based on interleukin (IL)13-mediated immunomodulation, following hypoxic and hypoglycemic stress (i.e. stroke-like conditions). Once validated, we believe that implementation of the proposed 3D brain organoid technology by academia and/or pharmaceutical industry will not only have great impact on the reliability of pre-clinical drug screening, and consequently on the medical and social investments associated with patient care, but also will find application in advanced human toxicology research.

Researcher(s)

• Promoter: Ponsaerts Peter
• Fellow: Van Breedam Elise

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project website

Project type(s)

• Research Project

Abstract

Development of three-dimensional (3D) in vitro cell culture models for human neuro-immunological research is currently a hot topic in medical cell biology research. Although multiple protocols have been described for generating human 3D brain organoids starting from pluripotent stem cells, current models display several limitations, including the lack of extracellular matrix (ECM), the absence of multiple types of immune cells and a functional blood-brain-barrier (BBB). With this project we aim to develop and optimize a new method for generating 3D neuro-immune cell culture models to study and modulate human neuro-inflammatory responses. For this, isogenic 3D cell cultures comprising human embryonic stem cell (hESC)-derived neurons, astrocytes and microglia will be established on decellularized mouse brain sections in order to provide growth and organizational support by original brain ECM proteins. In addition, hESC-derived astrocytes and endothelial cells will be used to create a BBB model for physical separation of hESC-derived macrophages. Further inclusion of genetic engineering strategies, to allow for real time bioluminescence imaging and (live cell) confocal microscopy, will be applied to ensure profound validation and high throughput screening applications. Once established, we will use this technology to further extend our research efforts to optimize therapeutic strategies based on interleukin (IL)13-mediated immunomodulation for cerebrovascular disease.

Researcher(s)

• Promoter: Ponsaerts Peter
• Co-promoter: Berneman Zwi
• Fellow: Le Blon Debbie

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The "Breakthrough of the Year" of 2013, awarded by Science, was the burgeoning field of cancer immunotherapy. In spite of some great results, the search continues towards an ideal functioning of our immune cells, leaving a paramount question unanswered: can we identify specific cellular attributes denoting optimal activation and immune performance in combating cancer? In this project we will investigate the interleukin (IL)-15-mediated activation of immune cells, more specifically dendritic cells (DCs) and gd T cells, and their expression of CD56 in a model of acute myeloid leukemia. First, IL-2 and IL-15 will be compared for their immunostimulatory effect on gd T cells, conceivably strengthening the use of IL-15 in, among other, adoptive immunotherapy protocols. Induction of activation and enhancement of effector functions of gd T cells by these cytokines will be correlated with their CD56 expression. Next, we will delineate the cross-talk between our CD56+ and IL-15 expressing IL-15 DCs and gd T cells. Furthermore, the role of CD56 on these immune cells will be unraveled. This will give us the opportunity to finally answer the question whether CD56 expression is being indicative of an activated state, whether it actively leads to tumor cell killing and whether or not homodimeric interactions do play a role. Finally, mechanistic insight will be gained into the individual contribution of the IL-15 signaling pathways in induction of CD56 expression and immune cell activation.

Researcher(s)

• Promoter: Van Tendeloo Vigor
• Co-promoter: Smits Evelien
• Fellow: Van Acker Heleen

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand the client. UA provides the client research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Cools Nathalie

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The five-year survival rate for acute myeloid leukemia (AML) is 26.6%, pointing to the need for new treatment options. We have recently provided the first clinical proof-of-concept evidence that vaccination with Wilms’ tumor 1 mRNA-electroporated dendritic cells (DC) can result in complete clearance of minimal residual disease. Our phase I/II study showed improved survival compared to historical data and demonstrable antileukemic effects. Now we want to confirm the results of our initial study in a multicenter randomized phase II clinical study in 138 patients with AML at high risk of relapse. The primary aim is to determine whether DC vaccination can significantly prevent relapse and increase survival. In addition, tumor marker levels and immune activation will be monitored. If the curative potential with low toxicity can be confirmed in this novel large randomized trial, our cell therapy can become a new standard postremission treatment for AML.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Currently therapeutic cancer vaccines have taken center stage in cancer immunotherapy. Such cancer vaccines are designed to delay or prevent cancer relapse after standard treatment with chemotherapy or radiotherapy, and to attack distant metastatic cancer cells. We have already successfully tested a personalized cell-based cancer vaccine for leukemia patients and we demonstrated that the vaccine could prevent leukemia relapse in about 35% of the vaccinated leukemia patients. This cancer vaccine consists of specially cultured immune cells of the patient that upon injection in the skin starts off an anti-tumor immune response against residual or chemotherapy-resistant leukemia cells. In this project we aim to make this personalized leukemia vaccine even more powerful in the test tube by innovative manipulations and by implementing new emerging anti-cancer strategies that have already proven successful in solid tumors.

Researcher(s)

• Promoter: Van Tendeloo Vigor
• Co-promoter: Lion Eva
• Fellow: Versteven Maarten

