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1. Antibody responses against SARS-CoV-2 variants induced by four different SARS-CoV-2 vaccines in health care workers in the Netherlands: A prospective cohort study.

Author

Marit J van Gils, Ayesha Lavell, Karlijn van der Straten, Brent Appelman, Ilja Bontjer, Meliawati Poniman, Judith A Burger, Melissa Oomen, Joey H Bouhuijs, Lonneke A van Vught, Marleen A Slim, Michiel Schinkel, Elke Wynberg, Hugo D G van Willigen, Marloes Grobben, Khadija Tejjani, Jacqueline van Rijswijk, Jonne L Snitselaar, Tom G Caniels, Amsterdam UMC COVID-19 S3/HCW study group, Alexander P J Vlaar, Maria Prins, Menno D de Jong, Godelieve J de Bree, Jonne J Sikkens, Marije K Bomers, and Rogier W Sanders

Subjects
Medicine
Abstract

BackgroundEmerging and future SARS-CoV-2 variants may jeopardize the effectiveness of vaccination campaigns. Therefore, it is important to know how the different vaccines perform against diverse SARS-CoV-2 variants.Methods and findingsIn a prospective cohort of 165 SARS-CoV-2 naive health care workers in the Netherlands, vaccinated with either one of four vaccines (BNT162b2, mRNA-1273, AZD1222 or Ad26.COV2.S), we performed a head-to-head comparison of the ability of sera to recognize and neutralize SARS-CoV-2 variants of concern (VOCs; Alpha, Beta, Gamma, Delta and Omicron). Repeated serum sampling was performed 5 times during a year (from January 2021 till January 2022), including before and after booster vaccination with BNT162b2. Four weeks after completing the initial vaccination series, SARS-CoV-2 wild-type neutralizing antibody titers were highest in recipients of mRNA-1273, followed by recipients of BNT162b2 (geometric mean titers (GMT) of 358 [95% CI 231-556] and 214 [95% CI 153-299], respectively; pConclusionsOverall, this study shows that the mRNA vaccines appear superior to adenovirus vector-based vaccines in inducing neutralizing antibodies against VOCs four weeks after initial vaccination and after booster vaccination, which implies the use of mRNA vaccines for both initial and booster vaccination.

Published
2022
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2. Personalised immunotherapy in sepsis: a scoping review protocol

Author

Peter Pickkers, Evangelos J Giamarellos-Bourboulis, Joanna C Dionne, M G Netea, Simon J W Oczkowski, Tom van der Poll, W Joost Wiersinga, Lonneke A van Vught, Alexander P J Vlaar, Marleen A Slim, Niels van Mourik, and Marcella C A Müller

Subjects
Medicine
Abstract

Introduction Sepsis, a life-threatening organ dysfunction syndrome occurring in the context of severe infections, remains a major burden on global health with high morbidity and high mortality rates. Despite recent advances in the understanding of its pathophysiology, the treatment of sepsis remains supportive of nature with few interventions specifically designed for treating this complex syndrome. The focus of sepsis trials has increasingly shifted towards targeting excessive inflammation and immunosuppression using immunomodulatory agents. However, it remains uncertain how to identify patients that could benefit from such treatment, whether treatments can be tailored to an individual’s immune profile, or at which stage of the disease the intervention should be initiated. In this scoping review, we provide a comprehensive overview of current available literature on immunostimulatory and immunosuppressive therapies against sepsis.Methods and analysis The aim of this scoping review is to describe and summarise current literature evaluating immunotherapy in adult patients with sepsis. The review will be performed using the framework formulated by Arksey and O’Malley. A comprehensive literature and study collection will be executed by searching PubMed, Embase, Cochrane CENTRAL and ClinicalTrials.gov to identify clinical trials and cohort studies concerning immunotherapy in adult patients with sepsis. Screening will be performed independently and in duplicate by two reviewers who will also independently extract data into prespecified spreadsheets. We will summarise evidence in tabular format with descriptive statistics. The reported evidence will convey knowledge on the types of immunotherapies studied, and currently being studied, in adult patients with sepsis.Ethics and dissemination Approval from a medical ethics committee is not required. Once completed, the review will be submitted for publication in a peer-reviewed journal. These results will be of value to clinicians and researchers with an interest in advancing sepsis care.

Published
2022
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3. Clinical Subtype Trajectories in Sepsis Patients Admitted to the ICU: A Secondary Analysis of an Observational Study

Author

Marleen A. Slim, MD, Rombout B. E. van Amstel, MD, Marcella C.A. Müller, MD, PhD, Olaf L. Cremer, MD, PhD, Alexander P. J. Vlaar, MD, PhD, Tom van der Poll, MD, PhD, W. Joost Wiersinga, MD, PhD, Christopher W. Seymour, MD, MSc, Lonneke A. van Vught, MD, PhD, and MARS Consortium

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

OBJECTIVES:. Sepsis is an evolving process and proposed subtypes may change over time. We hypothesized that previously established sepsis subtypes are dynamic, prognostic of outcome, and trajectories are associated with host response alterations. DESIGN:. A secondary analysis of two observational critically ill sepsis cohorts: the Molecular diAgnosis and Risk stratification of Sepsis (MARS) and the Medical Information Mart for Intensive Care-IV (MIMIC-IV). SETTING:. ICUs in the Netherlands and United States between 2011–2014 and 2008–2019, respectively. PARTICIPANTS:. Patient admission fulfilling the Sepsis-3 criteria upon ICU admission adjudicated to one of four previously identified subtypes, comprising 2,416 admissions in MARS and 10,745 in MIMIC-IV. MAIN OUTCOMES AND MEASURES:. Subtype stability and the changes per subtype on days 2, 4 and 7 of ICU admission were assessed. Next, the associated between change in clinical subtype and outcome and host response alterations. RESULTS:. In MARS, upon ICU admission, 6% (n = 150) of the patient admissions were α-type, 3% (n = 70) β-type, 55% (n = 1317) γ-type, and 36% (n = 879) δ-type; in MIMIC-IV, this was α = 22% (n = 2398), β = 22% (n = 2365), γ = 31% (n = 3296), and δ = 25% (2686). Overall, prevalence of subtypes was stable over days 2, 4, and 7. However, 28–56% (MARS/MIMIC-IV) changed from α on ICU admission to any of the other subtypes on day 2, 33–71% from β, 57–32% from γ, and 50–48% from δ. On day 4, overall subtype persistence was 33–36%. γ or δ admissions remaining in, or transitioning to, subtype γ on days 2, 4, and 7 exhibited lower mortality rates compared with those remaining in, or transitioning to, subtype δ. Longitudinal host response biomarkers reflecting inflammation, coagulation, and endothelial dysfunction were most altered in the δ-δ group, followed by the γ-δ group, independent of the day or biomarker domain. CONCLUSIONS AND RELEVANCE:. In two large cohorts, subtype change to δ was associated with worse clinical outcome and more aberrant biomarkers reflecting inflammation, coagulation, and endothelial dysfunction. These findings underscore the importance of monitoring sepsis subtypes and their linked host responses for improved prognostication and personalized treatment strategies.

Published
2024
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4. Time since SARS-CoV-2 infection and humoral immune response following BNT162b2 mRNA vaccination

Author

Brent Appelman, Karlijn van der Straten, A.H. Ayesha Lavell, Michiel Schinkel, Marleen A. Slim, Meliawati Poniman, Judith A. Burger, Melissa Oomen, Khadija Tejjani, Alexander P.J. Vlaar, W. Joost Wiersinga, Yvo M. Smulders, Lonneke A. van Vught, Rogier W. Sanders, Marit J. van Gils, Marije K. Bomers, and Jonne J. Sikkens

Subjects
Vaccine, BNT162b2, SARS-CoV-2, COVID-19, Humoral immune response, Neutralisation, Medicine, Medicine (General), R5-920
Abstract

Background: To optimise the use of available SARS-CoV-2 vaccines, some advocate delaying second vaccination for individuals infected within six months. We studied whether post-vaccination immune response is equally potent in individuals infected over six months prior to vaccination. Methods: We tested serum IgG binding to SARS-CoV-2 spike protein and neutralising capacity in 110 healthcare workers, before and after both BNT162b2 messenger RNA (mRNA) vaccinations. We compared outcomes between participants with more recent infection (n = 18, median two months, IQR 2-3), with infection-vaccination interval over six months (n = 19, median nine months, IQR 9-10), and to those not previously infected (n = 73). Findings: Both recently and earlier infected participants showed comparable humoral immune responses after a single mRNA vaccination, while exceeding those of previously uninfected persons after two vaccinations with 2.5 fold (p = 0.003) and 3.4 fold (p

Published
2021
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5. Clinical features and prognostic factors in Covid-19: A prospective cohort study

Author

Sanne de Bruin, Lieuwe D. Bos, Marian A. van Roon, Anita M. Tuip-de Boer, Alex R. Schuurman, Marleen J.A. Koel-Simmelinck, Harm Jan Bogaard, Pieter Roel Tuinman, Michiel A. van Agtmael, Jörg Hamann, Charlotte E. Teunissen, W. Joost Wiersinga, A.H. (Koos) Zwinderman, Matthijs C. Brouwer, Diederik van de Beek, Alexander P.J. Vlaar, Michiel van Agtmael, Anne Geke Algera, Brent Appelman, Frank van Baarle, Diane Bax, Martijn Beudel, Marije Bomers, Peter Bonta, Lieuwe Bos, Michela Botta, Justin de Brabander, Godelieve de Bree, David T.P. Buis, Marianna Bugiani, Esther Bulle, Osoul Chouchane, Alex Cloherty, Maurits C.F.J. de Rotte, Mirjam Dijkstra, Dave A. Dongelmans, Romein W.G. Dujardin, Paul Elbers, Lucas Fleuren, Suzanne Geerlings, Theo Geijtenbeek, Armand Girbes, Bram Goorhuis, Martin P. Grobusch, Florianne Hafkamp, Laura Hagens, Jorg Hamann, Vanessa Harris, Robert Hemke, Sabine M. Hermans, Leo Heunks, Markus Hollmann, Janneke Horn, Joppe W. Hovius, Menno D. de Jong, Rutger Koning, Endry H.T. Lim, Niels van Mourik, Jeannine Nellen, Esther J. Nossent, Frederique Paulus, Edgar Peters, Dan A.I. Piña-Fuentes, Tom van der Poll, Bennedikt Preckel, Jan M. Prins, Jorinde Raasveld, Tom Reijnders, Michiel Schinkel, Femke A.P. Schrauwen, Marcus J. Schultz, Alex Schuurmans, Jaap Schuurmans, Kim Sigaloff, Marleen A. Slim, Patrick Smeele, Marry Smit, Cornelis S. Stijnis, Willemke Stilma, Charlotte Teunissen, Patrick Thoral, Anissa M. Tsonas, Pieter R. Tuinman, Marc van der Valk, Denise Veelo, Carolien Volleman, Heder de Vries, Lonneke A. Vught, Michèle van Vugt, Dorien Wouters, and A.H (Koos) Zwinderman

