43 results on '"Hannah Kaiser"'
Search Results
2. Does Systemic Anti-Psoriatic Treatment Impact the Risk of Cardiovascular Disease? A Review Over Cardiovascular Imaging Studies
- Author
-
Hannah Kaiser, Charlotte Näslund-Koch, Amanda Kvist-Hansen, and Lone Skov
- Subjects
Psoriasis ,Cardiovascular disease ,Cardiovascular risk ,Cardiovascular imaging ,Treatment ,Biologics ,Dermatology ,RL1-803 - Abstract
Abstract Psoriasis is an immune-mediated inflammatory disease associated with an increased risk of cardiovascular disease (CVD). The risk of CVD increases with the severity of psoriasis, and exposure to systemic inflammation may partly explain the increased risk of CVD in these patients. This raises the question of whether anti-psoriatic treatment, in addition to treating the skin lesions, also lowers the risk of developing CVD. Different types of studies have examined the impact of systemic anti-psoriatic treatments on the risk of CVD in patients with psoriasis and epidemiological observational studies with, e.g., myocardial infarction and stroke as outcomes, and clinical studies investigating circulating inflammatory biomarkers in the blood indicate that anti-psoriatic therapy has a protective effect; however, no randomized controlled trial (RCT) has examined the impact of systemic anti-psoriatic treatment on future hard cardiovascular endpoints. This narrative review provides an overview of the clinical cardiovascular imaging studies examining the effect of systemic anti-psoriatic treatment on the risk of subclinical CVD in patients with psoriasis. We found a total of 24 clinical imaging studies, where 16 of these were observational cohort studies and eight were RCTs. The observational studies suggest an improvement in the risk of subclinical CVD based on different cardiovascular imaging biomarkers; however, the RCTs showed inconsistent results and mainly included vascular inflammation as the outcome. Future RCTs including other imaging biomarkers as surrogates for subclinical CVD, with longer follow-up and with hard cardiovascular endpoints are warranted to address whether systemic anti-psoriatic treatments reduce the risk of CVD.
- Published
- 2024
- Full Text
- View/download PDF
3. Prognostic implications of high-sensitivity cardiac troponin in patients with suspected myocardial infarction with or without psoriasis
- Author
-
Sanaz A. Guldmann, MD, DPhil, Manan Pareek, MD, PhD, Kasper F. Hjuler, MD, PhD, Hannah Kaiser, MD, Kristian Hay Kragholm, MD, PhD, and Alexander Egeberg, MD, PhD, DMSc
- Subjects
cardiovascular disease ,myocardial infarction ,psoriasis ,systemic inflammation ,troponin ,Dermatology ,RL1-803 - Published
- 2023
- Full Text
- View/download PDF
4. Biomarkers of subclinical atherosclerosis in patients with psoriasis
- Author
-
Hannah Kaiser, Xing Wang, Amanda Kvist-Hansen, Martin Krakauer, Peter Michael Gørtz, Benjamin D. McCauley, Lone Skov, Christine Becker, and Peter Riis Hansen
- Subjects
Medicine ,Science - Abstract
Abstract Psoriasis is linked with increased risk of cardiovascular disease (CVD) that is underestimated by traditional risk stratification. We conducted a large-scale plasma proteomic analysis by use of a proximity extension assay in 85 patients with a history of moderate-to-severe psoriasis with or without established atherosclerotic CVD. Differentially expressed proteins associated with CVD were correlated with subclinical atherosclerotic markers including vascular inflammation determined by 18F-fluorodeoxyglucose positron emission tomography/computed tomography, carotid intima-media thickness (CIMT), carotid artery plaques, and coronary artery calcium score (CCS) in the patients without CVD and statin treatment. We also examined the association between the neutrophil-to-lymphocyte ratio (NLR) and subclinical atherosclerosis. In unadjusted analyses, growth differentiation factor-15 (GDF-15) levels and NLR were increased, while tumor necrosis factor (TNF)-related activation-inducing ligand (TRANCE) and TNF-related apoptosis-induced ligand (TRAIL) levels were decreased in patients with established CVD compared to those without CVD. Among patients with psoriasis without CVD and statin treatment, GDF-15 levels were negatively associated with vascular inflammation in the ascending aorta and entire aorta, and positively associated with CIMT and CCS. NLR was positively associated with vascular inflammation in the carotid arteries. Our data suggest that circulating GDF-15 levels and NLR might serve as biomarkers of subclinical atherosclerosis in patients with psoriasis.
- Published
- 2021
- Full Text
- View/download PDF
5. Multiscale Biology of Cardiovascular Risk in Psoriasis: Protocol for a Case-Control Study
- Author
-
Hannah Kaiser, Amanda Kvist-Hansen, Christine Becker, Xing Wang, Benjamin D McCauley, Martin Krakauer, Peter Michael Gørtz, Kristoffer Mads Aaris Henningsen, Claus Zachariae, Lone Skov, and Peter Riis Hansen
- Subjects
Medicine ,Computer applications to medicine. Medical informatics ,R858-859.7 - Abstract
BackgroundPatients with psoriasis have increased risk of cardiovascular disease (CVD) independent of traditional risk factors. The molecular mechanisms underlying the psoriasis-CVD connection are not fully understood. Advances in high-throughput molecular profiling technologies and computational analysis techniques offer new opportunities to improve the understanding of disease connections. ObjectiveWe aim to characterize the complexity of cardiovascular risk in patients with psoriasis by integrating deep phenotypic data with systems biology techniques to perform comprehensive multiomic analyses and construct network models of the two interacting diseases. MethodsThe study aims to include 120 adult patients with psoriasis (60 with prior atherosclerotic CVD and 60 without CVD). Half of the patients are already receiving systemic antipsoriatic treatment. All patients complete a questionnaire, and a medical interview is conducted to collect medical history and information on, for example, socioeconomics, mental health, diet, and physical exercise. Participants are examined clinically with assessment of the Psoriasis Area and Severity Index and undergo imaging by transthoracic echocardiography, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT), and carotid artery ultrasonography. Skin swabs are collected for analysis of microbiome metagenomics; skin biopsies and blood samples are collected for transcriptomic profiling by RNA sequencing; skin biopsies are collected for immunohistochemistry; plasma samples are collected for analyses of proteomics, lipidomics, and metabolomics; blood samples are collected for high-dimensional mass cytometry; and feces samples are collected for gut microbiome metagenomics. Bioinformatics and systems biology techniques are utilized to analyze the multiomic data and to integrate data into a network model of CVD in patients with psoriasis. ResultsRecruitment was completed in September 2020. Preliminary results of 18F-FDG-PET/CT data have recently been published, where vascular inflammation was reduced in the ascending aorta (P=.046) and aortic arch (P=.04) in patients treated with statins and was positively associated with inflammation in the visceral adipose tissue (P
- Published
- 2021
- Full Text
- View/download PDF
6. Characterization of the Oral and Gut Microbiota in Patients with Psoriatic Diseases: A Systematic Review
- Author
-
Tanja Todberg, Hannah Kaiser, Claus Zachariae, Alexander Egeberg, Anne-Sofie Halling, and Lone Skov
- Subjects
psoriasis ,psoriatic arthritis ,microbiota ,immune system ,probiotics ,Dermatology ,RL1-803 - Abstract
Advances in technology have led to an increased number of studies investigating the microbiome in patients with psoriasis. This systematic review examined data regarding the oral and gut microbiota in patients with psoriasis and/or psoriatic arthritis and the effect of probiotics on the microbiota and severity of psoriasis. Of 1,643 studies, 23 were included (22 observational, 1 interventional). Studies examined the microbiota using culture or 16S rRNA gene sequencing analysis. All culture-based studies identified an increased presence of oral Candida in patients with psoriasis, whereas small variations in the oral microbiota were found in a 16S rRNA gene-based study. All 16S rRNA gene sequencing based studies agreed that the gut microbiota of patients with psoriatic disease differed from that of healthy controls, but the results were heterogeneous. Probiotics were associated with a significant improvement in the severity of psoriasis, but did not change microbiota. Overall, studies lacked relevant inclusion criteria and baseline information. In conclusion, the role of the microbiota in patients with psoriasis requires further investigation using more robust methods.