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The prognosis of patients diagnosed with malignant pleural mesothelioma (MPM) remains dismal with a median overall survival from diagnosis of only 12 months. The steadily increasing incidence of MPM along with the limited efficacy of the currently available treatment options for MPM prompts a search for new, more effective therapeutic modalities and strategies. Dendritic cells · (DCs), the immune system’s quinte-ssential antigen-presenting cells, are a promising armament for immunotherapy of MPM. In this phase 1/11 clinical study designed to improve most common care of MPM, DCs loaded with the mesothelioma-associated tumor antigen Wilms’ tumor 1 protein (WTl) will be used in conjunction with conventiona,l platinum/pemetrexed-based chemotherapy for the frontline treatment of newly diagnosed resectable and non-resectable MPM. Primary objective is to provide the first-in-human experimental demonstration that combining chemotherapy with WTl-targeted DC therapy is feasible and safe a·nd enables induction of systemic and in situ mesotheliomaspecific immune responses in MPM patients.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Development of three-dimensional (3D) in vitro cell culture models for neuroscience research is currently a hot topic in medical cell biology research. Although multiple protocols have been described for generating 3D brain organoids starting from pluripotent stem cells, current models display several limitations, including the lack of extracellular matrix (ECM) and the absence of glial and immune cells. With this project we aim to develop and optimize a new method for generating 3D neuro-immune cell culture models to study and modulate neuro-inflammatory responses. For this, 3D cell cultures comprising induced pluripotent stem cell (iPSC)-derived neurons, astrocytes and microglia will be established on decellularized mouse brain sections in order to provide growth and organizational support by the original brain ECM. Further inclusion of genetic engineering strategies, to allow for real time bioluminescence imaging and live cell confocal microscopy, will be applied to ensure high throughput screening applications. Once established, we will use this technology to further extend our research efforts to optimize therapeutic strategies based on interleukin (IL)13-mediated immunomodulation, following hypoxic and hypoglycemic stress. Once validated, we believe that implementation of this technology by pharmaceutical industry will have great impact on the reliability of pre-clinical drug screening, and consequently on the medical and social investments associated with patient care.

Researcher(s)

• Promoter: Ponsaerts Peter
• Fellow: Quarta Alessandra

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Multiple sclerosis (MS) is the leading cause of non-traumatic disability in young adults. Although growing insights into disease mechanisms underlying MS have resulted in the development of new therapeutic strategies, none of the currently available treatments results in permanent stabilization or cure of MS. Current research efforts are focused on further unraveling MS immunopathogenesis as well as on finding ways to specifically manipulate disease-causing immune cells in order to treat MS. In this context, dendritic cells (DC) are set forth as interesting cellular targets. Post-mortem studies of MS brains as well as studies in animal models suggest that migration of DC from the bloodstream through the blood-brain barrier (BBB) and subsequent accumulation of these cells in the brain parenchyma represent crucial events in MS pathogenesis. Hence, DC and the process of DC migration are interesting targets for the development of new therapeutic strategies. Here, we will study the transmigratory capacity of circulating DC from MS patients using an in vitro BBB model. By studying differences in phenotype and function between migrating and non-migrating DC from MS patients and healthy controls, we aim to identify new therapeutic targets in order to interfere with DC recruitment to the brain. Ultimately, this will allow us to generate tolerogenic DC exhibiting enhanced migratory capacity, with the potential to suppress ongoing myelin-specific responses in the central nervous system.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Berneman Zwi
• Fellow: Meena Megha

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Cools Nathalie

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Beutels Philippe
• Co-promoter: Leirs Herwig
• Co-promoter: Van Damme Pierre

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The purpose of the Chair is a full characferization of Von Willebrand Disease ( VWD) in Belgium, including all up-fo-date laboratory techniques, multimeric analysis and molecular investigation, and the setting up of a plasma and DNA bank for future research in VWD.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

This is a fundamental research project financed by the Research Foundation - Flanders (FWO). The project was subsidized after selection by the FWO-expert panel.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The emergence of new pathogens, such as the coronavirus causing the COVID-19 pandemic, and of antibiotic resistance has further increased mortality and morbidity of infectious diseases (ID). To reduce the impact of ID on individual and population health and to advance clinical research on ID, the European Clinical Research Alliance on Infectious Diseases (ECRAID; www.ecraid.eu) was established, a European research infrastructure. The pandemic demonstrated the importance of innovative research into the best management of COVID-19 patients in primary care, where most patients with ID are treated, ideally preventing hospital admission and worse. This is research where both Belgium and Europe lagged behind, and where Flanders could be a pioneer by supporting (B)ECRAID. BECRAID aims to establish a long-term, financially self-sustainable, research infrastructure for primary care research on ID in Flanders and to represent Flanders in the primary care research of ECRAID. BECRAID receives very strong support from its stakeholders and potential users in Flanders and beyond, and has the ambition to expand to nursing homes, to Belgium and even to other relevant diseases.

Researcher(s)

• Promoter: Coenen Samuel
• Co-promoter: Goossens Herman

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Colorectal cancer (CRC) is the third commonly diagnosed cancer and fourth cause of cancer death worldwide. An altered microbiome, also known as dysbiosis, can often be seen in CRC patients. Radiotherapy and immunotherapy are known treatment options for colorectal cancer, but are associated with toxicity and heterogeneous responses, respectively. Fecal microbiotal transplantation (FMT) has been shown to reduce radiation-induced toxicity and dysbiosis in mice and improve immunotherapy responsiveness in patients. To date, FMT has never been introduced with the dual therapy of radiotherapy and immunotherapy. Therefore, it is not clear whether this combined treatment will result in improved treatment outcome, lesser side-effects, tumor burden etc. In this project, we first intend to characterize the effects of dual radiotherapy and immunotherapy using the well-established azoxymethane (AOM)/dextran sodium sulfate (DSS) CRC mouse model. CRC mice will be treated with radiotherapy, immunotherapy or dual radiotherapy and immunotherapy, after which diagnostic microbial biomarkers for immunotherapy responsiveness and predictive microbial biomarkers of treatment outcome will be determined. Additionally, we plan to study if and how FMT can tackle radiation-induced dysbiosis and immunotherapy efficiency. Throughout the experiment, fecal samples will be collected and used to perform 16S microbial profiling. Tumor load (number, size, area), histo-pathological analysis (e.g. stem cell proliferation, apoptosis, mucus formation), inflammatory/immunological markers and proteomics analysis will be performed and correlated with the microbial dynamics to identify predictive and diagnostic biomarkers for treatment outcome and side-effects. Additionally, flow cytometry analysis, stainings and protein quantification assays for tight junctions will be used to assess bacterial translocation. FMT will be introduced in an anaerobic bag and similar experiments as explained above will be performed to determine if FMT can improve treatment outcome and side-effects. Meta-proteomics and meta-transcriptomics will be performed and will be integrated in an integrative omics analysis with the metagenomics to help understand the functional involvement of FMT in improving treatment outcome and side-effects.