Subjects
COVID-19, Prognosis, Biomarker, Pathway analysis, Clinical features, Medicine, Medicine (General), R5-920
Abstract

Background: Mortality rates are high among hospitalized patients with COVID-19, especially in those intubated on the ICU. Insight in pathways associated with unfavourable outcome may lead to new treatment strategies. Methods: We performed a prospective cohort study of patients with COVID-19 admitted to general ward or ICU who underwent serial blood sampling. To provide insight in the pathways involved in disease progression, associations were estimated between outcome risk and serial measurements of 64 biomarkers in potential important pathways of COVID-19 infection (inflammation, tissue damage, complement system, coagulation and fibrinolysis) using joint models combining Cox regression and linear mixed-effects models. For patients admitted to the general ward, the primary outcome was admission to the ICU or mortality (unfavourable outcome). For patients admitted to the ICU, the primary outcome was 12-week mortality. Findings: A total of 219 patients were included: 136 (62%) on the ward and 119 patients (54%) on the ICU; 36 patients (26%) were included in both cohorts because they were transferred from general ward to ICU. On the general ward, 54 of 136 patients (40%) had an unfavourable outcome and 31 (23%) patients died. On the ICU, 54 out of 119 patients (45%) died. Unfavourable outcome on the general ward was associated with changes in concentrations of IL-6, IL-8, IL-10, soluble Receptor for Advanced Glycation End Products (sRAGE), vascular cell adhesion molecule 1 (VCAM-1) and Pentraxin-3. Death on the ICU was associated with changes in IL-6, IL-8, IL-10, sRAGE, VCAM-1, Pentraxin-3, urokinase-type plasminogen activator receptor, IL-1-receptor antagonist, CD14, procalcitonin, tumor necrosis factor alfa, tissue factor, complement component 5a, Growth arrest–specific 6, angiopoietin 2, and lactoferrin. Pathway analysis showed that unfavourable outcome on the ward was mainly driven by chemotaxis and interleukin production, whereas death on ICU was associated with a variety of pathways including chemotaxis, cell-cell adhesion, innate host response mechanisms, including the complement system, viral life cycle regulation, angiogenesis, wound healing and response to corticosteroids. Interpretation: Clinical deterioration in patients with severe COVID-19 involves multiple pathways, including chemotaxis and interleukin production, but also endothelial dysfunction, the complement system, and immunothrombosis. Prognostic markers showed considerable overlap between general ward and ICU patients, but we identified distinct differences between groups that should be considered in the development and timing of interventional therapies in COVID-19. Funding: Amsterdam UMC, Amsterdam UMC Corona Fund, and Dr. C.J. Vaillant Fonds.

Published
2021
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6. The BNT162b2 mRNA SARS-CoV-2 vaccine induces transient afucosylated IgG1 in naive but not in antigen-experienced vaccinees

Author

Julie Van Coillie, Tamas Pongracz, Johann Rahmöller, Hung-Jen Chen, Chiara Elisabeth Geyer, Lonneke A. van Vught, Jana Sophia Buhre, Tonći Šuštić, Thijs Luc Junior van Osch, Maurice Steenhuis, Willianne Hoepel, Wenjun Wang, Anne Sophie Lixenfeld, Jan Nouta, Sofie Keijzer, Federica Linty, Remco Visser, Mads Delbo Larsen, Emily Lara Martin, Inga Künsting, Selina Lehrian, Vera von Kopylow, Carsten Kern, Hanna Bele Lunding, Menno de Winther, Niels van Mourik, Theo Rispens, Tobias Graf, Marleen Adriana Slim, René Peter Minnaar, Marije Kristianne Bomers, Jonne Jochum Sikkens, Alexander P.J. Vlaar, C. Ellen van der Schoot, Jeroen den Dunnen, Manfred Wuhrer, Marc Ehlers, Gestur Vidarsson, Spinello Antinori, Cinzia Bassoli, Giovanna Bestetti, Mario Corbellino, Alice Covizzi, Angelica Lupo, Laura Milazzo, Marco Schiuma, Alessandro Torre, Brent Appelman, Diederik van de Beek, Marije K. Bomers, Justin de Brabander, Matthijs C. Brouwer, David T.P. Buis, Nora Chekrouni, Marit J. van Gils, Menno D. de Jong, Ayesha H.A. Lavell, Sabine E. Olie, Edgar J.G. Peters, Tom D.Y. Reijnders, Michiel Schinkel, Alex R. Schuurman, Jonne J. Sikkens, Marleen A. Slim, Yvo M. Smulders, Joost W. Wiersinga, Center of Experimental and Molecular Medicine, Medical Biochemistry, ACS - Atherosclerosis & ischemic syndromes, AII - Inflammatory diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School, Clinical Immunology and Rheumatology, Intensive Care Medicine, ACS - Diabetes & metabolism, APH - Personalized Medicine, Landsteiner Laboratory, ACS - Microcirculation, Clinical Haematology, Infectious diseases, AII - Infectious diseases, Neurology, ANS - Neuroinfection & -inflammation, Internal medicine, and AMS - Rehabilitation & Development

Subjects
History, Glycosylation, Polymers and Plastics, Fucosylation, Biochemistry, Genetics and Molecular Biology(all), COVID-19, General Medicine, mRNA Vaccine, Biochemistry, Industrial and Manufacturing Engineering, General Biochemistry, Genetics and Molecular Biology, Antibodies, Business and International Management, Genetics and Molecular Biology(all)
Abstract

Background: Afucosylated IgG1 responses have only been found against membrane-embedded epitopes, including anti-S in SARS-CoV-2 infections. These responses, intrinsically protective through enhanced Fc gamma RIIIa binding, can also trigger exacerbated pro-inflammatory responses in severe COVID-19. We investigated if the BNT162b2 SARS-CoV-2 mRNA also induced afucosylated IgG responses. Methods: Blood from vaccinees during the first vaccination wave was collected. Liquid chromatography-Mass spectrometry (LC-MS) was used to study anti-S IgG1 Fc glycoprofiles. Responsiveness of alveolar-like macrophages to produce proinflammatory cytokines in presence of sera and antigen was tested. Antigen-specific B cells were characterized and glycosyltransferase levels were investigated by Fluorescence-Activated Cell Sorting (FACS). Findings: Initial transient afucosylated anti-S IgG1 responses were found in naive vaccinees, but not in antigen -experienced ones. All vaccinees had increased galactosylated and sialylated anti-S IgG1. Both naive and antigen -experienced vaccinees showed relatively low macrophage activation potential, as expected, due to the low antibody levels for naive individuals with afucosylated IgG1, and low afucosylation levels for antigen-experienced individuals with high levels of anti-S. Afucosylation levels correlated with FUT8 expression in antigen-specific plasma cells in naive individuals. Interestingly, low fucosylation of anti-S IgG1 upon seroconversion correlated with high anti-S IgG levels after the second dose. Interpretation: Here, we show that BNT162b2 mRNA vaccination induces transient afucosylated anti-S IgG1 responses in naive individuals. This observation warrants further studies to elucidate the clinical context in which potent afucosylated responses would be preferred. Copyright (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Published
2022
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7. Real-world Evidence of the Effects of Novel Treatments for COVID-19 on Mortality: A Nationwide Comparative Cohort Study of Hospitalized Patients in the First, Second, Third, and Fourth Waves in the Netherlands

Author

Marleen A, Slim, Brent, Appelman, Hessel, Peters-Sengers, Dave A, Dongelmans, Nicolette F, de Keizer, Rogier P, Schade, Mark G J, de Boer, Marcella C A, Müller, Alexander P J, Vlaar, W Joost, Wiersinga, Lonneke A, van Vught, N, Bokhizzou, Center of Experimental and Molecular Medicine, Graduate School, Epidemiology and Data Science, AII - Infectious diseases, AII - Inflammatory diseases, Intensive Care Medicine, APH - Quality of Care, Medical Informatics, APH - Methodology, ACS - Pulmonary hypertension & thrombosis, ACS - Microcirculation, Infectious diseases, AII - Cancer immunology, APH - Global Health, ACS - Diabetes & metabolism, APH - Personalized Medicine, Medical Microbiology and Infection Prevention, and Internal medicine

Subjects
Infectious Diseases, immunosuppressive treatments, Oncology, SARS-CoV-2, COVID-19, epidemiology, antiviral
Abstract

Background Large clinical trials on drugs for hospitalized coronavirus disease 2019 (COVID-19) patients have shown significant effects on mortality. There may be a discrepancy with the observed real-world effect. We describe the clinical characteristics and outcomes of hospitalized COVID-19 patients in the Netherlands during 4 pandemic waves and analyze the association of the newly introduced treatments with mortality, intensive care unit (ICU) admission, and discharge alive. Methods We conducted a nationwide retrospective analysis of hospitalized COVID-19 patients between February 27, 2020, and December 31, 2021. Patients were categorized into waves and into treatment groups (hydroxychloroquine, remdesivir, neutralizing severe acute respiratory syndrome coronavirus 2 monoclonal antibodies, corticosteroids, and interleukin [IL]-6 antagonists). Four types of Cox regression analyses were used: unadjusted, adjusted, propensity matched, and propensity weighted. Results Among 5643 patients from 11 hospitals, we observed a changing epidemiology during 4 pandemic waves, with a decrease in median age (67–64 years; P < .001), in in-hospital mortality on the ward (21%–15%; P < .001), and a trend in the ICU (24%–16%; P = .148). In ward patients, hydroxychloroquine was associated with increased mortality (1.54; 95% CI, 1.22–1.96), and remdesivir was associated with a higher rate of discharge alive within 29 days (1.16; 95% CI, 1.03–1.31). Corticosteroids were associated with a decrease in mortality (0.82; 95% CI, 0.69–0.96); the results of IL-6 antagonists were inconclusive. In patients directly admitted to the ICU, hydroxychloroquine, corticosteroids, and IL-6 antagonists were not associated with decreased mortality. Conclusions Both remdesivir and corticosteroids were associated with better outcomes in ward patients with COVID-19. Continuous evaluation of real-world treatment effects is needed.