- Published
- 2021
- Full Text
- View/download PDF
7. Statin Therapy and Vascular Inflammation Detected by Positron Emission Tomography/Computed Tomography in Patients with Psoriasis
- Author
-
Hannah Kaiser, Amanda Kvist-Hansen, Martin Krakauer, Peter Michael Gørtz, Kristoffer Mads Aaris Henningsen, Xing Wang, Christine Becker, Lone Skov, and Peter Riis Hansen
- Subjects
psoriasis ,statins ,vascular inflammation ,18f-fdg-pet/ct ,Dermatology ,RL1-803 - Published
- 2021
- Full Text
- View/download PDF
8. IL-17 Pathway Members as Potential Biomarkers of Effective Systemic Treatment and Cardiovascular Disease in Patients with Moderate-to-Severe Psoriasis
- Author
-
Xing Wang, Hannah Kaiser, Amanda Kvist-Hansen, Benjamin D. McCauley, Lone Skov, Peter Riis Hansen, and Christine Becker
- Subjects
psoriasis ,cardiovascular disease ,Olink ,proteomics ,IL-17A ,IL-17C ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Psoriasis is a chronic inflammatory condition associated with atherosclerotic cardiovascular disease (CVD). Systemic anti-psoriatic treatments mainly include methotrexate and biological therapies targeting TNF, IL-12/23 and IL-17A. We profiled plasma proteins from patients with moderate-to-severe psoriasis to explore potential biomarkers of effective systemic treatment and their relationship to CVD. We found that systemically well-treated patients (PASI < 3.0, n = 36) had lower circulating levels of IL-17 pathway proteins compared to untreated patients (PASI > 10, n = 23). Notably, IL-17C and PI3 were decreased with all four examined systemic treatment types. Furthermore, in patients without CVD, we observed strong correlations among IL-17C/PI3/PASI (r ≥ 0.82, p ≤ 1.5 × 10−12) pairs or between IL-17A/PASI (r = 0.72, p = 9.3 × 10−8). In patients with CVD, the IL-17A/PASI correlation was abolished (r = 0.2, p = 0.24) and the other correlations were decreased, e.g., IL-17C/PI3 (r = 0.61, p = 4.5 × 10−5). Patients with moderate-to-severe psoriasis and CVD had lower levels of IL-17A compared to those without CVD (normalized protein expression [NPX] 2.02 vs. 2.55, p = 0.013), and lower IL-17A levels (NPX < 2.3) were associated with higher incidence of CVD (OR = 24.5, p = 0.0028, 95% CI 2.1–1425.1). As a result, in patients with moderate-to-severe psoriasis, we propose circulating IL-17C and PI3 as potential biomarkers of effective systemic anti-psoriatic treatment, and IL-17A as potential marker of CVD.
- Published
- 2022
- Full Text
- View/download PDF
9. Neutrophil Pathways of Inflammation Characterize the Blood Transcriptomic Signature of Patients with Psoriasis and Cardiovascular Disease
- Author
-
Amanda Kvist-Hansen, Hannah Kaiser, Xing Wang, Martin Krakauer, Peter Michael Gørtz, Benjamin D. McCauley, Claus Zachariae, Christine Becker, Peter Riis Hansen, and Lone Skov
- Subjects
psoriasis ,cardiovascular disease ,RNA sequencing ,transcriptome ,neutrophils ,neutrophil to lymphocyte ratio ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Background: Patients with psoriasis have an increased risk of atherosclerotic cardiovascular disease (CVD). The molecular mechanisms behind this connection are not fully understood, but the involvement of neutrophils have drawn attention as a shared inflammatory factor. Methods: RNA sequencing using the Illumina platform was performed on blood from 38 patients with moderate to severe psoriasis; approximately half had prior CVD. The neutrophil to lymphocyte ratio (NLR) was obtained from blood samples. Subclinical atherosclerosis was assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography and ultrasound imaging. Transcriptomic analysis for differential expression and functional enrichment were performed, followed by correlation analyses of differentially expressed genes (DEGs), NLR and subclinical measurers of CVD. Results: 291 genes were differentially expressed between patients with psoriasis with and without CVD. These included 208 upregulated and 83 downregulated DEGs. Neutrophil degranulation was identified as the most significant process related to the upregulated DEGs. Genes for the neutrophil-associated markers MPO, MMP9, LCN2, CEACAM1, CEACAM6 and CEACAM8 were identified as being of special interest and their mRNA levels correlated with NLR, high-sensitive C-reactive protein and markers of subclinical CVD. Conclusions: Patients with psoriasis and CVD had an increased expression of genes related to neutrophil degranulation in their blood transcriptome compared with patients with psoriasis without CVD. NLR may be a potential biomarker of subclinical CVD in psoriasis.
- Published
- 2021
- Full Text
- View/download PDF
10. Association between Vascular Inflammation and Inflammation in Adipose Tissue, Spleen, and Bone Marrow in Patients with Psoriasis
- Author
-
Hannah Kaiser, Amanda Kvist-Hansen, Martin Krakauer, Peter Michael Gørtz, Kristoffer Mads Aaris Henningsen, Xing Wang, Christine Becker, Claus Zachariae, Lone Skov, and Peter Riis Hansen
- Subjects
psoriasis ,cardiovascular disease ,18F-FDG-PET/CT ,vascular inflammation ,adipose tissue ,Science - Abstract
Psoriasis is associated with atherosclerotic cardiovascular disease (CVD) with significant overlap of inflammatory pathways. A link between vascular inflammation and inflammation in multiple adipose tissue types, spleen, and bone marrow may exist. Therefore, we investigated these associations using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in patients with psoriasis (n = 83) where half had established CVD. Carotid ultrasound imaging was also performed. Inflammation was measured by FDG uptake in the aorta, visceral- (VAT), subcutaneous- (SAT), and pericardial (PAT) adipose tissues, and spleen and bone marrow, respectively. Vascular inflammation was associated with FDG uptakes in all adipose tissues, including VAT (β = 0.26; p < 0.001), SAT (β = 0.28; p < 0.001), PAT (β = 0.24; p < 0.001), spleen (β = 1.35; p = 0.001), and bone marrow (β = 1.14; p < 0.001). Adjustments for age, sex, body mass index, and high sensitivity C-reactive protein did not change the results. These associations were generally preserved in the patients without prior CVD. No associations were observed between vascular inflammation and carotid intima-media thickness or presence of carotid plaques, respectively. The results suggest an inflammatory link between vascular and adipose tissues, spleen, and bone marrow in patients with psoriasis.