Researcher(s)

• Promoter: Malhotra Surbhi
• Co-promoter: Kumar-Singh Samir

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Around 10% of newborns in Europe will be admitted to a neonatal intensive care unit (NICU). Critically ill babies are a highly vulnerable population for the acquisition of resistant bacteria. Sepsis is among the most common events in NICU and is known to be associated with high mortality and poor long-term outcomes. Despite rising awareness of high rates of resistant bacterial colonisation reported in NICU, there is very little robust specific data on globally applicable infection prevention and control (IPC) measures. NeoIPC focuses on new approaches to the prevention and management of resistant bacterial colonization and infection on NICU. The project builds on and further extends the collaboration between 13 partners with a proven track record in relevant areas, including neonatal infection, IPC, implementation science, microbiology and surveillance. NeoIPC aims to develop and implement an innovative approach towards the evaluation of IPC interventions combining a robust cost-efficient randomised trial combined with the evaluation of a suitable implementation science strategy and novel targeted clinical and genotypic surveillance. A further goal is to generate widely relevant pan-European network strategies to improve IPC in routine neonatal care. This will be achieved through six interrelated work packages to deliver a cluster randomised trialimplementation hybrid investigating the impact of skin antisepsis on infant hospital-acquired clinical sepsis and resistant bacterial colonisation, coupled with a comprehensive implementation strategy incorporating optimal targeted surveillance in a clinical network with tailored dissemination and exploitation to facilitate sustainable embedding of outputs. NeoIPC will generate globally transferrable outputs to reduce hospital transmission of resistant pathogens, foster and facilitate collaborative research and IPC implementation efforts with a broad and long-lasting impact for critically ill newborns and infants.

Researcher(s)

• Promoter: Malhotra Surbhi
• Co-promoter: Goossens Herman
• Co-promoter: Hens Niel

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

The ongoing COVID-19 pandemic creates an unprecedented burden worldwide. Vaccine-induced immunity is the only promising solution. There is continued need for phase 2 & 3 vaccine trials to reach long-term, large-scale immunity of the entire European population. VACCELERATE will be the pan-European backbone accelerating phase 2 & 3 COVID-19 vaccine trials. The overall objective of VACCELERATE is to connect all European stakeholders involved in vaccine development to provide a pan-European platform for clinical trial design and conduct. VACCELERATE constitutes the rapid response single entry-point to stakeholders from public health authorities to vaccine developers, to address respective needs and kickstart specifically phase 2 & 3 vaccine trials. VACCELERATE conducts capacity mapping of clinical trial and laboratory sites to identify suitable sites for individual phase 2 & 3 vaccine trials. Capacity building via training will increase quality in sites across Europe. Volunteer registries facilitate patient recruitment. Access to laboratory sites and a standardised set of assays essential for clinical phase 2 & 3 trials is provided. A harmonised European approach to vaccine trials is enabled by aligning educational standards, coordination of laboratory support and providing standardised assays and trial protocols. Harmonised data collection, open data sharing and pooling of data for stronger analysis enables data standardisation. VACCELERATE offers solutions for characteristic vaccine development issues during pandemics by closing gaps in public health knowledge and improving knowledge transfer. VACCELERATE amalgamates the vast but scattered expertise across Europe into one network to deliver strategic scientific leadership and guidance on vaccine trials in Europe. Beyond the COVID-19 pandemic, it will be an established pandemic preparedness network, ready to face emerging future pandemics, as well as a pivot in Europe?s capacity to develop vaccines.

Researcher(s)

• Promoter: Goossens Herman
• Promoter: Malhotra Surbhi

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

The general objective of this research community is to better understand the origin and structure of bacterial and fungal biofilms in humans so that effective action can be taken against them in the long term.

Researcher(s)

• Promoter: Malhotra Surbhi

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

The ORCHESTRA project provides an innovative approach to learn from the SARS-CoV-2 health crisis and derive recommendations for increasing preparedness for future outbreaks. The main outcome of the project is the creation of a new pan-European cohort built on existing and new large-scale population cohorts in European and non-European countries. ORCHESTRA aims to perform in-depth laboratory based assays on samples collected from Covid-19 patients during acute phase and during long-term sequelae as well as follow-up individuals post-vaccination. University of Antwerp laboratories are studying viral variants and the respiratory microbiome dynamics (Surbhi Malhotra) as well as analyzing the humoral and cell-mediated immune responses and cytokinome profiles (Samir Kumar -Singh). The laboratory analysis workpackage also aims to understand the role of human genetics, epigenetics and of the gut microbiome in disease pathogenesis and prognosis. This large consolidated wet-lab WP is led by the University of Antwerp. The project is funded by the European Union's Horizon 2020 research and innovation programme under the ERAvsCORONA Action Plan developed jointly by Commission services and national authorities.

Researcher(s)

• Promoter: Malhotra Surbhi
• Co-promoter: Kumar-Singh Samir

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Goals of PediCAP are Fill the knowledge gaps on antibiotic therapy of community-acquired pneumonia in pediatric age, in terms of optimal duration, oral step-down schedule evaluating effectiveness, safety and selection of antimicrobial resistance. Evaluate economic impact of antibiotic therapy in terms of cost-effectiveness. Implement the infrastructure that links study sites in order to share knowledge, develop study specific and general research skill straining programme and promote capacity development initiatives.