Published
2022
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8. Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial

Author

Alexander P J Vlaar, Martin Witzenrath, Pieter van Paassen, Leo M A Heunks, Bruno Mourvillier, Sanne de Bruin, Endry H T Lim, Matthijs C Brouwer, Pieter R Tuinman, José F K Saraiva, Gernot Marx, Suzana M Lobo, Rodrigo Boldo, Jesus A Simon-Campos, Alexander D Cornet, Anastasia Grebenyuk, Johannes M Engelbrecht, Murimisi Mukansi, Philippe G Jorens, Robert Zerbib, Simon Rückinger, Korinna Pilz, Renfeng Guo, Diederik van de Beek, Niels C Riedemann, Alexander P.J. Vlaar, Leo M.A. Heunks, Endry H.T. Lim, Matthijs C. Brouwer, Pieter R. Tuinman, José Francisco K. Saraiva, Suzana Lobo, Jesus Simon-Campos, Alexander D. Cornet, Johannes Engelbrecht, Philippe G. Jorens, Niels C. Riedemann, Pierre Bulpa, Fabio S. Taccone, Greet Hermans, Marc Diltoer, Michael Piagnerelli, Nikolaas De Neve, Antonio T. Freire, Felipe D. Pizzol, Anna Karolina Marinho, Victor H. Sato, Clovis Arns da Cunha, Mathilde Neuville, Jean Dellamonica, Djillali Annane, Antoine Roquilly, Jean Luc Diehl, Francis Schneider, Jean Paul Mira, Jean Baptiste Lascarrou, Luc Desmedt, Claire Dupuis, Carole Schwebel, Guillaume Thiéry, Matthias Gründling, Marc Berger, Tobias Welte, Michael Bauer, Ulrich Jaschinski, Klaus Matschke, Roberto Mercado-Longoria, Belinda Gomez Quintana, Jorge Alberto Zamudio-Lerma, Juan Moreno Hoyos Abril, Angel Aleman Marquez, Peter Pickkers, Luuk Otterspoor, Luis Hercilla Vásquez, Carlos Rafael Seas Ramos, Alejandro Peña Villalobos, Gonzalo Gianella Malca, Victoria Chávez, Victor Filimonov, Vladimir Kulabukhov, Pinak Acharya, Sjoerd A.M.E.G. Timmermans, Matthias H. Busch, Floor L.F. van Baarle, Rutger Koning, Liora ter Horst, Nora Chekrouni, Thijs M. van Soest, Marleen A. Slim, Lonneke A. van Vught, Rombout B.E. van Amstel, Sabine E. Olie, Ingeborg E. van Zeggeren, Marcel C.G. van de Poll, Claus Thielert, Dorothee Neukirchen, MUMC+: MA Klinische Immunologie (9), RS: Carim - B02 Vascular aspects thrombosis and Haemostasis, Intensive care medicine, ACS - Pulmonary hypertension & thrombosis, ACS - Diabetes & metabolism, Supporting clinical sciences, Intensive Care, PANAMO Study Group, Intensive Care Medicine, ACS - Microcirculation, AII - Inflammatory diseases, Graduate School, ANS - Amsterdam Neuroscience, AII - Amsterdam institute for Infection and Immunity, Neurology, and ANS - Neuroinfection & -inflammation

Subjects
Pulmonary and Respiratory Medicine, therapy, critically ill, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], COVID-19, Human medicine, PANAMO, Critical Care and Intensive Care Medicine, infectious diseases, Anti-C5a antibody, vilobelimab
Abstract

Contains fulltext : 287661.pdf (Publisher’s version ) (Closed access) BACKGROUND: Vilobelimab, an anti-C5a monoclonal antibody, was shown to be safe in a phase 2 trial of invasively mechanically ventilated patients with COVID-19. Here, we aimed to determine whether vilobelimab in addition to standard of care improves survival outcomes in this patient population. METHODS: This randomised, double-blind, placebo-controlled, multicentre phase 3 trial was performed at 46 hospitals in the Netherlands, Germany, France, Belgium, Russia, Brazil, Peru, Mexico, and South Africa. Participants aged 18 years or older who were receiving invasive mechanical ventilation, but not more than 48 h after intubation at time of first infusion, had a PaO(2)/FiO(2) ratio of 60-200 mm Hg, and a confirmed SARS-CoV-2 infection with any variant in the past 14 days were eligible for this study. Eligible patients were randomly assigned (1:1) to receive standard of care and vilobelimab at a dose of 800 mg intravenously for a maximum of six doses (days 1, 2, 4, 8, 15, and 22) or standard of care and a matching placebo using permuted block randomisation. Treatment was not continued after hospital discharge. Participants, caregivers, and assessors were masked to group assignment. The primary outcome was defined as all-cause mortality at 28 days in the full analysis set (defined as all randomly assigned participants regardless of whether a patient started treatment, excluding patients randomly assigned in error) and measured using Kaplan-Meier analysis. Safety analyses included all patients who had received at least one infusion of either vilobelimab or placebo. This study is registered with ClinicalTrials.gov, NCT04333420. FINDINGS: From Oct 1, 2020, to Oct 4, 2021, we included 368 patients in the ITT analysis (full analysis set; 177 in the vilobelimab group and 191 in the placebo group). One patient in the vilobelimab group was excluded from the primary analysis due to random assignment in error without treatment. At least one dose of study treatment was given to 364 (99%) patients (safety analysis set). 54 patients (31%) of 177 in the vilobelimab group and 77 patients (40%) of 191 in the placebo group died in the first 28 days. The all-cause mortality rate at 28 days was 32% (95% CI 25-39) in the vilobelimab group and 42% (35-49) in the placebo group (hazard ratio 0·73, 95% CI 0·50-1·06; p=0·094). In the predefined analysis without site-stratification, vilobelimab significantly reduced all-cause mortality at 28 days (HR 0·67, 95% CI 0·48-0·96; p=0·027). The most common TEAEs were acute kidney injury (35 [20%] of 175 in the vilobelimab group vs 40 [21%] of 189 in the placebo), pneumonia (38 [22%] vs 26 [14%]), and septic shock (24 [14%] vs 31 [16%]). Serious treatment-emergent adverse events were reported in 103 (59%) of 175 patients in the vilobelimab group versus 120 (63%) of 189 in the placebo group. INTERPRETATION: In addition to standard of care, vilobelimab improves survival of invasive mechanically ventilated patients with COVID-19 and leads to a significant decrease in mortality. Vilobelimab could be considered as an additional therapy for patients in this setting and further research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections. FUNDING: InflaRx and the German Federal Government.

Published
2022
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9. ImmunoSep (Personalised Immunotherapy in Sepsis) international double-blind, double-dummy, placebo-controlled randomised clinical trial: study protocol

Author

Antigone Kotsaki, Peter Pickkers, Michael Bauer, Thierry Calandra, Mihaela Lupse, W Joost Wiersinga, Sylvain Meylan, Frank Bloos, Tom van der Poll, Marleen A Slim, Niels van Mourik, Marcella C A Müller, Lonneke van Vught, Alexander P J Vlaar, Aline de Nooijer, Lieke Bakkerus, Sebastian Weis, Nikolaos Antonakos, Mihai G Netea, Evangelos J Giamarellos-Bourboulis, Center of Experimental and Molecular Medicine, Infectious diseases, AII - Infectious diseases, APH - Global Health, Graduate School, Intensive Care Medicine, ACS - Pulmonary hypertension & thrombosis, ACS - Diabetes & metabolism, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, and ACS - Microcirculation

Subjects
Adult intensive & critical care, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], General Medicine, INFECTIOUS DISEASES, IMMUNOLOGY
Abstract

IntroductionSepsis is a major cause of death among hospitalised patients. Accumulating evidence suggests that immune response during sepsis cascade lies within a spectrum of dysregulated host responses. On the one side of the spectrum there are patients whose response is characterised by fulminant hyperinflammation or macrophage activation-like syndrome (MALS), and on the other side patients whose immune response is characterised by immunoparalysis. A sizeable group of patients are situated between the two extremes. Recognising immune endotype is very important in order to choose the appropriate immunotherapeutic approach for each patient resulting in the best chance to improve the outcome.Methods and analysisImmunoSep is a randomised placebo-controlled phase 2 clinical trial with a double-dummy design in which the effect of precision immunotherapy on sepsis phenotypes with MALS and immunoparalysis is studied. Patients are stratified using biomarkers. Specifically, 280 patients will be 1:1 randomly assigned to placebo or active immunotherapy as adjunct to standard-of-care treatment. In the active immunotherapy arm, patients with MALS will receive anakinra (recombinant interleukin-1 receptor antagonist) intravenously, and patients with immunoparalysis will receive subcutaneous recombinant human interferon-gamma. Τhe primary endpoint is the comparative decrease of the mean total Sequential Organ Failure Assessment score by at least 1.4 points by day 9 from randomisation.Ethics and disseminationThe protocol is approved by the German Federal Institute for Drugs and Medical Devices; the National Ethics Committee of Greece and by the National Organization for Medicines of Greece; the Central Committee on Research Involving Human Subjects and METC Oost Netherland for the Netherlands; the National Agency for Medicine and Medical Products of Romania; and the Commission Cantonale d’éthique de la recherche sur l’être human of Switzerland. The results will be submitted for publication in peer-reviewed journals.Trial registration numberNCT04990232.