- Published
- 2021
- Full Text
- View/download PDF
11. Age-dependent effects of UCP2 deficiency on experimental acute pancreatitis in mice.
- Author
-
Sarah Müller, Hannah Kaiser, Burkhard Krüger, Brit Fitzner, Falko Lange, Cristin N Bock, Horst Nizze, Saleh M Ibrahim, Georg Fuellen, Olaf Wolkenhauer, and Robert Jaster
- Subjects
Medicine ,Science - Abstract
Reactive oxygen species (ROS) have been implicated in the pathogenesis of acute pancreatitis (AP) for many years but experimental evidence is still limited. Uncoupling protein 2 (UCP2)-deficient mice are an accepted model of age-related oxidative stress. Here, we have analysed how UCP2 deficiency affects the severity of experimental AP in young and older mice (3 and 12 months old, respectively) triggered by up to 7 injections of the secretagogue cerulein (50 μg/kg body weight) at hourly intervals. Disease severity was assessed at time points from 3 hours to 7 days based on pancreatic histopathology, serum levels of alpha-amylase, intrapancreatic trypsin activation and levels of myeloperoxidase (MPO) in lung and pancreatic tissue. Furthermore, in vitro studies with pancreatic acini were performed. At an age of 3 months, UCP2-/- mice and wild-type (WT) C57BL/6 mice were virtually indistinguishable with respect to disease severity. In contrast, 12 months old UCP2-/- mice developed a more severe pancreatic damage than WT mice at late time points after the induction of AP (24 h and 7 days, respectively), suggesting retarded regeneration. Furthermore, a higher peak level of alpha-amylase activity and gradually increased MPO levels in pancreatic and lung tissue were observed in UCP2-/- mice. Interestingly, intrapancreatic trypsin activities (in vivo studies) and intraacinar trypsin and elastase activation in response to cerulein treatment (in vitro studies) were not enhanced but even diminished in the knockout strain. Finally, UCP2-/- mice displayed a diminished ratio of reduced and oxidized glutathione in serum but no increased ROS levels in pancreatic acini. Together, our data indicate an aggravating effect of UCP2 deficiency on the severity of experimental AP in older but not in young mice. We suggest that increased severity of AP in 12 months old UCP2-/- is caused by an imbalanced inflammatory response but is unrelated to acinar cell functions.
- Published
- 2014
- Full Text
- View/download PDF
12. Prevalence and risk factors for atopic dermatitis in Greenlandic children
- Author
-
Anna M Andersson, Hannah Kaiser, Lone Skov, Anders Koch, and Jacob P Thyssen
- Subjects
Dermatology - Abstract
Background The epidemiology of atopic dermatitis (AD) in Greenland has been sparsely investigated. Aim To examine the point and overall prevalence, cumulative incidence at different ages, and associated risk factors for AD among children in Greenland. Methods Between 2019 and 2020, three towns in Greenland, representing 48% of the total population, were visited. A cross-sectional study was conducted, including children aged 0–7 years attending daycare centres. Parents completed a questionnaire with questions on AD and related risk factors. A diagnosis of AD was based on the UK Working Party’s criteria along with a clinical examination. Results In total, 839 children aged 0–7 years were included. The overall prevalence of AD was 35% according to physician’s diagnosis and assessment. The point prevalence was 28% and peaked among 1-year-old children (36%) and declined with age. The cumulative incidence at ages 1–6 years varied between 29% and 41% and was highest in 1-year-old children and showed a slight decline with increasing age. In the fully adjusted multivariate model, AD was associated with being of Inuit descent [odds ratio (OR) 1.7, 95% confidence interval (CI) 1.1–2.8]; food allergy in the child (OR 3.6, 95% CI 2.3–5.6); ear infection in the child (OR 1.4, 95% CI 1.0–1.9); having a mother with a high educational level (OR 1.5, 95% CI 1.0–2.3); maternal atopy (OR 1.4, 95% CI 1.1–2.0); and paternal atopy (OR 2.0, 95% CI 1.5–2.8). No environmental risk factors were identified. Conclusion The overall prevalence of AD in children in Greenland is high and has likely increased over the past 20 years. The point prevalence was highest in the youngest children indicating early onset of disease. Inuit descent, family atopy predisposition and having a higher socioeconomic status (based on parental educational level and housing) increased the risk of AD. Insight into possible Inuit-specific genetic predisposition is needed.
- Published
- 2022
13. Prognostic implications of high-sensitivity cardiac troponin in patients with suspected myocardial infarction with or without psoriasis
- Author
-
Sanaz A. Guldmann, Manan Pareek, Kasper F. Hjuler, Hannah Kaiser, Kristian Hay Kragholm, and Alexander Egeberg
- Subjects
systemic inflammation ,myocardial infarction ,cardiovascular disease ,troponin ,Dermatology ,psoriasis - Published
- 2023
14. Neutrophil‐to‐lymphocyte ratio and the systemic immune‐inflammation index as potential biomarkers of effective treatment and subclinical atherosclerotic cardiovascular disease in patients with psoriasis
- Author
-
Amanda Kvist‐Hansen, Hannah Kaiser, Martin Krakauer, Peter M. Gørtz, Xing Wang, Christine Becker, Claus Zachariae, Peter R. Hansen, and Lone Skov
- Subjects
Infectious Diseases ,Dermatology - Published
- 2023
15. Lectins enhance SARS-CoV-2 infection and influence neutralizing antibodies
- Author
-
Antonio Lanzavecchia, Lisa A. Purcell, Young-Jun Park, Nuria Izquierdo-Useros, Siro Bianchi, Stefano Jaconi, Marcel Meury, Maria De Agostini, Exequiel Dellota, Davide Corti, Fabio Benigni, David Veesler, Amalio Telenti, Elisabetta Cameroni, Florian A. Lempp, Herbert W. Virgin, Júlia Vergara-Alert, Martin Montiel-Ruiz, Hannah Kaiser, Jiayi Zhou, Javier Martinez-Picado, Anshu Joshi, Julia Noack, Alexandra C. Walls, Leah Soriaga, and John E. Bowen
- Subjects
chemistry.chemical_classification ,Multidisciplinary ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Cell ,Lectin ,Biology ,Neutralization ,Microbiology ,medicine.anatomical_structure ,Enzyme ,chemistry ,medicine ,biology.protein ,Antibody ,Receptor ,hormones, hormone substitutes, and hormone antagonists ,Function (biology) - Abstract
SARS-CoV-2 infection—which involves both cell attachment and membrane fusion—relies on the angiotensin-converting enzyme 2 (ACE2) receptor, which is paradoxically found at low levels in the respiratory tract1–3, suggesting that there may be additional mechanisms facilitating infection. Here we show that C-type lectin receptors, DC-SIGN, L-SIGN and the sialic acid–binding immunoglobulin-like lectin 1 (SIGLEC1) function as attachment receptors by enhancing ACE2-mediated infection and modulating the neutralizing activity of different classes of spike-specific antibodies. Antibodies to the amino-terminal domain or to the conserved site at the base of the receptor-binding domain, while poorly neutralizing infection of ACE2-overexpressing cells, effectively block lectin-facilitated infection. Conversely, antibodies to the receptor binding motif, while potently neutralizing infection of ACE2-overexpressing cells, poorly neutralize infection of cells expressing DC-SIGN or L-SIGN and trigger fusogenic rearrangement of the spike, promoting cell-to-cell fusion. Collectively, these findings identify a lectin-dependent pathway that enhances ACE2-dependent infection by SARS-CoV-2 and reveal distinct mechanisms of neutralization by different classes of spike-specific antibodies. C-type lectins and SIGLEC1 function as attachment receptors for SARS-CoV-2 and enhance ACE2-mediated infection.
- Published
- 2021
16. Imprinted antibody responses against SARS-CoV-2 Omicron sublineages
- Author
-
Young-Jun Park, Dora Pinto, Alexandra C. Walls, Zhuoming Liu, Anna De Marco, Fabio Benigni, Fabrizia Zatta, Chiara Silacci-Fregni, Jessica Bassi, Kaitlin R. Sprouse, Amin Addetia, John E. Bowen, Cameron Stewart, Martina Giurdanella, Christian Saliba, Barbara Guarino, Michael A. Schmid, Nicholas M. Franko, Jennifer K. Logue, Ha V. Dang, Kevin Hauser, Julia di Iulio, William Rivera, Gretja Schnell, Anushka Rajesh, Jiayi Zhou, Nisar Farhat, Hannah Kaiser, Martin Montiel-Ruiz, Julia Noack, Florian A. Lempp, Javier Janer, Rana Abdelnabi, Piet Maes, Paolo Ferrari, Alessandro Ceschi, Olivier Giannini, Guilherme Dias de Melo, Lauriane Kergoat, Hervé Bourhy, Johan Neyts, Leah Soriaga, Lisa A. Purcell, Gyorgy Snell, Sean P. J. Whelan, Antonio Lanzavecchia, Herbert W. Virgin, Luca Piccoli, Helen Y. Chu, Matteo Samuele Pizzuto, Davide Corti, David Veesler, University of Washington [Seattle], Humabs BioMed SA, Washington University School of Medicine [Saint Louis, MO], Vir Biotechnology Inc [San Francisco], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Università della Svizzera italiana = University of Italian Switzerland (USI), Lugano Regional Hospital [Lugano], University of New South Wales [Sydney] (UNSW), University hospital of Zurich [Zurich], Bellinzona Regional Hospital [Bellinzona], Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), University of Texas Southwestern Medical Center [Dallas], and This study was supported by the National Institute of Allergy and Infectious Diseases (DP1AI158186 and HHSN272201700059C to D.V.), a Pew Biomedical Scholars Award (D.V.), an Investigators in the Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund (D.V.), Fast Grants (D.V.), the University of Washington Arnold and Mabel Beckman cryoEM center and the National Institute of Health grant S10OD032290 (to D.V.). S.P.J.W. supported be NIH grant AI163019. D.V. is an Investigator of the Howard Hughes Medical Institute. O.G. is funded by the Swiss Kidney Foundation.