Researcher(s)

• Promoter: Malhotra Surbhi
• Co-promoter: Goossens Herman

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Antimicrobial resistance (AMR) is of great public health concern, causing numerous losses of lives worldwide and threatening to reverse many of the considerable strides modern medicine has made over the last century. There is a need to stratify antibiotic and alternative treatments in terms of the actual benefit for the patient, improving patient outcome and limit the impact on AMR. High quality, effective and appropriate diagnostic tests to steer appropriate use of antibiotics are available. However, implementation of these tests into daily healthcare practice is hampered due to lack of insight in the medical, technological and health economical value and limited knowledge about psychosocial, ethical, regulatory and organisational barriers to their implementation into clinical practice. VALUE-Dx will define and understand these value indicators and barriers to adoption of diagnostics of Community-Acquired Acute Respiratory Tract Infections (CA-ARTI) in order to develop and improve health economic models to generate insight in the whole value of diagnostics and develop policy and regulatory recommendations. In addition, efficient clinical algorithms and user requirement specifications of tests will be developed fuelling the medical and technological value of CA-ARTI diagnostics. The value of diagnostics will be tested and demonstrated in a unique pan-European clinical and laboratory research infrastructure allowing for innovative adaptive trial designs to evaluate novel CA-ARTI diagnostics. Close and continuous interaction with the VALUE-Dx multi-stakeholder platform provides for optimal alignment of VALUE-Dx activities with stakeholder opinions, expert knowledge and interests. A variety of dissemination and advocacy measures will promote wide-spread adoption of clinical and cost-effective innovative diagnostics to achieve more personalized, evidence-based antibiotic prescription in order to transform clinical practice, improve patient outcomes and combat AMR.

Researcher(s)

• Promoter: Goossens Herman
• Co-promoter: Coenen Samuel
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Malhotra Surbhi

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Respiratory tract infections (RTIs) are one of the most common causes of mortality and morbidity among infectious diseases worldwide. However, the aetiology of RTIs is often undiagnosed due to the complicated presence of a myriad of bacterial, viral and fungal pathogens and opportunistic microorganisms in the complex respiratory microbiome. Moreover, RTI diagnosis is challenged by the current limitations of conventional culture-based tests and hypothesis-based narrow-spectrum molecular tests. With the causative pathogens often unknown at the time of treatment, not surprisingly, RTIs account for a high antibiotic consumption rate where most of the antibiotic prescriptions are empirical, especially for critical patients in intensive care units (ICUs). Accordingly, patients are exposed to the risks of antibiotic overtreatment, adverse effects and complications such as Clostridium difficile infections. In addition, empiric treatments with broad-spectrum antibiotics can promote the selection and dissemination of multidrug-resistant pathogens. Thus, a rapid and accurate microbiological diagnosis could prevent inadvertent antibiotic prescription or allow a timely switch to the required targeted antibacterial therapy. In this respect, metagenomics next-generation sequencing (mNGS), and more specifically long-read sequencing, has been speculated to offer enhanced diagnostic capabilities by providing a culture-independent, hypothesis-free all-in-one assay for pathogen identification in RTI diagnostics. Despite these advantages demonstrated by a number of proof-of-concept studies, applying metagenomics into clinical diagnosis is challenging, particularly for respiratory samples (such as bronchoalveolar lavage – BAL, endotracheal aspirate – ETA, sputum) due to the abundant presence of commensal flora, extracellular DNA and human host DNA. In this project, we aim to utilise state-of-the-art nanopore long-read sequencing to develop a complete, rapid mNGS workflow integrated into a point-of-care (POC) set-up to enable a one-step RTI diagnosis directly from respiratory samples. The designed workflow includes a patentable standardised method, "disclosure method A", for processing respiratory samples developed to overcome the sample-bound difficulties of high host DNA. In this workflow, we will also develop a bioinformatics pipeline method, "disclosure method B", for sequencing result analysis that can be protected with copyright. We also aim to evaluate the feasibility and demonstrate the superiority of this workflow and developed methods over conventional culture-based and molecular methods in terms of sensitivity, specificity, turn-around-time, and cost-effectiveness.

Researcher(s)

• Promoter: Malhotra Surbhi

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Antimicrobial resistance (AMR) is on the rise, resulting in 700 000 deaths worldwide every year. In Croatia and Hungary, AMR is responsible for the rapid increase in morbidity and mortality rates. The EU-funded AmReSu project will strengthen the innovation capacity in AMR surveillance in both countries, focussing on whole genome sequencing in correlation with next-generation sequencing techniques. It will also establish an "AMR surveillance vision." The project relies on the cooperation of Semmelweis University in Budapest and Klinika za infektivne bolesti "Dr. Fran Mihaljevic" in Zagreb with two internationally leading research institutions, the Laboratory of Medical Microbiology at the University of Antwerp and the Health Research Institute of the Balearic Islands. AmReSu will facilitate knowledge transfer, exchanges of best practices via training activities and the promotion of research excellence.

Researcher(s)

• Promoter: Malhotra Surbhi
• Co-promoter: Goossens Herman

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

CAP-IT is a multicenter randomized double-blind 2x2 factorial noninferiority trial investigating the efficacy, safety and impact on antimicrobial resistance of amoxicillin administered as a shorter or longer course at a lower or higher dose for uncomplicated childhood pneumonia. The analysis at the University of Antwerp (UA) will comprise two parts: (i) research on S. pneumoniae colonization with respect to circulating (vaccine) serotypes in the UK and pneumococcal penicillin resistance; and (ii) evaluation of the microbial communities present in the respiratory tract of patients to identify and quantify the microbial shift as well as changes in the presence of antimicrobial resistance genes related to the effect of the different durations and doses of amoxicillin administered in CAP-IT. These data will be generated using metagenomics and metatranscriptomic sequencing using both PacBio and Illumina technologies.