Published
2022

10. Indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2 activity and severe course of COVID-19

Author

René Lutter, Dorien Wouters, A H Koos Zwinderman, Markus Hollmann, Esther J. Nossent, Jorinde Raasveld, Bram Goorhuis, Syun-Ru Yeh, Kim C. E. Sigaloff, Michiel A. van Agtmael, Lieuwe D. J. Bos, Martin P. Grobusch, Michèle van Vugt, Anissa Tsonas, Leo Heunks, Marije K. Bomers, Michela Botta, Frederique Paulus, Joppe W. Hovius, Menno D. de Jong, Suzanne Geerlings, Zachary Geeraerts, Carolien Volleman, Jaap Schuurmans, Jeannine Nellen, Dan A.I. Piña-Fuentes, Edgar Peters, Frédéric M. Vaz, Vanessa Harris, Heder de Vries, Patrick Thoral, Jörg Hamann, Anne Geke Algera, Romein W.G. Dujardin, Laura Hagens, Femke A.P. Schrauwen, Lucas Fleuren, Bennedikt Preckel, Paul Elbers, Rutger Koning, Jan M. Prins, Tom Reijnders, Marry Smit, Alex Cloherty, Justin de Brabander, Harm Jan Bogaard, Eva Roos, Alexander P.J. Vlaar, Armand Girbes, Matthijs C. Brouwer, Cornelis S. Stijnis, Tom van der Poll, Brent Appelman, Theo Geijtenbeek, Diane Bax, Florianne Hafkamp, Anissa M. Tsonas, Michiel Schinkel, Charlotte E. Teunissen, Robert Hemke, Annemiek Dijkhuis, Frank van Baarle, Alex Schuurmans, Paul van der Valk, Buis T P David, Lonneke A. Vught, Marc van der Valk, Peter Bonta, Janneke Horn, Bernadette Schurink, Maurits C.F.J. de Rotte, Sanne de Bruin, Esther Bulle, Endry H.T. Lim, Denise Veelo, Lihui Guo, Marcus J. Schultz, Marleen A. Slim, Sabine M. Hermans, Martijn Beudel, Marianna Bugiani, JanWillem Duitman, Lonneke A. van Vught, W. Joost Wiersinga, Godelieve J. de Bree, Niels van Mourik, Mirjam Dijkstra, Dave A. Dongelmans, Osoul Chouchane, Diederik van de Beek, Willemke Stilma, Pathology, Pulmonary medicine, Amsterdam Neuroscience - Neuroinfection & -inflammation, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Neuroscience - Complex Trait Genetics, Internal medicine, AII - Infectious diseases, Intensive care medicine, Neurology, ACS - Pulmonary hypertension & thrombosis, Laboratory Medicine, Amsterdam Cardiovascular Sciences, ACS - Diabetes & metabolism, Radiology and nuclear medicine, Anesthesiology, Medical Microbiology and Infection Prevention, AMS - Rehabilitation & Development, VU University medical center, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Reproduction & Development (AR&D), Graduate School, Pulmonology, Intensive Care Medicine, ACS - Microcirculation, Vascular Medicine, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases, Experimental Immunology, APH - Personalized Medicine, Center of Experimental and Molecular Medicine, ANS - Neurodegeneration, Laboratory for General Clinical Chemistry, Genetic Metabolic Diseases, APH - Quality of Care, Infectious diseases, APH - Global Health, Global Health, APH - Health Behaviors & Chronic Diseases, AII - Amsterdam institute for Infection and Immunity, Radiology and Nuclear Medicine, AMS - Sports, AMS - Musculoskeletal Health, APH - Methodology, ACS - Heart failure & arrhythmias, ANS - Neuroinfection & -inflammation, Nursing, APH - Digital Health, and APH - Aging & Later Life

Subjects
Adult, Programmed cell death, Cell, 3-Hydroxyanthranilic Acid, Apoptosis, Severity of Illness Index, Pathology and Forensic Medicine, chemistry.chemical_compound, Medicine, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Prospective Studies, Receptor, Indoleamine 2,3-dioxygenase, Lung, Kynurenine, Aged, business.industry, Myocardium, Tryptophan, Brain, COVID-19, Middle Aged, Quinolinic Acid, medicine.anatomical_structure, chemistry, Immunology, Autopsy, business, Quinolinic acid, Hormone
Abstract

COVID-19 is a pandemic with high morbidity and mortality. In an autopsy cohort of COVID-19 patients, we found extensive accumulation of the tryptophan degradation products 3-hydroxy-anthranilic acid and quinolinic acid in the lungs, heart, and brain. This was not related to the expression of the tryptophan-catabolizing indoleamine 2,3-dioxygenase (IDO)-1, but rather to that of its isoform IDO-2, which otherwise is expressed rarely. Bioavailability of tryptophan is an absolute requirement for proper cell functioning and synthesis of hormones, whereas its degradation products can cause cell death. Markers of apoptosis and severe cellular stress were associated with IDO-2 expression in large areas of lung and heart tissue, whereas affected areas in brain were more restricted. Analyses of tissue, cerebrospinal fluid, and sequential plasma samples indicate early initiation of the kynurenine/aryl-hydrocarbon receptor/IDO-2 axis as a positive feedback loop, potentially leading to severe COVID-19 pathology. © 2021 The Authors. The Journal of Pathology published by John WileySons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Published
2021
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11. Antibody responses against SARS-CoV-2 variants induced by four different SARS-CoV-2 vaccines

Author

Menno D. de Jong, Melissa Oomen, Lonneke A. van Vught, Godelieve J. de Bree, Judith A. Burger, A.H. Ayesha Lavell, Elke Wynberg, Tom G. Caniels, Marije K. Bomers, Alexander P.J. Vlaar, Jonne L. Snitselaar, Jonne J. Sikkens, Marloes Grobben, Hugo D.G. van Willigen, Marleen A. Slim, Brent Appelman, Karlijn van der Straten, Rogier W. Sanders, Maria Prins, Ilja Bontjer, Joey H. Bouhuijs, Michiel Schinkel, Kadija Tejjani, Meliawatti Poniman, and Marit J. van Gils

Subjects
biology, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Alpha (ethology), Virology, Neutralization, Viral vector, Vaccination, Titer, biology.protein, Medicine, Antibody, Neutralizing antibody, business
Abstract

BackgroundEmerging and future SARS-CoV-2 variants may jeopardize the effectiveness of vaccination campaigns. Therefore, it is important to know how the different vaccines perform against diverse SARS-CoV-2 variants.MethodsIn a prospective cohort of 165 SARS-CoV-2 naive health care workers, vaccinated with either one of four vaccines (BNT162b2, mRNA-1273, AZD1222 or Ad26.COV2.S), we performed a head-to-head comparison of the ability of sera to recognize and neutralize SARS-CoV-2 variants of concern (VOCs; Alpha, Beta, Gamma, Delta and Omicron). Repeated serum sampling was performed 5 times during a year (from January 2021 till January 2022), including before and after booster vaccination with BNT162b2.FindingsFour weeks after completing the initial vaccination series, SARS-CoV-2 wild-type neutralizing antibody titers were highest in recipients of BNT162b2 and mRNA-1273 (geometric mean titers (GMT) of 197 [95% CI 149-260] and 313 [95% CI 218-448], respectively), and substantially lower in those vaccinated with the adenovirus vector-based vaccines AZD1222 and Ad26.COV2.S (GMT of 26 [95% CI 18-37] and 14 [95% CI 8-25] IU/ml, respectively). These findings were robust for adjustment to age and sex. VOCs neutralization was reduced in all vaccine groups, with the largest (9- to 80-fold) reduction in neutralization observed against the Omicron variant. The booster BNT162b2 vaccination increased neutralizing antibody titers for all groups with substantial improvement against the VOCs including the Omicron variant. Study limitations include the lack of cellular immunity data.ConclusionsOverall, this study shows that the mRNA vaccines appear superior to adenovirus vector-based vaccines in inducing neutralizing antibodies against VOCs four weeks after initial vaccination and after booster vaccination.

Published
2021
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12. Time Since SARS-CoV-2 Infection and Humoral Immune Response Following BNT162b2 mRNA Vaccination

Author

A.H. Ayesha Lavell, Lonneke A. van Vught, Melissa Oomen, Khadija Tejjani, Hcw, Judith A. Burger, Michiel Schinkel, Karlijn van der Straten, Marleen A. Slim, Marit J. van Gils, Marije K. Bomers, Jonne J. Sikkens, Rogier W. Sanders, Alexander P.J. Vlaar, Meliawati Poniman, Yvo M. Smulders, Joost Wiersinga, and Brent Appelman

Subjects
Vaccination, Titer, Messenger RNA, Immune system, business.industry, Informed consent, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, Medicine, business, Antigen binding, Neutralization
Abstract

Background: To optimise the use of available SARS-CoV-2 vaccines, some advocate delaying second vaccination for individuals infected within six months. We studied whether post-vaccination immune response is equally potent in individuals infected over six months prior to vaccination. Methods: We tested serum IgG binding to SARS-CoV-2 spike protein and neutralising capacity in 110 healthcare workers, before and after both BNT162b2 messenger RNA (mRNA) vaccinations. We compared outcomes between participants with more recent infection (n=18, median two months, IQR 2-3), with infection-vaccination interval over six months (n=19, median nine months, IQR 9-10), and to those not previously infected (n=73). Findings: Both recently and earlier infected participants showed comparable humoral immune responses after a single mRNA vaccination, while exceeding those of previously uninfected persons after two vaccinations with 2·5 fold (p=0·003) and 3·4 fold (p

Published
2021
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13. Reliability of visual assessment by non-expert nuclear medicine physicians and appropriateness of indications of [

Author

Sven R, Suwijn, Constant V M, Verschuur, Marleen A, Slim, Jan, Booij, and Rob M A, de Bie

Subjects
Indication, Short Communication, mental disorders, Visual assessment, Reliability, DAT SPECT, nervous system diseases
Abstract

Purpose To determine the reliability of visual assessment of [123I]FP-CIT SPECT imaging by non-experts in dopamine transporter (DAT) SPECT imaging in patients with early drug-naive Parkinson’s disease (PD). Also, we explored the indications of DAT SPECT imaging in clinical practice by neurologists. Methods We collected [123I]FP-CIT SPECT scans of the Levodopa in EArly Parkinson’s disease (LEAP) trial participants that were made prior to recruitment, as part of routine clinical work-up. All scans were reassessed by an expert in DAT imaging. A survey on the use of DAT SPECT imaging was sent to all referring neurologists. Results The concordance of the initial local assessment and the expert reassessment was 98.7%. The survey showed that neurologists requested DAT SPECT imaging in only 73.6% of patients to differentiate between a neurodegenerative disease and non-neurodegenerative parkinsonism. Conclusions Visual assessment of [123I]FP-CIT SPECT imaging by community nuclear medicine physicians in patients with early PD is reliable. Neurologists who request DAT SPECT scans are not always aware that the high accuracy is limited only to the differentiation between neurodegenerative and non-neurodegenerative parkinsonism. A significant portion of neurologists who request DAT SPECT scans is not always aware that the high accuracy is limited to the differentiation between neurodegenerative and non-neurodegenerative parkinsonism as DAT SPECT cannot reliably distinguish the various Parkinsonian syndromes.