- Subjects
Multidisciplinary ,SARS-CoV-2 ,COVID-19 ,Antibodies, Viral ,Antibodies, Neutralizing ,Article ,Memory B Cells ,Neutralization Tests ,Antibody Formation ,Spike Glycoprotein, Coronavirus ,Humans ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Immunologic Memory ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Immune Evasion - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma-neutralizing antibodies against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5, and that breakthrough infections, but not vaccination alone, induce neutralizing antibodies in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains, whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months after infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant-neutralizing antibody that is a strong candidate for clinical development. ispartof: SCIENCE vol:378 issue:6620 pages:619-+ ispartof: location:United States status: published
- Published
- 2022
17. The potent broadly neutralizing antibody VIR-3434 controls Hepatitis B and D Virus infection and reduces HBsAg in humanized mice
- Author
-
Florian A. Lempp, Tassilo Volz, Elisabetta Cameroni, Fabio Benigni, Jiayi Zhou, Laura E. Rosen, Julia Noack, Fabrizia Zatta, Hannah Kaiser, Siro Bianchi, Gloria Lombardo, Stefano Jaconi, Hasan Imam, Leah B. Soriaga, Nadia Passini, David M. Belnap, Andreas Schulze, Marc Lütgehetmann, Amalio Telenti, Andrea L. Cathcart, Gyorgy Snell, Lisa A. Purcell, Christy M. Hebner, Stephan Urban, Maura Dandri, Davide Corti, and Michael A. Schmid
- Abstract
Background & AimsChronic hepatitis B is a major global public health problem, and coinfection with hepatitis delta virus (HDV) worsens disease outcome. Here, we describe a hepatitis B virus (HBV) surface antigen (HBsAg)-targeting monoclonal antibody (mAb) with the potential to promote functional cure of chronic hepatitis B and D to address this unmet medical need.MethodsHBsAg-specific mAbs were isolated from memory B cells of HBV vaccinated individuals. In vitro neutralization was determined against HBV and HDV enveloped with HBsAg representing eight HBV genotypes. Human liver-chimeric mice were treated twice weekly with a candidate mAb starting three weeks post HBV inoculation (spreading phase) or during stable HBV or HBV/HDV coinfection (chronic phase).ResultsFrom a panel of human anti-HBs mAbs, VIR-3434 was selected and engineered for pre-clinical development. VIR-3434 targets a putative conserved, conformational epitope within the antigenic loop of HBsAg and neutralized HBV and HDV infection with >12,000-fold higher potency than Hepatitis B Immunoglobulins in vitro. Neutralization was pan-genotypic against strains representative of HBV genotypes A-H. In the spreading phase of HBV infection in human liver-chimeric mice, a parental mAb of VIR-3434 (HBC34) prevented HBV dissemination and intrahepatic HBV RNA and cccDNA increase. In the chronic phase of HBV infection or co-infection with HDV, HBC34 treatment decreased circulating HBsAg by >1 log and HDV RNA by >2 logs.ConclusionsThis in vitro and in vivo characterization identified the potent anti-HBs mAb VIR-3434, which reduces circulating HBsAg and HBV/HDV viremia in human liver-chimeric mice. VIR-3434 is currently in clinical development for treatment of patients with chronic hepatitis B or D.Lay summaryChronic infection with hepatitis B virus places approximately 290 million individuals worldwide at risk for severe liver disease and cancer. Currently available treatments result in low rates of functional cure or require lifelong therapy that does not eliminate the risk of liver disease. We isolated and characterized a potent, human antibody that neutralizes hepatitis B and D viruses and reduces infection in a mouse model. This antibody could provide a new treatment for patients with chronic hepatitis B and D.HighlightsIdentification of a human mAb VIR-3434 that potently neutralizes HBV and HDVVIR-3434 targets a conserved, conformational epitope of the HBsAg antigenic loopVIR-3434 treatment blocks intrahepatic HBV spread in human liver-chimeric miceVIR-3434 treatment reduces circulating HBsAg and HDV RNA in co-infected miceData have enabled clinical development of VIR-3434 against chronic hepatitis B/D
- Published
- 2022
18. Assessing progress towards universal health coverage in Cambodia: Evidence using survey data from 2009 to 2019
- Author
-
Andrea Hannah Kaiser, Okore Okorafor, Björn Ekman, Srean Chhim, Sokunthea Yem, and Jesper Sundewall
- Subjects
Health (social science) ,History and Philosophy of Science - Published
- 2023
19. The cost-effectiveness of sexual and reproductive health and rights interventions in low- and middle-income countries: a scoping review
- Author
-
Andrea Hannah, Kaiser, Björn, Ekman, Madeleine, Dimarco, and Jesper, Sundewall
- Subjects
HQ1-2044 ,economic evaluation ,Reproductive Rights ,sexual and reproductive health and rights ,Cost-Benefit Analysis ,Review Article ,universal health coverage ,Diseases of the genitourinary system. Urology ,Reproductive Health ,Pregnancy ,health benefits package ,Humans ,The family. Marriage. Woman ,Female ,scoping review ,RC870-923 ,Sexual Health ,lower- and middle-income countries ,Developing Countries ,cost-effectiveness - Abstract
Sexual and reproductive health and rights (SRHR) are an essential component of universal health coverage (UHC). In determining which SRHR interventions to include in their UHC benefits package, countries are advised to evaluate each service based on robust and reliable data, including cost-effectiveness data. We conducted a scoping review of full economic evaluations of the essential SRHR interventions included in the comprehensive package presented by the Guttmacher-Lancet Commission on SRHR. Of the 462 economic evaluations that met the inclusion criteria, the quantity of publications varied across regions, countries, and the components of the SRHR package, with the majority of publications reporting on HIV/AIDS, reproductive cancer, as well as antenatal care, childbirth, and postnatal care. Systematic reviews are needed for these components in support of more conclusive findings and actionable recommendations for programmes and policy. Further evaluations for interventions included in the remaining components are needed to provide a stronger evidence base for decision-making. The economic evaluations reviewed for this article were inherently varied in their applied methodologies, SRHR interventions and comparators, cost and effectiveness data, and cost-effectiveness thresholds, among others. Despite these differences, the vast majority of publications reported the evaluated SRHR interventions to be cost-effective.