Researcher(s)

• Promoter: Malhotra Surbhi

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Clostridioides difficile constitutes the main source of healthcare-associated infectious diarrhea across the globe, causing a disease known as C. difficile infection (CDI) associated with prolonged hospital stay and increased mortality. Whole-genome sequencing (WGS) approaches applied to the study of C. difficile have revealed a highly variable 4.1-4.3 Mb genome that is not only rich in mobile genetic elements but is also highly complex to assemble due to the presence of numerous repeat regions. Thus, conventional short-read sequencing technologies have had limited success in resolving C. difficile genomes and have led to incomplete, and incorrectly assembled genomes. In this study, we intend to employ single-molecule real-time (SMRT) long-read sequencing to obtain complete, gapless C. difficile genomes and enable a high-resolution genome-wide analysis and comparison of clinical reference strains isolated from patients across Europe contained in the ECDC/Leeds-Leiden reference collection. This sequenced collection will be made publicly available in the European Nucleotide Archive (ENA)/NCBI to stimulate further research on different aspects, both fundamental and clinical, of CDI with the aim of developing better preventive, therapeutic/diagnostic, and typing strategies.

Researcher(s)

• Promoter: Malhotra Surbhi

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Colistin (CL) is a last line antibiotic used to treat hospital-associated infections due to multi- and extremely-drug resistant Gram-negative bacterial pathogens, and also in veterinary medicine to treat post-weaning diarrhoea in food animals. Increasing use has led to the emergence of both chromosomal and transferable plasmid-mediated (mcr) colistin resistance in pathogens. While the chromosomal mechanisms involve mutations in several genes, which also modify the bacterial metabolic pathways, the mcr-mediated mechanism confers low-level colistin resistance, and its role, relevance and fate in mediating colistin resistance in human pathogens remain to be explored. Another phenomenon that remains to be understood is of heteroresistance wherein bacterial subpopulations exhibit different susceptibilities to colistin and can lead to treatment failures during infection. Recent advances in next-generation sequencing have made it possible to study the genome and gene expression at the single cell level. In this project, we intend to study the complexities of resistance and heteroresistance evolution in a population utilizing whole genome sequencing and beyond state of the art NGS techniques of single-cell sequencing and gene expression analysis on pathogenic bacteria, Klebsiella pneumoniae and E. coli, evoluted in vitro under colistin pressure as well as in a mouse model of infection and finally in respiratory samples from patients treated with colistin.

Researcher(s)

• Promoter: Malhotra Surbhi
• Co-promoter: Xavier Basil Britto
• Fellow: Rajakani Sahaya Glingston

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

In sub-Saharan Africa, invasive non-typhoidal Salmonella (iNTS) is the major cause of bacterial bloodstream infections among young children and disease management is jeopardised by increasing antimicrobial resistance (AMR). The O-antigen portion of Salmonella lipopolysaccharide (LPS) is recognised as key target antigen for protective immunity and O-antigen-based vaccines covering the main serovars Salmonella Typhimurium and Enteritidis are in development. Some of the vaccine candidates are about to enter phase 1 clinical trials; however, efficacy in Africa will not be tested for several years. O-antigen structural variability can have an impact on the protective immunity of corresponding vaccines. Serotyping and genomic investigation of recent iNTS isolates from the Democratic Republic of the Congo (DRC) have shown increasing rates of iNTS isolates with variation in O-antigen structure. In particular, more than 45 % of the recent Salmonella Typhimurium isolates do not present O:5 specificity, associated to O-antigen O-acetylation. In this project, we will analyse the genomic variation of O-antigen of Salmonella Typhimurium DRC isolates within the African context. The genomic basis of differences in O-antigenic structure will be proven by mutagenesis experiments. We will determine the O-antigen structure from a panel of Salmonella Typhimurium isolates recently collected in DRC, ascertaining the nature of the O-antigen genomic variations. The coverage of current O-antigen based vaccines against iNTS is likely to be impacted by the O-antigen structural variability, and this project will yield key insights on how to improve the current vaccines.

Researcher(s)

• Promoter: Van Puyvelde Sandra

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Early availability of information on bacterial pathogens and their antimicrobial susceptibility is of key importance for the management of infectious disease patients. MIC-STRIP is a novel phenotypic approach that achieves readout of the antibiotic susceptibility profile of a bacterial infection within 4 hours, moving the time to modify antibiotic treatment from the next day to within the same day.

Researcher(s)

• Promoter: Goossens Herman
• Co-promoter: Verwulgen Stijn

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

ECRAID will develop a business plan in line with European-funded networks to create a clinical research infrastructure that will operate from 2021. This business plan is called ECRAID-Plan. It is working with the network partners and Monitor Deloitte to develop a business plan. The business plan will outline ECRAID services, operations, governance structure, and financial sustainability plans. ECRAID is seeking to strengthen alliances with the private sector and international organisations involved in infectious disease interventions to boost investments into protecting European public health.

Researcher(s)

• Promoter: Goossens Herman
• Co-promoter: Coenen Samuel

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

The unquestionably needed reform of health and care systems in Europe requires the adoption of innovation and integrated solutions. One way forward is to rethink procurement policies. A positive transformation in this area would be to elevate procurement practices towards an approach that awards the value offered by innovation or integrated solution. The value will be awarded by multi-disciplinary teams responding to specific patients, health care actors and system needs, while taking societal and economic perspectives into account. The EU Coordination and Support Action (CSA) under Horizon 2020 'Innovation in Healthcare' is a highly welcomed initiative. This EU initiative aims at the adoption of innovation in health and care systems and advancing procurement of innovation practices.

Researcher(s)

• Promoter: Goossens Herman
• Co-promoter: Moons Pieter

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

New interventions are required to prevent the emergence of antimicrobial resistance in contemporary sexually transmitted infection (STI) epidemics in men who have sex with men (MSM). Here, we perform a double-blinded single centre, crossover, randomized controlled trial of antibacterial vs. placebo mouthwash to study reduction in incidence of gonorrhoea/chlamydia/syphilis in MSM taking preexposure prophylaxis.