Published
2019

14. Reliability of visual assessment by non-expert nuclear medicine physicians and appropriateness of indications of [123I]FP-CIT SPECT imaging by neurologists in patients with early drug-naive Parkinson’s disease

Author

Marleen A. Slim, Jan Booij, Sven R. Suwijn, Rob M.A. de Bie, Constant V. M. Verschuur, Amsterdam Neuroscience - Neurodegeneration, Graduate School, Radiology and Nuclear Medicine, Neurology, and APH - Aging & Later Life

Subjects
lcsh:Medical physics. Medical radiology. Nuclear medicine, 0301 basic medicine, Levodopa, Parkinson's disease, lcsh:R895-920, Concordance, DAT SPECT, 03 medical and health sciences, 0302 clinical medicine, Spect imaging, parasitic diseases, Visual assessment, mental disorders, Medicine, Radiology, Nuclear Medicine and imaging, Cardiac imaging, business.industry, Parkinsonism, Reliability, medicine.disease, nervous system diseases, Indication, Drug-naïve, 030104 developmental biology, business, Nuclear medicine, 030217 neurology & neurosurgery, medicine.drug
Abstract

Purpose To determine the reliability of visual assessment of [123I]FP-CIT SPECT imaging by non-experts in dopamine transporter (DAT) SPECT imaging in patients with early drug-naive Parkinson’s disease (PD). Also, we explored the indications of DAT SPECT imaging in clinical practice by neurologists. Methods We collected [123I]FP-CIT SPECT scans of the Levodopa in EArly Parkinson’s disease (LEAP) trial participants that were made prior to recruitment, as part of routine clinical work-up. All scans were reassessed by an expert in DAT imaging. A survey on the use of DAT SPECT imaging was sent to all referring neurologists. Results The concordance of the initial local assessment and the expert reassessment was 98.7%. The survey showed that neurologists requested DAT SPECT imaging in only 73.6% of patients to differentiate between a neurodegenerative disease and non-neurodegenerative parkinsonism. Conclusions Visual assessment of [123I]FP-CIT SPECT imaging by community nuclear medicine physicians in patients with early PD is reliable. Neurologists who request DAT SPECT scans are not always aware that the high accuracy is limited only to the differentiation between neurodegenerative and non-neurodegenerative parkinsonism. A significant portion of neurologists who request DAT SPECT scans is not always aware that the high accuracy is limited to the differentiation between neurodegenerative and non-neurodegenerative parkinsonism as DAT SPECT cannot reliably distinguish the various Parkinsonian syndromes.