- Published
- 2021
20. Robust and durable prophylactic protection conferred by RNA interference in preclinical models of SARS-CoV-2
- Author
-
Yesseinia I. Anglero-Rodriguez, Florian A. Lempp, James McIninch, Mark K. Schlegel, Christopher R. Brown, Donald J. Foster, Adam B. Castoreno, Tuyen Nguyen, Megha Subramanian, Martin Montiel-Ruiz, Hannah Kaiser, Anna Sahakyan, Roberto Spreafico, Svetlana Shulga Morskaya, Joseph D. Barry, Daniel Berman, Stephanie Lefebvre, Anne Kasper, Timothy Racie, Diann Weddle, Melissa Mobley, Arlin Rogers, Joseph Dybowski, Saeho Chong, Jayaprakash Nair, Amy Simon, Kevin Sloan, Seungmin Hwang, Herbert W. Virgin, Kevin Fitzgerald, Martin A. Maier, Gregory Hinkle, Christy M. Hebner, Akin Akinc, and Vasant Jadhav
- Abstract
RNA interference is a natural antiviral mechanism that could be harnessed to combat SARS-CoV-2 infection by targeting and destroying the viral genome. We screened lipophilic small-interfering RNA (siRNA) conjugates targeting highly conserved regions of the SARS-CoV-2 genome and identified leads targeting outside of the spike-encoding region capable of achieving ≥3-log viral reduction. Serial passaging studies demonstrated that a two-siRNA combination prevented development of resistance compared to a single-siRNA approach. A two-siRNA combination delivered intranasally protected Syrian hamsters from weight loss and lung pathology by viral infection upon prophylactic administration but not following onset of infection. Together, the data support potential utility of RNAi as a prophylactic approach to limit SARS-CoV-2 infection that may help combat emergent variants, complement existing interventions, or protect populations where vaccines are less effective. Most importantly, this strategy has implications for developing medicines that may be valuable in protecting against future coronavirus pandemics.
- Published
- 2022
21. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift
- Author
-
Elisabetta Cameroni, Christian Saliba, John E. Bowen, Laura E. Rosen, Katja Culap, Dora Pinto, Laura A. VanBlargan, Anna De Marco, Samantha K. Zepeda, Julia di Iulio, Fabrizia Zatta, Hannah Kaiser, Julia Noack, Nisar Farhat, Nadine Czudnochowski, Colin Havenar-Daughton, Kaitlin R. Sprouse, Josh R. Dillen, Abigail E. Powell, Alex Chen, Cyrus Maher, Li Yin, David Sun, Leah Soriaga, Jessica Bassi, Chiara Silacci-Fregni, Claes Gustafsson, Nicholas M. Franko, Jenni Logue, Najeeha Talat Iqbal, Ignacio Mazzitelli, Jorge Geffner, Renata Grifantini, Helen Chu, Andrea Gori, Agostino Riva, Olivier Giannini, Alessandro Ceschi, Paolo Ferrari, Pietro Cippà, Alessandra Franzetti-Pellanda, Christian Garzoni, Peter J. Halfmann, Yoshihiro Kawaoka, Christy Hebner, Lisa A. Purcell, Luca Piccoli, Matteo Samuele Pizzuto, Alexandra C. Walls, Michael S. Diamond, Amalio Telenti, Herbert W. Virgin, Antonio Lanzavecchia, David Veesler, Gyorgy Snell, and Davide Corti
- Subjects
COVID-19 Vaccines ,Multidisciplinary ,SARS-CoV-2 ,Antibodies, Monoclonal ,Convalescence ,Vesiculovirus ,Antibodies, Monoclonal, Humanized ,Antibodies, Viral ,Antibodies, Neutralizing ,Article ,Cell Line ,Mice ,Neutralization Tests ,Spike Glycoprotein, Coronavirus ,Animals ,Epitopes, B-Lymphocyte ,Humans ,Angiotensin-Converting Enzyme 2 ,Antigenic Drift and Shift ,Broadly Neutralizing Antibodies ,Immune Evasion - Abstract
SUMMARYThe recently emerged SARS-CoV-2 Omicron variant harbors 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody therapeutics. Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2. Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent individuals. Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb1, retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab2, S2X2593 and S2H974, neutralized Omicron. The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift. Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.
- Published
- 2021
22. Neutrophil Pathways of Inflammation Characterize the Blood Transcriptomic Signature of Patients with Psoriasis and Cardiovascular Disease
- Author
-
Christine Becker, Hannah Kaiser, Lone Skov, Xing Wang, Amanda Kvist-Hansen, Peter Riis Hansen, Benjamin D. McCauley, Claus Zachariae, Martin Krakauer, and Peter Michael Gørtz
- Subjects
Male ,Neutrophils ,Disease ,MMP9 ,Neutrophil Activation ,Transcriptome ,neutrophils ,cardiovascular disease ,Biology (General) ,Spectroscopy ,Subclinical infection ,RNA sequencing ,General Medicine ,psoriasis ,Middle Aged ,Cardiovascular disease ,Prognosis ,Computer Science Applications ,Chemistry ,Cardiovascular Diseases ,Female ,medicine.symptom ,subclinical atherosclerosis ,QH301-705.5 ,Inflammation ,Catalysis ,Article ,Inorganic Chemistry ,Psoriasis ,medicine ,Humans ,Subclinical atherosclerosis ,Physical and Theoretical Chemistry ,Neutrophil to lymphocyte ratio ,neutrophil to lymphocyte ratio ,Molecular Biology ,QD1-999 ,business.industry ,Sequence Analysis, RNA ,Organic Chemistry ,medicine.disease ,Immunology ,Neutrophil degranulation ,business ,transcriptome ,Biomarkers - Abstract
Background: Patients with psoriasis have an increased risk of atherosclerotic cardiovascular disease (CVD). The molecular mechanisms behind this connection are not fully understood, but the involvement of neutrophils have drawn attention as a shared inflammatory factor. Methods: RNA sequencing using the Illumina platform was performed on blood from 38 patients with moderate to severe psoriasis, approximately half had prior CVD. The neutrophil to lymphocyte ratio (NLR) was obtained from blood samples. Subclinical atherosclerosis was assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography and ultrasound imaging. Transcriptomic analysis for differential expression and functional enrichment were performed, followed by correlation analyses of differentially expressed genes (DEGs), NLR and subclinical measurers of CVD. Results: 291 genes were differentially expressed between patients with psoriasis with and without CVD. These included 208 upregulated and 83 downregulated DEGs. Neutrophil degranulation was identified as the most significant process related to the upregulated DEGs. Genes for the neutrophil-associated markers MPO, MMP9, LCN2, CEACAM1, CEACAM6 and CEACAM8 were identified as being of special interest and their mRNA levels correlated with NLR, high-sensitive C-reactive protein and markers of subclinical CVD. Conclusions: Patients with psoriasis and CVD had an increased expression of genes related to neutrophil degranulation in their blood transcriptome compared with patients with psoriasis without CVD. NLR may be a potential biomarker of subclinical CVD in psoriasis.