Researcher(s)

• Promoter: Malhotra Surbhi
• Co-promoter: Hens Niel

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

This project aims to advance the currently available sequencing technologies at the University of Antwerp (UA) by acquiring a third generation sequencing (3GS) platform. The flagship of the third generation, single-molecule longread sequencers, PacBio Sequel, harnesses the natural process of DNA replication and enables real-time observation of DNA synthesis. 3GS promises to open new avenues for sequencing-based research beyond the current state-of-the-art for this consortium, which consists of more than 14 UA research groups in various disciplines of medicine, biology and bioinformatics. Furthermore, several third parties have also committed to utilize this technology for their ongoing and future research studies. 3GS will be utilized by this consortium to (i) sequence prokaryotic and eukaryotic genomes, and difficult-to-sequence genome regions, (ii) identify new genes and mutations in various rare Mendelian disorders, (iii) identify epigenetic modifications to better understand biological processes like gene expression and host-pathogen interactions, (iv) precisely profile the human, murine, and environmental microbiome in disease and under various environmental stressors, and (v) develop novel preventive therapies for infection-prone disorders for better drug targeting. The analysis of the large amount of genomic and transcriptomic data generated by the various research groups will be coordinated by the UZA/UA bioinformatics group Biomina.

Researcher(s)

• Promoter: Malhotra Surbhi
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Laukens Kris
• Co-promoter: Mortier Geert
• Co-promoter: Smet Annemieke
• Co-promoter: Vanden Berghe Wim
• Co-promoter: Van Rie Annelies

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

While the threat of antimicrobial resistance is growing, so are the challenges to bringing forward new therapeutic options for patients infected with resistant organisms. There is a need for a better understanding of how antimicrobial resistance is evolving globally, of what novel molecular mechanisms can be exploited as new forms of antimicrobial therapy and of how to more efficiently develop new treatments so they can be more rapidly brought to patients in need. The over-arching concept of New Drugs for Bad Bugs (ND4BB) is to create an innovative public-private collaborative partnership that will positively impact all aspects of ARB through the discovery and development of novel agents for the treatment, prevention and management of patients with bacterial infections. COMBACTE is one of the first projects to be launched under this programme with the aim of developing a broad European network of fully capable and Good Clinical Practice (GCP) compliant clinical investigation sites to execute clinical trials enabling the registration of novel agents to be used in the treatment of patients with bacterial infections.

Researcher(s)

• Promoter: Goossens Herman

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Clostridium difficile infection (CDI) is one of the most prevalent healthcare associated infections, affecting both hospitalized patients and individuals in the community; notably, there is an increasing realization that cases also occur in subjects not recently exposed to healthcare interventions, including antibiotics. CDI poses an extensive burden of morbidity, mortality and healthcare resource utilization, and so requires effective prevention and management strategies. Epidemiological data are, however, limited and studies typically have examined only part of a healthcare economy and usually have been focused on single countries/healthcare systems. Thus, there is a lack of robust, comprehensive data on the impact of CDI across countries in Europe. Furthermore, we know that large variations in the frequency of testing and the sensitivity of CDI diagnostics across European countries mean that the size of the problem is underestimated. Combating Bacterial Resistance in Europe-CDI (COMBACTE-CDI) therefore aims to develop a detailed understanding of the epidemiology and clinical impact of CDI across multiple European countries. Our project proposal provides a collaborative approach comprising three scientific work packages (WPs). A large epidemiology study will be undertaken across Europe in WP1 to quantify the burden of CDI (incidence, distribution, recurrence, morbidity, mortality, transmission) across the whole healthcare economy. This will be followed by a case/control study in WP2, which along with data collected in a questionnaire will enable the consortium to assess current practices in Europe (guidelines, testing, surveillance, treatment, cost) and their potential impacts. WP3 will create a rich, European, research platform that will provide support for future proof-of-concept and clinical studies of new prevention and treatment strategies for CDI. The three interrelated research WPs will be supported by a management work package (WP4).

Researcher(s)

• Promoter: Goossens Herman

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Since two decades, methicillin-resistant Staphylococcus aureus (MRSA) has become a major cause of medical device-associated and postsurgical wound infections in hospitals and of pneumonia in the community. In these infections, MRSA favors the biofilm phenotype, living in a community encased in an extracellular matrix that affords protection against the host immune system and antibiotics, making these infections recalcitrant to treatment. Our laboratory has shown that two highly pathogenic and globally successful MRSA clones, USA300 and EMRSA-15, are prolific biofilm formers. Interestingly, our transcriptomics data has revealed spectacularly different mechanisms of biofilm formation between these two clones. For instance, in USA300-S391 biofilms, Hfq, a global regulator of small non-coding RNAs which in turn control rapid bacterial virulence gene expression as well as mecR, which regulates the expression of ß-lactam resistance conferring mecA gene, were both found to be highly upexpressed. EMRSA-15 biofilms, however, were not found to be MecR- or Hfq-dependent, but instead showed upexpression of multiple prophages. This fundamental project aims to dissect the role of mecR, Hfq, and prophages in mediating biofilm formation in USA300 and EMRSA-15. Identifying genes regulated by these key determinants could be better alternatives for biofilm disruption or additive therapies to antibiotics that are currently ineffective against MRSA.

Researcher(s)

• Promoter: Malhotra Surbhi
• Co-promoter: Goossens Herman
• Fellow: De Backer Sarah

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

NeoAMR is a research and development programme run by the Global Antibiotic R&D Partnership (GARDP), a joint initiative of DNDi and the WHO, which aims to develop and deliver new treatments for bacterial infections where drug resistance is present or emerging, or for which inadequate treatment exists. The overarching goal of NeoAMR is to develop new improved treatment regimens for the management of neonatal sepsis in settings with high prevalence of multidrug-resistant and extensively drug-resistant pathogens. Penta is a partner in this project, leveraging its network and experience as a part of NeoAMR research activities.