Published
2019

16. Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection

Author

Astrid Marchal, Elizabeth T. Cirulli, Iva Neveux, Evangelos Bellos, Ryan S. Thwaites, Kelly M. Schiabor Barrett, Yu Zhang, Ivana Nemes-Bokun, Mariya Kalinova, Andrew Catchpole, Stuart G. Tangye, András N. Spaan, Justin B. Lack, Jade Ghosn, Charles Burdet, Guy Gorochov, Florence Tubach, Pierre Hausfater, Clifton L. Dalgard, Shen-Ying Zhang, Qian Zhang, Christopher Chiu, Jacques Fellay, Joseph J. Grzymski, Vanessa Sancho-Shimizu, Laurent Abel, Jean-Laurent Casanova, Aurélie Cobat, Alexandre Bolze, Alessandro Aiuti, Saleh Al-Muhsen, Fahd Al-Mulla, Ali Amara, Mark S. Anderson, Evangelos Andreakos, Andrés A. Arias, Lisa M. Arkin, Hagit Baris Feldman, Paul Bastard, Alexandre Belot, Catherine M. Biggs, Dusan Bogunovic, Anastasiia Bondarenko, Alessandro Borghesi, Ahmed A. Bousfiha, Petter Brodin, Yenan Bryceson, Manish J. Butte, Giorgio Casari, John Christodoulou, Roger Colobran, Antonio Condino-Neto, Stefan N. Constantinescu, Megan A. Cooper, Murkesh Desai, Beth A. Drolet, Xavier Duval, Jamila El Baghdadi, Philippine Eloy, Sara Espinosa-Padilla, Carlos Flores, José Luis Franco, Antoine Froidure, Peter K. Gregersen, Bodo Grimbacher, Filomeen Haerynck, David Hagin, Rabih Halwani, Lennart Hammarström, James R. Heath, Elena W.Y. Hsieh, Eystein Husebye, Kohsuke Imai, Yuval Itan, Emmanuelle Jouanguy, Elżbieta Kaja, Timokratis Karamitros, Kai Kisand, Cheng-Lung Ku, Yu-Lung Lau, Yun Ling, Carrie L. Lucas, Tom Maniatis, Davood Mansouri, László Maródi, France Mentré, Isabelle Meyts, Joshua D. Milner, Kristina Mironska, Trine H. Mogensen, Tomohiro Morio, Lisa F.P. Ng, Luigi D. Notarangelo, Antonio Novelli, Giuseppe Novelli, Cliona O'Farrelly, Satoshi Okada, Keisuke Okamoto, Tayfun Ozcelik, Qiang Pan-Hammarström, Jean W. Pape, Rebeca Perez de Diego, Jordi Perez-Tur, David S. Perlin, Graziano Pesole, Anna M. Planas, Carolina Prando, Aurora Pujol, Anne Puel, Lluis Quintana-Murci, Sathishkumar Ramaswamy, Laurent Renia, Igor Resnick, Carlos Rodríguez-Gallego, Anna Sediva, Mikko R.J. Seppänen, Mohammad Shahrooei, Anna Shcherbina, Ondrej Slaby, Andrew L. Snow, Pere Soler-Palacín, Vassili Soumelis, Ivan Tancevski, Ahmad Abou Tayoun, Şehime Gülsün Temel, Christian Thorball, Pierre Tiberghien, Sophie Trouillet-Assant, Stuart E. Turvey, K. M. Furkan Uddin, Mohammed J. Uddin, Diederik van de Beek, Donald C. Vinh, Horst von Bernuth, Joost Wauters, Mayana Zatz, Pawel Zawadzki, Serge Bureau, Yannick Vacher, Anne Gysembergh-Houal, Lauren Demerville, Abla Benleulmi-Chaachoua, Sebastien Abad, Radhiya Abassi, Abdelrafie Abdellaoui, Abdelkrim Abdelmalek, Hendy Abdoul, Helene Abergel, Fariza Abeud, Sophie Abgrall, Noemie Abisror, Marylise Adechian, Nordine Aderdour, Hakeem Farid Admane, Frederic Adnet, Sara Afritt, Helene Agostini, Claire Aguilar, Sophie Agut, Tommaso Francesco Aiello, Marc Ait Kaci, Hafid Ait Oufella, Gokula Ajeenthiravasan, Virginie Alauzy, Fanny Alby-Laurent, Lucie Allard, Marie-Alexandra Alyanakian, Blanca Amador Borrero, Sabrina Amam, Lucile Amrouche, Marc Andronikof, Dany Anglicheau, Nadia Anguel, Djillali Annane, Mohammed Aounzou, Caroline Aparicio, Gladys Aratus, Jean-Benoit Arlet, Jeremy Arzoine, Elisabeth Aslangul, Mona Assefi, Adeline Aubry, Laetitia Audiffred, Etienne Audureau, Christelle Nathalie Auger, Jean-Charles Auregan, Celine Awotar, Sonia Ayllon Milla, Delphine Azan, Laurene Azemar, Billal Azzouguen, Marwa Bachir Elrufaai, Aïda Badsi, Prissile Bakouboula, Coline Balcerowiak, Fanta Balde, Elodie Baldivia, Eliane-Flore Bangamingo, Amandine Baptiste, Fanny Baran-Marszak, Caroline Barau, Nathalie Barget, Flore Baronnet, Romain Barthelemy, Jean-Luc Baudel, Camille Baudry, Elodie Baudry, Laurent Beaugerie, Adel Belamri, Nicolas Belaube, Rhida Belilita, Pierre Bellassen, Rawan Belmokhtar, Isabel Beltran, Ruben Benainous, Mourad Benallaoua, Robert Benamouzig, Amélie Benbara, Jaouad Benhida, Anis Benkhelouf, Jihene Benlagha, Chahinez Benmostafa, Skander Benothmane, Miassa Bentifraouine, Laurence Berard, Quentin Bernier, Enora Berti, Astrid Bertier, Laure Berton, Simon Bessis, Alexandra Beurton, Celine Bianco, Clara Bianquis, Frank Bidar, Philippe Blanche, Clarisse Blayau, Alexandre Bleibtreu, Emmanuelle Blin, Coralie Bloch-Queyrat, Marie-Christophe Boissier, Diane Bollens, Marion Bolzoni, Rudy pierre Bompard, Nicolas Bonnet, Justine Bonnouvrier, Shirmonecrystal Botha, Wissam Boucenna, Fatiha Bouchama, Olivier Bouchaud, Hanane Bouchghoul, Taoueslylia Boudjebla, Noel Boudjema, Catherine Bouffard, Adrien Bougle, Meriem Bouguerra, Leila Bouras, Agnes Bourcier, Anne Bourgarit Durand, Anne Bourrier, Fabrice Bouscarat, Diane Bouvry, Nesrine Bouziri, Ons Bouzrara, Sarah Bribier, Delphine Brugier, Melanie Brunel, Eida Bui, Anne Buisson, Iryna Bukreyeva, Côme Bureau, Jacques Cadranel, Johann Cailhol, Ruxandra Calin, Clara Campos Vega, Pauline Canavaggio, Marta Cancella, Delphine Cantin, Albert Cao, Lionel Carbillon, Nicolas Carlier, Clementine Cassard, Guylaine Castor, Marion Cauchy, Olivier Cha, Benjamin Chaigne, Salima Challal, Karine Champion, Patrick Chariot, Julie Chas, Simon Chauveau, Anthony Chauvin, Clement Chauvin, Nathalie Chavarot, Kamélia Chebbout, Mustapha Cherai, Ilaria Cherubini, Amelie Chevalier, Thibault Chiarabini, Thierry Chinet, Richard Chocron, Pascaline Choinier, Juliette Chommeloux, Christophe Choquet, Laure Choupeaux, Benjamin Chousterman, Dragosmarius Ciocan, Ada Clarke, Gaëlle Clavere, Florian Clavier, Karine Clement, Sebastien Clerc, Yves Cohen, Fleur Cohen, Adrien Cohen, Audrey Coilly, Hester Colboc, Pauline Colin, Magalie Collet, Chloé Comarmond, Emeline Combacon, Alain Combes, Celine Comparon, Jean-Michel Constantin, Hugues Cordel, Anne-Gael Cordier, Adrien Costantini, Nathalie Costedoat Chalumeau, Camille Couffignal, Doriane Coupeau, Alain Creange, Yannie Cuvillier Lamarre, Charlène Da Silveira, Sandrine Dautheville Guibal El Kayani, Nathalie De Castro, Yann De Rycke, Lucie Del Pozo, Quentin Delannoy, Mathieu Delay, Robin Deleris, Juliette Delforge, Laëtitia Delphine, Noemie Demare, Sophie Demeret, Alexandre Demoule, Aurore Deniau, François Depret, Sophie Derolez, Ouda Derradji, Nawal Derridj, Vincent Descamps, Lydia Deschamps, Celine Desconclois, Cyrielle Desnos, Karine Desongins, Robin Dhote, Benjamin Diallo, Morgane Didier, Myriam Diemer, Stephane Diez, Juliette Djadi-Prat, Fatima-Zohra Djamouri Monnory, Siham Djebara, Naoual Djebra, Minette Djietcheu, Hadjer Djillali, Nouara Djouadi, Severine Donneger, Catarina Dos Santos, Nathalie Dournon, Martin Dres, Laura Droctove, Marie Drogrey, Margot Dropy, Elodie Drouet, Valérie Dubosq, Evelyne Dubreucq, Estelle Dubus, Boris Duchemann, Thibault Duchenoy, Emmanuel Dudoignon, Romain Dufau, Florence Dumas, Clara Duran, Emmanuelle Duron, Antoine Durrbach, Claudine Duvivier, Nathan Ebstein, Jihane El Khalifa, Alexandre Elabbadi, Caroline Elie, Gabriel Ernotte, Anne Esling, Martin Etienne, Xavier Eyer, Muriel Sarah Fartoukh, Takoua Fayali, Marion Fermaut, Arianna Fiorentino, Souha Fliss, Marie-Céline Fournier, Benjamin Fournier, Hélène Francois, Olivia Freynet, Yvann Frigout, Isaure Fromont, Axelle Fuentes, Thomas Furet, Joris Galand, Marc Garnier, Agnes Gaubert, Stéphane Gaudry, Samuel Gaugain, Damien Gauthier, Maxime Gautier, Sophie Georgin-Lavialle, Daniela Geromin, Mohamed Ghalayini, Bijan Ghaleh, Myriam Ghezal, Aude Gibelin, Linda Gimeno, Benoit Girard, Bénédicte Giroux Leprieur, Doryan Gomes, Elisabete Gomes-Pires, Anne Gouge, Amel Gouja, Helene Goulet, Sylvain Goupil, Jeanne Goupil De Bouille, Julien Gras, Segolene Greffe, Lamiae Grimaldi, Paul Guedeney, Bertrand Guidet, Matthias Guillo, Mariechristelle Gulczynski, Tassadit Hadjam, Didier Haguenauer, Soumeya Hammal, Nadjib Hammoudi, Olivier Hanon, Anarole Harrois, Coraline Hautem, Guillaume Hekimian, Nicholas Heming, Olivier Hermine, Sylvie Ho, Marie Houllier, Benjamin Huot, Tessa Huscenot, Wafa Ibn Saied, Ghilas Ikherbane, Meriem Imarazene, Patrick Ingiliz, Lina Iratni, Stephane Jaureguiberry, Jean-Francois Jean-Marc, Deleena Jeyarajasingham, Pauline Jouany, Veronique Jouis, Clement Jourdaine, Ouifiya Kafif, Rim Kallala, Sandrine Katsahian, Lilit Kelesyan, Vixra Keo, Flora Ketz, Warda Khamis, Enfel Khelili, Mehdi Khellaf, Christy Gaëlla Kotokpo Youkou, Ilias Kounis, Gaelle Kpalma, Jessica Krause, Vincent Labbe, Karine Lacombe, Jean-Marc Lacorte, Anne Gaelle Lafont, Emmanuel Lafont, Lynda Lagha, Lionel Lamhaut, Aymeric Lancelot, Cecilia Landman, Fanny Lanternier, Cecile Larcheveque, Caroline Lascoux Combe, Ludovic Lassel, Benjamin Laverdant, Christophe Lavergne, Jean-Rémi Lavillegrand, Pompilia Lazureanu, Loïc Le Guennec, Lamia Leberre, Claire Leblanc, Marion Leboyer, Francois Lecomte, Marine Lecorre, Romain Leenhardt, Marylou Lefebvre, Bénédicte Lefebvre, Paul Legendre, Anne Leger, Laurence Legros, Justyna Legrosse, Sébastien Lehuunghia, Julien Lemarec, Jeremie Leporrier-Ext, Manon Lesein, Hubert Lesur, Vincent Levy, Albert Levy, Edwige Lopes, Amanda Lopes, Vanessa Lopez, Julien Lopinto, Olivier Lortholary, Badr Louadah, Bénédicte Loze, Marie-Laure Lucas, Axelle Lucasamichi, Liem Binh Luong, Arouna Magazimama-Ext, David Maingret, Lakhdar Mameri, Philippe Manivet, Cylia Mansouri, Estelle Marcault, Jonathan Marey, Nathalie Marin, Clémence Marois, Olivier Martin, Lou Martineau, Cannelle Martinez-Lopez, Pierre Martyniuck, Pauline Mary De Farcy, Nessrine Marzouk, Rafik Masmoudi, Alexandre Mebazaa, Frédéric Mechai, Fabio Mecozzi, Chamseddine Mediouni, Bruno Megarbane, Mohamed Meghadecha, Élodie Mejean, Arsene Mekinian, Nour Mekki Abdelhadi, Rania Mekni, Thinhinan Sabrina Meliti, Breno Melo Lima, Paris Meng, Soraya Merbah, Fadhila Messani, Yasmine Messaoudi, Baboo-Irwinsingh Mewasing, Lydia Meziane, Carole Michelot-Burger, Françoise Mignot, Fadi Hillary Minka, Makoto Miyara, Pierre Moine, Jean-Michel Molina, Anaïs Montegnies-Boulet, Alexandra Monti, Claire Montlahuc, Anne-Lise Montout, Alexandre Moores, Caroline Morbieu, Helene Mortelette, Stéphane Mouly, Rosita Muzaffar, Cherifa Iness Nacerddine, Marine Nadal, Hajer Nadif, Kladoum Nassarmadji, Pierre Natella, Sandrine Ndingamondze, Stefan Neraal, Caroline Nguyen, Bao N'Guyen, Isabelle Nion Larmurier, Luc Nlomenyengue, Nicolas Noel, Hilario Nunes, Edris Omar, Zineb Ouazene, Elise Ouedraogo, Wassila Ouelaa, Anissa Oukhedouma, Yasmina Ould Amara, Herve Oya, Johanna Oziel, Thomas Padilla, Elena Paillaud, Solenne Paiva, Beatrice Parfait, Perrine Parize, Christophe Parizot, Antoine Parrot, Arthur Pavot, Laetitia Peaudecerf, Frédéric Pene, Marion Pepin, Julie Pernet, Claire Pernin, Mylène Petit, Olivier Peyrony, Marie-Pierre Pietri, Olivia Pietri, Marc Pineton De Chambrun, Michelle Pinson, Claire Pintado, Valentine Piquard, Christine Pires, Benjamin Planquette, Sandrine Poirier, Anne-Laure Pomel, Stéphanie Pons, Diane Ponscarme, Annegaelle Pourcelot, Valérie Pourcher, Anne Pouvaret, Florian Prever, Miresta Previlon, Margot Prevost, Marie-Julie Provoost, Cyril Quemeneur, Cédric Rafat, Agathe Rami, Brigitte Ranque, Maurice Raphael, Jean Herle Raphalen, Anna Rastoin, Mathieu Raux, Amani Rebai, Michael Reby, Alexis Regent, Asma Regrag, Matthieu Resche-Rigon, Quentin Ressaire, Christian Richard, Mariecaroline Richard, Maxence Robert, Benjamin Rohaut, Camille Rolland-Debord, Jacques Ropers, Anne-Marie Roque-Afonso, Charlotte Rosso, Mélanie Rousseaux, Nabila Rousseaux, Swasti Roux, Lorène Roux, Claire Rouzaud, Antoine Rozes, Emma Rubenstein, Jean-Marc Sabate, Sheila Sabet, Sophie-Caroline Sacleux, Nathalie Saidenberg Kermanach, Faouzi Saliba, Dominique Salmon, Laurent Savale, Guillaume Savary, Rebecca Sberro, Anne Scemla, Frederic