- Published
- 2021
23. Broad betacoronavirus neutralization by a stem helix-specific human antibody
- Author
-
Megan Smithey, Rana Abdelnabi, John E. Bowen, M. Alejandra Tortorici, Hannah Kaiser, Saiful Islam, Katja Culap, Nicole Sprugasci, Dora Pinto, Herbert W. Virgin, Pietro E. Cippà, Gyorgy Snell, Antonio Lanzavecchia, Olivier Giannini, Michael P. Housley, Nadine Czudnochowski, Fabio Benigni, Barbara Guarino, Amalio Telenti, Johan Neyts, David I. Hong, Roberta Marzi, Antonino Cassotta, Samuele Ceruti, Eneida Vetti, Stefano Jaconi, Julia di Iulio, David Veesler, Laura E. Rosen, Agostino Riva, Chiara Silacci-Fregni, Elisabetta Cameroni, Florian A. Lempp, Alessandro Ceschi, Martina Beltramello, Colin Havenar-Daughton, Jessica Bassi, Lotte Coelmont, Siro Bianchi, Luca Piccoli, Julia Noack, Jun Siong Low, Istvan Bartha, Caroline S. Foo, Maximilian M. Sauer, Davide Corti, Josipa Jerak, Paolo Ferrari, Christian Garzoni, Matteo Samuele Pizzuto, Alexandra C. Walls, and Federica Sallusto
- Subjects
Protein Conformation, alpha-Helical ,Somatic cell ,viruses ,PROTEIN ,ACE2 ,medicine.disease_cause ,Membrane Fusion ,Neutralization ,Jurkat Cells ,0302 clinical medicine ,DOMAIN ,NANOPARTICLE VACCINES ,Cricetinae ,INFECTION ,Lung ,Coronavirus ,chemistry.chemical_classification ,0303 health sciences ,Multidisciplinary ,biology ,virus diseases ,Antibodies, Monoclonal ,Viral Load ,Multidisciplinary Sciences ,Spike Glycoprotein, Coronavirus ,Science & Technology - Other Topics ,CORONAVIRUS SPIKE GLYCOPROTEIN ,Antibody ,medicine.drug_class ,SARS-COV-2 ,Cross Reactions ,Monoclonal antibody ,Peptide Mapping ,03 medical and health sciences ,Betacoronavirus ,Immunoglobulin Fab Fragments ,Neutralization Tests ,medicine ,Animals ,Humans ,030304 developmental biology ,Science & Technology ,IDENTIFICATION ,MUTATIONS ,SARS-CoV-2 ,Lipid bilayer fusion ,Convalescence ,Viral Vaccines ,Virus Internalization ,biology.organism_classification ,Virology ,Antibodies, Neutralizing ,Immunoglobulin Fc Fragments ,chemistry ,biology.protein ,Glycoprotein ,030217 neurology & neurosurgery ,RESPONSES - Abstract
The spillovers of betacoronaviruses in humans and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight the need for broad coronavirus countermeasures. We describe five monoclonal antibodies (mAbs) cross-reacting with the stem helix of multiple betacoronavirus spike glycoproteins isolated from COVID-19 convalescent individuals. Using structural and functional studies, we show that the mAb with the greatest breadth (S2P6) neutralizes pseudotyped viruses from three different subgenera through the inhibition of membrane fusion, and we delineate the molecular basis for its cross-reactivity. S2P6 reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions. Stem helix antibodies are rare, oftentimes of narrow specificity, and can acquire neutralization breadth through somatic mutations. These data provide a framework for structure-guided design of pan-betacoronavirus vaccines eliciting broad protection. ispartof: SCIENCE vol:373 issue:6559 pages:1109-1115 ispartof: location:United States status: published
- Published
- 2021
24. Evaluation of Cell-Based and Surrogate SARS-CoV-2 Neutralization Assays
- Author
-
Peter B. Rupert, Meei-Li Huang, Haiying Zhu, Andrew Fiore-Gartland, Arnold Park, Colleen McLaughlin, Chance Brock, April K. Randhawa, Roland K. Strong, Maurine D. Miner, Yixuan J. Hou, Matthew Buerger, Ralph S. Baric, Emily S Ford, Leonidas Stamatatos, Anton M Sholukh, Hannah Kaiser, Russell St Germain, Florian A. Lempp, Keith R. Jerome, Andrew B. Stuart, Joyce Y C Lu, Emily L Bossard, Bhanupriya Madarampalli, Margaret K. Doll, Jia Jin Kee, Kurt Diem, Lawrence Corey, Longping V. Tse, and David C. Montefiori
- Subjects
Microbiology (medical) ,viruses ,Antibodies, Viral ,Neutralization ,law.invention ,law ,Neutralization Tests ,neutralization assay ,Virology ,antibody ,Chlorocebus aethiops ,Animals ,Humans ,Vero Cells ,biology ,Chemistry ,SARS-CoV-2 ,COVID-19 ,biology.organism_classification ,Antibodies, Neutralizing ,Nucleoprotein ,Titer ,HEK293 Cells ,Vesicular stomatitis virus ,Lentivirus ,Spike Glycoprotein, Coronavirus ,Vero cell ,Recombinant DNA ,biology.protein ,Antibody - Abstract
Determinants of protective immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection require the development of well-standardized, reproducible antibody assays. This need has led to the emergence of a variety of neutralization assays. Head-to-head evaluation of different SARS-CoV-2 neutralization platforms could facilitate comparisons across studies and laboratories. Five neutralization assays were compared using 40 plasma samples from convalescent individuals with mild to moderate coronavirus disease 2019 (COVID-19): four cell-based systems using either live recombinant SARS-CoV-2 or pseudotyped viral particles created with lentivirus (LV) or vesicular stomatitis virus (VSV) packaging and one surrogate enzyme-linked immunosorbent assay (ELISA)-based test that measures inhibition of the spike protein receptor binding domain (RBD) binding its receptor human angiotensin converting enzyme 2 (hACE2). Vero cells, Vero E6 cells, HEK293T cells expressing hACE2, and TZM-bl cells expressing hACE2 and transmembrane serine protease 2 were tested. All cell-based assays showed 50% neutralizing dilution (ND50) geometric mean titers (GMTs) that were highly correlated (Pearson r = 0.81 to 0.89) and ranged within 3.4-fold. The live virus assay and LV pseudovirus assays with HEK293T/hACE2 cells showed very similar mean titers, 141 and 178, respectively. ND50 titers positively correlated with plasma IgG targeting SARS-CoV-2 spike protein and RBD (r = 0.63 to 0.89), but moderately correlated with nucleoprotein IgG (r = 0.46 to 0.73). ND80 GMTs mirrored ND50 data and showed similar correlation between assays and with IgG concentrations. The VSV pseudovirus assay and LV pseudovirus assay with HEK293T/hACE2 cells in low- and high-throughput versions were calibrated against the WHO SARS-CoV-2 IgG standard. High concordance between the outcomes of cell-based assays with live and pseudotyped virions enables valid cross-study comparison using these platforms.
- Published
- 2021
25. Broad sarbecovirus neutralization by a human monoclonal antibody
- Author
-
Jesse D. Bloom, Fabio Benigni, Anna De Marco, Fabrizia Zatta, Laura E. Rosen, Stefano Jaconi, Istvan Bartha, Tyler N. Starr, Michael P. Housley, Elisabetta Cameroni, Julia di Iulio, Gyorgy Snell, Rana Abdelnabi, Davide Corti, Chiara Silacci Fregni, Jiayi Zhou, Katja Culap, Exequiel Dellota, Herbert W. Virgin, Nicole Sprugasci, John E. Bowen, Isabella Giacchetto-Sasselli, M. Alejandra Tortorici, David Veesler, Nadine Czudnochowski, Dora Pinto, Shi Yan Caroline Foo, Martina Beltramello, Colin Havenar-Daughton, Christian Saliba, Zhuoming Liu, Matteo Samuele Pizzuto, Samantha K Zepeda, Hannah Kaiser, Amalio Telenti, Johan Neyts, Roberta Marzi, Martin Montiel-Ruiz, Alexandra C. Walls, Michael A. Schmid, Z. Wang, Sean P. J. Whelan, Barbara Guarino, Eneida Vetti, Florian A. Lempp, and Amin Addetia
- Subjects
education.field_of_study ,Multidisciplinary ,Zoonotic Infection ,biology ,medicine.drug_class ,Population ,biology.organism_classification ,Monoclonal antibody ,Virology ,Epitope ,Antigenic drift ,Article ,Antigen ,medicine ,biology.protein ,Antibody ,education ,Mesocricetus - Abstract
The recent emergence of SARS-CoV-2 variants of concern1-10 and the recurrent spillovers of coronaviruses11,12 into the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here we describe a human monoclonal antibody designated S2X259, which recognizes a highly conserved cryptic epitope of the receptor-binding domain and cross-reacts with spikes from all clades of sarbecovirus. S2X259 broadly neutralizes spike-mediated cell entry of SARS-CoV-2, including variants of concern (B.1.1.7, B.1.351, P.1, and B.1.427/B.1.429), as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of angiotensin-converting enzyme 2 (ACE2) binding to the receptor-binding domain. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses an escape profile that is limited to a single substitution, G504D. We show that prophylactic and therapeutic administration of S2X259 protects Syrian hamsters (Mesocricetus auratus) against challenge with the prototypic SARS-CoV-2 and the B.1.351 variant of concern, which suggests that this monoclonal antibody is a promising candidate for the prevention and treatment of emergent variants and zoonotic infections. Our data reveal a key antigenic site that is targeted by broadly neutralizing antibodies and will guide the design of vaccines that are effective against all sarbecoviruses.