Researcher(s)

• Promoter: Goossens Herman

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Human respiratory syncytial virus (RSV) causes severe disease in the very young, elderly and in high risk groups. We have estimated that RSV was associated with 34 million cases of acute lower respiratory tract infection (ALRI), 3.4 million ALRI hospitalisations and 55,000 to 199,000 deaths in children <5 years in 2005 [1]. These estimates were based on limited data and there is a substantial gap in knowledge (on morbidity and associated healthcare and social costs) across Europe. RSV infection in childhood is associated with subsequent wheezing and asthma [2-4]. These long-term sequelae pose a substantial additional burden on the healthcare system. In addition, RSV is a significant cause of ALRI morbidity in elderly and COPD patients [5, 6]. Most published data on RSV disease burden in the elderly (aged >65 years) are from the United States and from hospital settings. The knowledge gaps have an impact on Europe's ability to make evidence-based decisions nationally regarding novel vaccines and therapeutics. There is a parallel need to assemble clinical resources to identify the correlates of severe RSV disease for clinical management, classification of disease severity in clinical trials and identification of biomarkers for severe disease.

Researcher(s)

• Promoter: Goossens Herman
• Co-promoter: Revets Hilde

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Respiratory syncytial virus (RSV) is not well known outside medical circles, yet most people have probably suffered from it in childhood, as it is the most common cause of severe respiratory illness in infants and children worldwide. The elderly and people with weakened immune systems are also vulnerable to RSV infection. While most people's symptoms are mild, it can result in pneumonia and 3.4 million cases annually require hospitalisation. There is no specific treatment or vaccine for RSV. The goal of the RESCEU project is to gather information on the scale of RSV infection in Europe and its economic impacts. It will then use this information to design best practice guidelines to improve the way RSV cases are monitored in Europe, and to shape future vaccination programmes. The team will also gather and analyse patient samples to identify biological markers associated with severe RSV infection. This information could aid in diagnosis and facilitate the development of new treatments and vaccines.

Researcher(s)

• Promoter: Goossens Herman
• Co-promoter: Coenen Samuel

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Selection and transmission are key determinants for the dissemination of antimicrobial resistance (AMR) across the planet. These determinants of AMR are frequently studied in laboratory settings while in reality they occur in complex systems, e.g. in microbial communities that colonize human and animal guts or in environmental ecosystems. The central aim of STARCS (Selection and Transmission of Antimicrobial Resistance in Complex Systems) is to characterize and quantify the processes of selection and transmission of AMR genes and drug-resistant bacteria in complex (eco)systems from a 'One Health' perspective and to integrate these elements into predictive mathematical models, which will be used to inform policy development. To reach this goal, the consortium will (i) develop and implement innovative metagenomic methodologies to map the expression of AMR genes and their linkage to bacterial hosts and mobile genetic elements in human, animal and environmental samples, (ii) use relevant animal models (using mice and ducks) and observational studies (in hospitals and in dogs and their owners) to analyse and quantify the processes of selection and transmission of drug-resistant Enterobacteriaceae (specifically Extended Spectrum Beta-Lactamase producing Escherichia coli) and (iii) implement state-of-the-art epidemiological modelling to quantify the spread of ESBL-producing E. coli between humans and animals. STARCS will develop technological breakthroughs to assess selection and transmission dynamics on the level of the resistance gene, the mobile genetic element, the bacterium, the human-animalenvironment interface and in clinical settings. This project will deliver important knowledge into selection and transmission of AMR, will provide the scientific community with novel tools to study selection and transfer of AMR in complex systems and will result in much-needed guidance towards policy decisions by international and national institutions. Ultimately the results from STARCS will form an evidence-based foundation for the development of new regulations, aimed at curbing the spread of AMR.

Researcher(s)

• Promoter: Malhotra Surbhi

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

The i-4-1-Health project is aimed at the prevention of infectious diseases and the combat against antibiotic resistance in both humans and animals (One Health) in the border region Flanders-Netherlands. Bacteria are showing an increased resistance against antibiotics. This makes the efficient treatment of infectious diseases more difficult leading to illness, mortality and increased health care costs. The underlying reasons include all parts of the society, like health care, population, agriculture, and the environment. Collaboration with the different disciplines and sectors in the border region is needed to prevent the spread of pathogens. The 26 partners will in a similar way provide insight into the risks of infection, antibiotic use and DNA of resistant bacteria with help of apps and a platform for advances molecular biology analyses. These innovative tools help to map the antimicrobial resistance in the stock farming, the human population and the public health sector. In this way the routes of infection diseases can be traced prematurely and related risks for the society can be minimized. Main objective of this project is the installment of a sustained collaboration that can be further extended in the future.

Researcher(s)

• Promoter: Goossens Herman

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Infectious diseases are a major burden to public health and the global economy, not in the least due to antimicrobial resistance. Rapid point of care (POC) in vitro diagnostics (IVD) are key tools in the effective clinical management of patients with infectious diseases. Yet there is still a large unmet clinical need for more rapid POC IVDs generating more clinically relevant, actionable information. Effectively addressing this need requires a change in the current approach in training researchers on IVDs, generating a new 'breed' of IVD researchers capable of closing the gap between the clinical and technological perspective. ND4ID takes up this challenge by offering 15 ESRs a world-class first of its kind training programme where they will be exposed to the full breadth of disciplines spanning clinical, technological and market-oriented viewpoints, from both the academic and non-academic sector. Through a set of synergistic research projects on novel POC assays, targeting the most important and urgent clinical needs at world leading academic or private sector research groups, the ESRs are offered a holistic training program, preparing them to be lead players in the future IVD field. This training through research is augmented by a unique comprehensive network-wide training programme covering clinical, technical and translational knowledge and skills of relevance to IVD research, development and exploitation. As such, ND4ID will deliver ESRs that will be in high demand serving as an example for other academic and non-academic actors active in training IVD researchers and further strengthening Europe's position in the internally competitive arena of IVD technology.