Schlemmer, Mathieu Schwartz, Saïd Sedfi, Samia Sefir-Kribel, Philippe Seksik, Pierre Sellier, Agathe Selves, Nicole Sembach, Luca Semerano, Marie-Victoire Senat, Damien Sene, Alexandra Serris, Lucile Sese, Naima Sghiouar, Johanna Sigaux, Martin Siguier, Johanne Silvain, Noémie Simon, Tabassome Simon, Lina Innes Skandri, Miassa Slimani, Aurélie Snauwaert, Harry Sokol, Heithem Soliman, Nisrine Soltani, Benjamin Soyer, Gabriel Steg, Lydia Suarez, Tali-Anne Szwebel, Kossi Taffame, Yacine Tandjaoui-Lambiotte, Claire Tantet, Mariagrazia Tateo, Igor Theodose, Pierre clement Thiebaud, Caroline Thomas, Kelly Tiercelet, Julie Tisserand, Carole Tomczak, Krystel Torelino, Fatima Touam-Ext, Lilia Toumi, 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Nseir, Aurélie Papadopoulos, Christelle Paul, Nathan Peiffer-Smadja, Thomas Perpoint, Ventzislava Petrov-Sanchez, Gilles Peytavin, Huong Pham, Olivier Picone, Oriane Puéchal, Christian Rabaud, Manuel Rosa-Calatrava, Bénédicte Rossignol, Patrick Rossignol, Carine Roy, Marion Schneider, Richa Su, Coralie Tardivon, Marie-Capucine Tellier, François Téoulé, Olivier Terrier, Jean-François Timsit, Christelle Tual, Sylvie Van Der Werf, Noémie Vanel, Aurélie Veislinger, Benoit Visseaux, Aurélie Wiedemann, Yazdan Yazdanpanah, Loubna Alavoine, Charlotte Charpentier, Aline Dechanet, Jean-Luc Ecobichon, Wahiba Frezouls, Nadhira Houhou, Jonathan Lehacaut, Pauline Manchon, Mariama Nouroudine, Caroline Quintin, Michael Thy, Sylvie van der Werf, Valérie Vignali, Abir Chahine, Nawal Waucquier, Maria-Claire Migaud, Félix Djossou, Mayka Mergeay-Fabre, Aude Lucarelli, Magalie Demar, Léa Bruneau, Patrick Gérardin, Adrien Maillot, Christine Payet, Bruno Laviolle, Fabrice Laine, Christophe Paris, Mireille Desille-Dugast, Julie Fouchard, Thierry Pistone, Pauline Perreau, Valérie Gissot, Carole L.E. Goas, Samatha Montagne, Lucie Richard, Kévin Bouiller, Maxime Desmarets, Alexandre Meunier, Marilou Bourgeon, Benjamin Lefévre, Hélène Jeulin, Karine Legrand, Sandra Lomazzi, Bernard Tardy, Amandine Gagneux-Brunon, Frédérique Bertholon, Elisabeth Botelho-Nevers, Christelle Kouakam, Leturque Nicolas, Layidé Roufai, Karine Amat, Hélène Espérou, Samia Hendou, Giuseppe Foti, Giuseppe Citerio, Ernesto Contro, Alberto Pesci, Maria Grazia Valsecchi, Marina Cazzaniga, Giacomo Bellani, Jorge Abad, Giulia Accordino, Micol Angelini, Sergio Aguilera-Albesa, Aina Aguiló-Cucurull, Esra Akyüz Özkan, Ilad Alavi Darazam, Jonathan Antonio Roblero Albisures, Juan C. Aldave, Miquel Alfonso Ramos, Taj Ali Khan, Anna Aliberti, Seyed Alireza Nadji, Gulsum Alkan, Suzan A. AlKhater, Jerome Allardet-Servent, Luis M. Allende, Rebeca Alonso-Arias, Mohammed S. Alshahrani, Laia Alsina, Zahir Amoura, Arnau Antolí, Romain Arrestier, Mélodie Aubart, Teresa Auguet, Iryna Avramenko, Gökhan Aytekin, Axelle Azot, Seiamak Bahram, Fanny Bajolle, Fausto Baldanti, Aurélie Baldolli, Maite Ballester, Benoit Barrou, Federica Barzaghi, Sabrina Basso, Gulsum Iclal Bayhan, Liliana Bezrodnik, Agurtzane Bilbao, Geraldine Blanchard-Rohner, Ignacio Blanco, Adeline Blandinières, Daniel Blázquez-Gamero, Marketa Bloomfield, Mireia Bolivar-Prados, Raphael Borie, Elisabeth Botdhlo-Nevers, Aurore Bousquet, David Boutolleau, Claire Bouvattier, Oksana Boyarchuk, Juliette Bravais, M. Luisa Briones, Marie-Eve Brunner, Raffaele Bruno, Maria Rita P. Bueno, Huda Bukhari, Jacinta Bustamante, Juan José Cáceres Agra, Ruggero Capra, Raphael Carapito, Maria Carrabba, Carlos Casasnovas, Marion Caseris, Irene Cassaniti, Martin Castelle, Francesco Castelli, Martín Castillo de Vera, Mateus V. Castro, Emilie Catherinot, Jale Bengi Celik, Alessandro Ceschi, Martin Chalumeau, Bruno Charbit, Cécile Boulanger, Père Clavé, Bonaventura Clotet, Anna Codina, Cloé Comarmond, Patrizia Comoli, Angelo G. Corsico, Taner Coşkuner, Aleksandar Cvetkovski, Cyril Cyrus, David Dalmau, François Danion, David Ross Darley, Vincent Das, Nicolas Dauby, Stéphane Dauger, Paul De Munte, Loic de Pontual, Amin Dehban, Geoffroy Delplancq, Isabelle Desguerre, Antonio Di Sabatino, Jean-Luc Diehl, Stephanie Dobbelaere, Elena Domínguez-Garrido, Clément Dubost, Olov Ekwall, Şefika Elmas Bozdemir, Marwa H. Elnagdy, Melike Emiroglu, Akifumi Endo, Emine Hafize Erdeniz, Selma Erol Aytekin, Maria Pilar Etxart Lasa, Romain Euvrard, Giovanna Fabio, Laurence Faivre, Antonin Falck, Muriel Fartoukh, Morgane Faure, Miguel Fernandez Arquero, Ricard Ferrer, Jose Ferreres, Bruno Francois, Victoria Fumadó, Kitty S.C. Fung, Francesca Fusco, Alenka Gagro, Blanca Garcia Solis, Pierre Garçon, Pascale Gaussem, Zeynep Gayretli, Juana Gil-Herrera, Laurent Gilardin, Audrey Giraud Gatineau, Mònica Girona-Alarcón, Karen Alejandra Cifuentes Godínez, Jean-Christophe Goffard, Nacho Gonzales, Luis I. Gonzalez-Granado, Rafaela González-Montelongo, Antoine Guerder, Belgin Gülhan, Victor Daniel Gumucio, Leif Gunnar Hanitsch, Jan Gunst, Marta Gut, Jérôme Hadjadj, Selda Hancerli, Tetyana Hariyan, Nevin Hatipoglu, Deniz Heppekcan, Elisa Hernandez-Brito, Po-ki Ho, María Soledad Holanda-Peña, Juan P. Horcajada, Sami Hraiech, Linda Humbert, Ivan F.N. Hung, Alejandro D. Iglesias, Antonio Íñigo-Campos, Matthieu Jamme, María Jesús Arranz, Marie-Thérèse Jimeno, Iolanda Jordan, Saliha Kanık-Yüksek, Yalcin Kara, Aydın Karahan, Adem Karbuz, Kadriye Kart Yasar, Ozgur Kasapcopur, Kenichi Kashimada, Sevgi Keles, Yasemin Kendir Demirkol, Yasutoshi Kido, Can Kizil, Ahmet Osman Kılıç, Adam Klocperk, Antonia Koutsoukou, Zbigniew J. Król, Hatem Ksouri, Paul Kuentz, Arthur M.C. Kwan, Yat Wah M. Kwan, Janette S.Y. Kwok, Jean-Christophe Lagier, David S.Y. Lam, Vicky Lampropoulou, Fleur Le Bourgeois, Yee-Sin Leo, Rafael Leon Lopez, Daniel Leung, Michael Levin, Michael Levy, Romain Lévy, Zhi Li, Daniele Lilleri, Edson Jose Adrian Bolanos Lima, Agnes Linglart, Eduardo López-Collazo, José M. Lorenzo-Salazar, Céline Louapre, Catherine Lubetzki, Kwok-Cheung Lung, Charles-Edouard Luyt, David C. Lye, Cinthia Magnone, Enrico Marchioni, Carola Marioli, Majid Marjani, Laura Marques, Jesus Marquez Pereira, Andrea Martín-Nalda, David Martínez Pueyo, Javier Martinez-Picado, Iciar Marzana, Carmen Mata-Martínez, Alexis Mathian, Larissa R.B. Matos, Gail V. Matthews, Julien Mayaux, Raquel McLaughlin-Garcia, Philippe Meersseman, Jean-Louis Mège, Armand Mekontso-Dessap, Isabelle Melki, Federica Meloni, Jean-François Meritet, Paolo Merlani, Özge Metin Akcan, Mehdi Mezidi, Isabelle Migeotte, Maude Millereux, Matthieu Million, Tristan Mirault, Clotilde Mircher, Mehdi Mirsaeidi, Yoko Mizoguchi, Bhavi P. Modi, Francesco Mojoli, Elsa Moncomble, Abián Montesdeoca Melián, Antonio Morales Martinez, Francisco Morandeira, Pierre-Emmanuel Morange, Clémence Mordacq, Guillaume Morelle, Stéphane J. Mouly, Adrián Muñoz-Barrera, Cyril Nafati, Shintaro Nagashima, Yu Nakagama, Bénédicte Neven, João Farela Neves, Yuk-Yung Ng, Hubert Nielly, Yeray Novoa Medina, Esmeralda Nuñez Cuadros, Semsi Nur Karabela, J. Gonzalo Ocejo-Vinyals, Mehdi Oualha, Amani Ouedrani, Tayfun Özçelik, Aslinur Ozkaya-Parlakay, Michele Pagani, Maria Papadaki, Philippe Parola, Tiffany Pascreau, Stéphane Paul, Estela Paz-Artal, Sigifredo Pedraza, Nancy Carolina González Pellecer, Silvia Pellegrini, Rebeca Pérez de Diego, Xosé Luis Pérez-Fernández, Aurélien Philippe, Quentin Philippot, Adrien Picod, Marc Pineton de Chambrun, Antonio Piralla, Laura Planas-Serra, Dominique Ploin, Julien Poissy, Géraldine Poncelet, Garyphallia Poulakou, Marie S. Pouletty, Persia Pourshahnazari, Jia Li Qiu-Chen, Paul Quentric, Thomas Rambaud, Didier Raoult, Violette Raoult, Anne-Sophie Rebillat, Claire Redin, Léa Resmini, Pilar Ricart, Jean-Christophe Richard, Raúl Rigo-Bonnin, Nadia Rivet, Jacques G. Rivière, Gemma Rocamora-Blanch, Mathieu P. Rodero, Carlos Rodrigo, Luis Antonio Rodriguez, Carlos Rodriguez-Gallego, Agustí Rodriguez-Palmero, Carolina Soledad Romero, Anya Rothenbuhler, Damien Roux, Nikoletta Rovina, Flore Rozenberg, Yvon Ruch, Montse Ruiz, Maria Yolanda Ruiz del Prado, Juan Carlos Ruiz-Rodriguez, Joan Sabater-Riera, Kai Saks, Maria Salagianni, Oliver Sanchez, Adrián Sánchez-Montalvá, Silvia Sánchez-Ramón, Laire Schidlowski, Agatha Schluter, Julien Schmidt, Matthieu Schmidt, Catharina Schuetz, Cyril E. Schweitzer, Francesco Scolari, Luis Seijo, Analia Gisela Seminario, Piseth Seng, Sevtap Senoglu, Mikko Seppänen, Alex Serra Llovich, Virginie Siguret, Eleni Siouti, David M. Smadja, Nikaia Smith, Ali Sobh, Xavier Solanich, Jordi Solé-Violán, Catherine Soler, Betül Sözeri, Giulia Maria Stella, Yuriy Stepanovskiy, Annabelle Stoclin, Fabio Taccone, Jean-Luc Taupin, Simon J. Tavernier, Loreto Vidaur Tello, Benjamin Terrier, Guillaume Thiery, Karolina Thorn, Caroline Thumerelle, Imran Tipu, Martin Tolstrup, Gabriele Tomasoni, Julie Toubiana, Josep Trenado Alvarez, Vasiliki Triantafyllia, Jesús Troya, Owen T.Y. Tsang, Liina Tserel, Eugene Y.K. Tso, Alessandra Tucci, Şadiye Kübra Tüter Öz, Matilde Valeria Ursini, Takanori Utsumi, Pierre Vabres, Juan Valencia-Ramos, Ana Maria Van Den Rym, Isabelle Vandernoot, Valentina Velez-Santamaria, Silvia Patricia Zuniga Veliz, Mateus C. Vidigal, Sébastien Viel, Cédric Villain, Marie E. Vilaire-Meunier, Judit Villar-García, Audrey Vincent, Dimitri Van der Linden, Alla Volokha, Fanny Vuotto, Els Wauters, Alan K.L. Wu, Tak-Chiu Wu, Aysun Yahşi, Osman Yesilbas, Mehmet Yildiz, Barnaby E. Young, Ufuk Yükselmiş, Marco Zecca, Valentina Zuccaro, Jens Van Praet, Bart N. Lambrecht, Eva Van Braeckel, Cédric Bosteels, Levi Hoste, Eric Hoste, Fré Bauters, Jozefien De Clercq, Catherine Heijmans, Hans Slabbynck, Leslie Naesens, Benoit Florkin, Mary-Anne Young, Amanda Willis, Paloma Lapuente-Suanzes, Ana de Andrés-Martín, Matilda Berkell, Valerio Carelli, Alessia Fiorentino, Surbhi Malhotra, Alessandro Mattiaccio, Tommaso Pippucci, Marco Seri, Evelina Tacconelli, Michiel van Agtmael, Anne Geke Algera, Brent Appelman, Frank van Baarle, Diane Bax, Martijn Beudel, Harm Jan Bogaard, Marije Bomers, Peter Bonta, Lieuwe Bos, Michela Botta, Justin de Brabander, Godelieve de Bree, Sanne de Bruin, David T.P. Buis, Marianna Bugiani, Esther Bulle, Osoul Chouchane, Alex Cloherty, Mirjam Dijkstra, Dave A. Dongelmans, Romein W.G. Dujardin, Paul Elbers, Lucas Fleuren, Suzanne Geerlings, Theo Geijtenbeek, Armand Girbes, Bram Goorhuis, Martin P. Grobusch, Florianne Hafkamp, Laura Hagens, Jorg Hamann, Vanessa Harris, Robert Hemke, Sabine M. Hermans, Leo Heunks, Markus Hollmann, Janneke Horn, Joppe W. Hovius, Menno D. de Jong, Rutger Koning, Endry H.T. Lim, Niels van Mourik, Jeaninne Nellen, Esther J. Nossent, Frederique Paulus, Edgar Peters, Dan A.I. Pina-Fuentes, Tom van der Poll, Bennedikt Preckel, Jan M. Prins, Jorinde Raasveld, Tom Reijnders, Maurits C.F. J. de Rotte, Michiel Schinkel, Marcus J. Schultz, Femke A.P. Schrauwen, Alex Schuurmans, Jaap Schuurmans, Kim Sigaloff, Marleen A. Slim, Patrick Smeele, Marry Smit, Cornelis S. Stijnis, Willemke Stilma, Charlotte Teunissen, Patrick Thoral, Anissa M. Tsonas, Pieter R. Tuinman, Marc van der Valk, Denise P. Veelo, Carolien Volleman, Heder de Vries, Lonneke A. Vught, Michèle van Vugt, Dorien Wouters, A.H. Zwinderman, Matthijs C. Brouwer, W. Joost Wiersinga, Alexander P.J. Vlaar, Miranda F. Tompkins, Camille Alba, Daniel N. Hupalo, John Rosenberger, Gauthaman Sukumar, Matthew D. Wilkerson, Xijun Zhang, Justin Lack, Andrew J. Oler, Kerry Dobbs, Ottavia M. Delmonte, Jeffrey J. Danielson, Andrea Biondi, Laura Rachele Bettini, Mariella D’Angiò, Ilaria Beretta, Luisa Imberti, Alessandra Sottini, Virginia Quaresima, Eugenia Quiros-Roldan, Camillo Rossi, Riccardo Castagnoli, Daniela Montagna, Amelia Licari, and Gian Luigi Marseglia