- Published
- 2021
26. SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape
- Author
-
Jason A. Wojcechowskyj, Marcel Meury, Dora Pinto, Exequiel Dellota, Fabio Benigni, Jesse D. Bloom, M. Alejandra Tortorici, Florian A. Lempp, Anna De Marco, Josh Dillen, Christy M. Hebner, Amin Addetia, Fabrizia Zatta, Laura E. Rosen, Elisabetta Cameroni, Nadine Czudnochowski, Amalio Telenti, Johan Neyts, Stefano Jaconi, Allison J. Greaney, Zhuoming Liu, Patrick Hernandez, John E. Bowen, Roberta Marzi, Jiayi Zhou, Maria L. Agostini, Hannah Kaiser, William G. Glass, Rana Abdelnabi, Ivy Zhang, Tristan I. Croll, Adam S. Dingens, Gyorgy Snell, Shi-Yan Caroline Foo, Davide Corti, Luca Piccoli, Martin Montiel-Ruiz, David Veesler, Sean P. J. Whelan, Gloria Lombardo, Herbert W. Virgin, Martina Beltramello, Colin Havenar-Daughton, Spencer Stumpf, Tyler N. Starr, Michael P. Housley, Jessica Bassi, John D. Chodera, Katja Culap, Nicole Sprugasci, Julia di Iulio, Chiara Silacci-Fregni, Matteo Samuele Pizzuto, Alexandra C. Walls, Young-Jun Park, Jay C. Nix, Heather Tucker, Starr, Tyler N [0000-0001-6713-6904], Liu, Zhuoming [0000-0001-8198-0976], Park, Young-Jun [0000-0003-2901-6949], Hernandez, Patrick [0000-0001-9704-5093], Marzi, Roberta [0000-0001-6025-6735], Dingens, Adam S [0000-0001-9603-9409], Bowen, John E [0000-0003-3590-9727], Tortorici, M Alejandra [0000-0002-2260-2577], Walls, Alexandra C [0000-0002-9636-8330], Rosen, Laura E [0000-0002-8030-0219], Zhou, Jiayi [0000-0002-4231-3422], Montiel-Ruiz, Martin [0000-0001-6200-9578], Kaiser, Hannah [0000-0002-3991-7401], Culap, Katja [0000-0002-0956-0018], Jaconi, Stefano [0000-0001-7527-4434], Foo, Shi-Yan Caroline [0000-0002-6380-4917], Nix, Jay C [0000-0002-4041-4975], Havenar-Daughton, Colin [0000-0002-2880-3927], Piccoli, Luca [0000-0002-1085-6502], Neyts, Johan [0000-0002-0033-7514], Telenti, Amalio [0000-0001-6290-7677], Lempp, Florian A [0000-0001-6103-8078], Pizzuto, Matteo S [0000-0001-5776-654X], Chodera, John D [0000-0003-0542-119X], Virgin, Herbert W [0000-0001-8580-7628], Veesler, David [0000-0002-6019-8675], Corti, Davide [0000-0002-5797-1364], Bloom, Jesse D [0000-0003-1267-3408], Snell, Gyorgy [0000-0003-1475-659X], and Apollo - University of Cambridge Repository
- Subjects
Male ,Models, Molecular ,viruses ,Antibody Affinity ,Antibodies, Viral ,Epitope ,Neutralization ,Epitopes ,RESPIRATORY SYNDROME CORONAVIRUS ,Models ,Cricetinae ,Monoclonal ,Viral ,Lung ,Multidisciplinary ,REFINEMENT ,biology ,Effector ,B-Lymphocyte ,Antibodies, Monoclonal ,virus diseases ,Middle Aged ,Spike Glycoprotein ,Multidisciplinary Sciences ,Vaccinology ,5.1 Pharmaceuticals ,Spike Glycoprotein, Coronavirus ,Pneumonia & Influenza ,Science & Technology - Other Topics ,Epitopes, B-Lymphocyte ,Female ,Development of treatments and therapeutic interventions ,Antibody ,Biotechnology ,Adult ,COVID-19 Vaccines ,General Science & Technology ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Cross Reactions ,Antibodies ,Article ,Cell Line ,Vaccine Related ,NEUTRALIZING ANTIBODY ,Biodefense ,Animals ,Humans ,Potency ,Aged ,Immune Evasion ,Science & Technology ,RECEPTOR-BINDING DOMAIN ,SARS-LIKE ,Mesocricetus ,MUTATIONS ,SARS-CoV-2 ,Prevention ,Molecular ,COVID-19 ,Pneumonia ,Virology ,In vitro ,COVID-19 Drug Treatment ,Coronavirus ,Emerging Infectious Diseases ,Good Health and Well Being ,Cell culture ,biology.protein ,Immunization ,Broadly Neutralizing Antibodies ,RESPONSES - Abstract
An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape1–3, have activity against diverse sarbecoviruses4–7, and be highly protective through viral neutralization8–11 and effector functions12,13. Understanding how these properties relate to each other and vary across epitopes would aid the development of therapeutic antibodies and guide vaccine design. Here we comprehensively characterize escape, breadth and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a trade-off between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E128) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth and potency among antibodies that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics. A survey of SARS-CoV-2 RBD antibodies identifies those with activity against diverse SARS-CoV-2 variants and SARS-related coronaviruses, highlighting epitopes and features to prioritize in antibody and vaccine development.
- Published
- 2021
27. Characterization of the Oral and Gut Microbiota in Patients with Psoriatic Diseases: A Systematic Review
- Author
-
Hannah Kaiser, Lone Skov, Claus Zachariae, Anne-Sofie Halling, Tanja Todberg, and Alexander Egeberg
- Subjects
Dermatology ,Gut flora ,digestive system ,Oral Microbiota ,Psoriatic arthritis ,Immune system ,Psoriasis ,RNA, Ribosomal, 16S ,medicine ,microbiota ,Humans ,In patient ,Microbiome ,psoriatic arthritis ,biology ,business.industry ,Microbiota ,Probiotics ,Arthritis, Psoriatic ,General Medicine ,psoriasis ,medicine.disease ,biology.organism_classification ,Gastrointestinal Microbiome ,stomatognathic diseases ,immune system ,probiotics ,RL1-803 ,Immunology ,16s rrna gene sequencing ,business - Abstract
Advances in technology have led to an increased number of studies investigating the microbiome in patients with psoriasis. This systematic review examined data regarding the oral and gut microbiota in patients with psoriasis and/or psoriatic arthritis and the effect of probiotics on the microbiota and severity of psoriasis. Of 1,643 studies, 23 were included (22 observational, 1 interventional). Studies examined the microbiota using culture or 16S rRNA gene sequencing analysis. All culture-based studies identified an increased presence of oral Candida in patients with psoriasis, whereas small variations in the oral microbiota were found in a 16S rRNA gene-based study. All 16S rRNA gene sequencing based studies agreed that the gut microbiota of patients with psoriatic disease differed from that of healthy controls, but the results were heterogeneous. Probiotics were associated with a significant improvement in the severity of psoriasis, but did not change microbiota. Overall, studies lacked relevant inclusion criteria and baseline information. In conclusion, the role of the microbiota in patients with psoriasis requires further investigation using more robust methods.