Researcher(s)

• Promoter: Goossens Herman
• Co-promoter: Moons Pieter

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

The general objective of this research group is to gain a better understanding of the formation process and structural characteristics of bacterial and fungal biofilms in humans to ensure future effective therapeutic interventions.

Researcher(s)

• Promoter: Malhotra Surbhi

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Since two decades, methicillin-resistant Staphylococcus aureus (MRSA) are major causes of medical device-associated and postsurgical wound infections in hospitals and of pneumonia in the community. Recent research shows that in these infections, MRSA favour the biofilm phenotype, living in a community encased in an extracellular matrix that affords protection against the host immune system and antibiotics, making these infections recalcitrant to treatment. Recent data from our laboratory shows that the two most highly pathogenic and globally successful MRSA clones, USA300 and EMRSA-15, are also prolific biofilm formers. Interestingly, transcriptomics has revealed spectacularly different mechanisms of biofilm formation between the two clones. This fundamental project thus aims to dissect the role of novel regulators in mediating biofilm formation in USA300 and EMRSA-15. Identifying genes regulated by these key determinants would initialize identification of targets for biofilm disruption that might be better alternatives to antibiotics that are currently ineffective against MRSA.

Researcher(s)

• Promoter: Malhotra Surbhi
• Co-promoter: Goossens Herman

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

COMBACTE‐CARE (aligned with the COMBACTE infrastructure) will (1) increase the efficiency of antibiotic R&D through analysing observational clinical and microbiological data sets and making recommendations for the development of novel antibiotic agents for MDR GNB; will (2) provide new knowledge on the clinical management and outcomes of patients (neonates/children and adults) with serious hospitalised infections and will validate this knowledge for clinical outcomes for patients in areas of emerging and endemic antibiotic resistance; will (3) support the sustainability of New Drugs for Bad Bugs (ND4BB) supported investigator and laboratory networks (COMBACTE); will (4) conduct prospective clinical trials with novel trial designs to deliver safety, pharmacology, and proof of efficacy data for novel agents directed towards treatment of infections due to priority MDR pathogens; will (5) validate novel bacterial identification and follow‐up diagnostics or clinical endpoints with the aim of reducing the size and cost of clinical trials; and will (6) provide new knowledge on biomarkers predicting poor outcome in patients with serious healthcare‐associated infections.

Researcher(s)

• Promoter: Goossens Herman

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand EU. UA provides EU research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Malhotra Surbhi
• Co-promoter: Goossens Herman

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

The current VAXINFECTIO research is the result of the complimentary work in the multidisciplinary fields of microbiology, vaccinology, and immunology. In the past 6 years, the Methusalem grant has significantly contributed to the development and international recognition in those major fields. The future Methusalem research is aimed at further development of the integrated vaccine and microbiological research, with a special focus on increasing the understanding of the immune response in prophylactic and therapeutic vaccines (including tumor vaccines) and the containment of antibiotic resistance

Researcher(s)

• Promoter: Goossens Herman

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Goossens Herman
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Malhotra Surbhi

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

COMPARE aims to harness the rapid advances in molecular technology to improve identification and mitigation of emerging infectious diseases and foodborne outbreaks. To this purpose COMPARE will establish a "One serves all" analytical framework and data exchange platform that will allow real time analysis and interpretation of sequencebased pathogen data in combination with associated data (e.g. clinical, epidemiological data) in an integrated inter-sectorial, interdisciplinary, international, "one health" approach.

Researcher(s)

• Promoter: Goossens Herman
• Co-promoter: Malhotra Surbhi

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

The PREPARE project will transform Europe's response to future severe epidemics or pandemics by providing infrastructure, co-ordination and integration of existing clinical research networks, both in community and hospital settings. It represents a new model of collaboration and will provide a one-stop shop for policy makers, public health agencies, regulators and funders of research into pathogens with epidemic potential.

Researcher(s)

• Promoter: Goossens Herman

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

While the threat of antimicrobial resistance is growing, so are the challenges to bringing forward new therapeutic options for patients infected with resistant organisms. There is a need for a better understanding of how antimicrobial resistance is evolving globally, of what novel molecular mechanisms can be exploited as new forms of antimicrobial therapy and of how to more efficiently develop new treatments so they can be more rapidly brought to patients in need. The over-arching concept of New Drugs for Bad Bugs (ND4BB) is to create an innovative public-private collaborative partnership that will positively impact all aspects of ARB through the discovery and development of novel agents for the treatment, prevention and management of patients with bacterial infections. COMBACTE is one of the first projects to be launched under this programme with the aim of developing a broad European network of fully capable and Good Clinical Practice (GCP) compliant clinical investigation sites to execute clinical trials enabling the registration of novel agents to be used in the treatment of patients with bacterial infections.

Researcher(s)

• Promoter: Goossens Herman

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

The research of Surbhi Malhotra has focused on the molecular epidemiology and genetics of resistance to antimicrobials in oral streptococci. Applying molecular biological techniques on oro-pharyngeal streptococcal flora in healthy individuals as a model, she demonstrated that antibiotic use is the single most important driver of antibiotic-resistance in vivo, that antibiotics belonging to the same class can differ widely in resistance gene selection, and that differences in predominance of certain resistance genes in geographically distinct areas might be linked to the preferential use of specific antibiotic subclasses. Her current research interests include studying the impact of antibiotic use on the naso-oro-pharyngeal and intestinal microflora, mechanisms of biofilm formation, bacterial pathogenetic mechanisms, and developing rapid diagnostic assays for pathogens causing community-acquired and nosocomial infections.

Researcher(s)

• Promoter: Malhotra Surbhi
• Fellow: Malhotra Surbhi

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project