Subjects
HLA, association, asymptomatic infection, COVID-19, population stratification, Genetics, QH426-470
Abstract

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Published
2024
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17. Comparative analysis of spike-specific IgG Fc glycoprofiles elicited by adenoviral, mRNA, and protein-based SARS-CoV-2 vaccines

Author

Julie Van Coillie, Tamas Pongracz, Tonći Šuštić, Wenjun Wang, Jan Nouta, Mathieu Le Gars, Sofie Keijzer, Federica Linty, Olvi Cristianawati, Jim B.D. Keijser, Remco Visser, Lonneke A. van Vught, Marleen A. Slim, Niels van Mourik, Merel J. Smit, Adam Sander, David E. Schmidt, Maurice Steenhuis, Theo Rispens, Morten A. Nielsen, Benjamin G. Mordmüller, Alexander P.J. Vlaar, C. Ellen van der Schoot, Ramon Roozendaal, Manfred Wuhrer, Gestur Vidarsson, Brent Appelman, Diederik van de Beek, Marije K. Bomers, Justin de Brabander, Matthijs C. Brouwer, David T.P. Buis, Nora Chekrouni, Marit J. van Gils, Menno D. de Jong, Ayesha H.A. Lavell, Sabine E. Olie, Edgar J.G. Peters, Tom D.Y. Reijnders, Michiel Schinkel, Alex R. Schuurman, Jonne J. Sikkens, Yvo M. Smulders, Joost W. Wiersinga, Antinori Spinello, Cinzia Bassoli, Giovanna Bestetti, Mario Corbellino, Alice Covizzi, Angelica Lupo, Laura Milazzo, Marco Schiuma, Alessandro Torre, Willem A. de Jongh, Ali Salanti, Thor G. Theander, Matthew B.B. McCall, and Meral Esen

Subjects
Immunology, Immune response, Microbiology, Glycomics, Science
Abstract

Summary: IgG antibodies are important mediators of vaccine-induced immunity through complement- and Fc receptor-dependent effector functions. Both are influenced by the composition of the conserved N-linked glycan located in the IgG Fc domain. Here, we compared the anti-Spike (S) IgG1 Fc glycosylation profiles in response to mRNA, adenoviral, and protein-based COVID-19 vaccines by mass spectrometry (MS). All vaccines induced a transient increase of antigen-specific IgG1 Fc galactosylation and sialylation. An initial, transient increase of afucosylated IgG was induced by membrane-encoding S protein formulations. A fucose-sensitive ELISA for antigen-specific IgG (FEASI) exploiting FcγRIIIa affinity for afucosylated IgG was used as an orthogonal method to confirm the LC-MS-based afucosylation readout. Our data suggest that vaccine-induced anti-S IgG glycosylation is dynamic, and although variation is seen between different vaccine platforms and individuals, the evolution of glycosylation patterns display marked overlaps.

Published
2023
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