- Published
- 2021
28. Multiscale Biology of Cardiovascular Risk in Psoriasis: Protocol for a Case-Control Study (Preprint)
- Author
-
Hannah Kaiser, Amanda Kvist-Hansen, Christine Becker, Xing Wang, Benjamin D McCauley, Martin Krakauer, Peter Michael Gørtz, Kristoffer Mads Aaris Henningsen, Claus Zachariae, Lone Skov, and Peter Riis Hansen
- Abstract
BACKGROUND Patients with psoriasis have increased risk of cardiovascular disease (CVD) independent of traditional risk factors. The molecular mechanisms underlying the psoriasis-CVD connection are not fully understood. Advances in high-throughput molecular profiling technologies and computational analysis techniques offer new opportunities to improve the understanding of disease connections. OBJECTIVE We aim to characterize the complexity of cardiovascular risk in patients with psoriasis by integrating deep phenotypic data with systems biology techniques to perform comprehensive multiomic analyses and construct network models of the two interacting diseases. METHODS The study aims to include 120 adult patients with psoriasis (60 with prior atherosclerotic CVD and 60 without CVD). Half of the patients are already receiving systemic antipsoriatic treatment. All patients complete a questionnaire, and a medical interview is conducted to collect medical history and information on, for example, socioeconomics, mental health, diet, and physical exercise. Participants are examined clinically with assessment of the Psoriasis Area and Severity Index and undergo imaging by transthoracic echocardiography, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT), and carotid artery ultrasonography. Skin swabs are collected for analysis of microbiome metagenomics; skin biopsies and blood samples are collected for transcriptomic profiling by RNA sequencing; skin biopsies are collected for immunohistochemistry; plasma samples are collected for analyses of proteomics, lipidomics, and metabolomics; blood samples are collected for high-dimensional mass cytometry; and feces samples are collected for gut microbiome metagenomics. Bioinformatics and systems biology techniques are utilized to analyze the multiomic data and to integrate data into a network model of CVD in patients with psoriasis. RESULTS Recruitment was completed in September 2020. Preliminary results of 18F-FDG-PET/CT data have recently been published, where vascular inflammation was reduced in the ascending aorta (P=.046) and aortic arch (P=.04) in patients treated with statins and was positively associated with inflammation in the visceral adipose tissue (PP=.007), pericardial adipose tissue (PP=.001), and bone marrow (P CONCLUSIONS This systems biology approach with integration of multiomics and clinical data in patients with psoriasis with or without CVD is likely to provide novel insights into the biological mechanisms underlying these diseases and their interplay that can impact future treatment. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/28669
- Published
- 2021
29. Multiscale Biology of Cardiovascular Risk in Psoriasis: Protocol for a Case-Control Study
- Author
-
Peter Riis Hansen, Christine Becker, Peter Michael Gørtz, Lone Skov, Amanda Kvist-Hansen, Claus Zachariae, Kristoffer Mads Aaris Henningsen, Hannah Kaiser, Xing Wang, Benjamin D. McCauley, and Martin Krakauer
- Subjects
Oncology ,Proteomics ,mass cytometry ,medicine.medical_specialty ,System biology ,Bioinformatics ,Adipose tissue ,microbiome ,Disease ,Biology ,proteomics ,Psoriasis Area and Severity Index ,cardiovascular disease ,Internal medicine ,Psoriasis ,Study protocol ,medicine ,Protocol ,Mass cytometry ,Medical history ,Microbiome ,cardiovascular imaging ,system biology ,Case-control study ,General Medicine ,psoriasis ,bioinformatics ,medicine.disease ,Cardiovascular disease ,Cardiovascular imaging ,Lipidomics ,lipidomics ,study protocol - Abstract
Background Patients with psoriasis have increased risk of cardiovascular disease (CVD) independent of traditional risk factors. The molecular mechanisms underlying the psoriasis-CVD connection are not fully understood. Advances in high-throughput molecular profiling technologies and computational analysis techniques offer new opportunities to improve the understanding of disease connections. Objective We aim to characterize the complexity of cardiovascular risk in patients with psoriasis by integrating deep phenotypic data with systems biology techniques to perform comprehensive multiomic analyses and construct network models of the two interacting diseases. Methods The study aims to include 120 adult patients with psoriasis (60 with prior atherosclerotic CVD and 60 without CVD). Half of the patients are already receiving systemic antipsoriatic treatment. All patients complete a questionnaire, and a medical interview is conducted to collect medical history and information on, for example, socioeconomics, mental health, diet, and physical exercise. Participants are examined clinically with assessment of the Psoriasis Area and Severity Index and undergo imaging by transthoracic echocardiography, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT), and carotid artery ultrasonography. Skin swabs are collected for analysis of microbiome metagenomics; skin biopsies and blood samples are collected for transcriptomic profiling by RNA sequencing; skin biopsies are collected for immunohistochemistry; plasma samples are collected for analyses of proteomics, lipidomics, and metabolomics; blood samples are collected for high-dimensional mass cytometry; and feces samples are collected for gut microbiome metagenomics. Bioinformatics and systems biology techniques are utilized to analyze the multiomic data and to integrate data into a network model of CVD in patients with psoriasis. Results Recruitment was completed in September 2020. Preliminary results of 18F-FDG-PET/CT data have recently been published, where vascular inflammation was reduced in the ascending aorta (P=.046) and aortic arch (P=.04) in patients treated with statins and was positively associated with inflammation in the visceral adipose tissue (P Conclusions This systems biology approach with integration of multiomics and clinical data in patients with psoriasis with or without CVD is likely to provide novel insights into the biological mechanisms underlying these diseases and their interplay that can impact future treatment. International Registered Report Identifier (IRRID) DERR1-10.2196/28669
- Published
- 2021
30. The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2
- Author
-
Andrea L. Cathcart, Colin Havenar-Daughton, Florian A. Lempp, Daphne Ma, Michael A. Schmid, Maria L. Agostini, Barbara Guarino, Julia Di iulio, Laura E. Rosen, Heather Tucker, Joshua Dillen, Sambhavi Subramanian, Barbara Sloan, Siro Bianchi, Dora Pinto, Christian Saliba, Katja Culap, Jason A Wojcechowskyj, Julia Noack, Jiayi Zhou, Hannah Kaiser, Sooyoung Lee, Nisar Farhat, Arthur Chase, Martin Montiel-Ruiz, Exequiel Dellota, Arnold Park, Roberto Spreafico, Anna Sahakyan, Elvin J. Lauron, Nadine Czudnochowski, Elisabetta Cameroni, Sarah Ledoux, Yoshihiro Kawaoka, Adam Werts, Christophe Colas, Leah Soriaga, Amalio Telenti, Lisa A. Purcell, Seungmin Hwang, Gyorgy Snell, Herbert W. Virgin, Davide Corti, and Christy M. Hebner
- Subjects
medicine.drug_class ,biochemical phenomena, metabolism, and nutrition ,Biology ,Monoclonal antibody ,Virology ,Fragment crystallizable region ,Virus ,Epitope ,In vitro ,In vivo ,medicine ,biology.protein ,bacteria ,Antibody ,Viral load - Abstract
VIR-7831 and VIR-7832 are dual action monoclonal antibodies (mAbs) targeting the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). VIR-7831 and VIR-7832 were derived from a parent antibody (S309) isolated from memory B cells of a 2003 severe acute respiratory syndrome coronavirus (SARS-CoV) survivor. Both mAbs contain an “LS” mutation in the Fc region to prolong serum half-life and potentially enhance distribution to the respiratory mucosa. In addition, VIR-7832 encodes an Fc GAALIE mutation that has been shown previously to evoke CD8+ T-cells in the context of an in vivo viral respiratory infection. VIR-7831 and VIR-7832 potently neutralize wild-type and variant authentic virus in vitro as well as variant pseudotyped viruses. In addition, they retain activity against monoclonal antibody resistance mutations conferring reduced susceptibility to currently authorized mAbs. The VIR-7831/VIR-7832 epitope does not overlap with mutational sites in current variants of concern and continues to be highly conserved among circulating sequences consistent with the high barrier to resistance observed in vitro. Furthermore, both mAbs can recruit effector mechanisms in vitro that may contribute to clinical efficacy via elimination of infected host cells. In vitro studies with these mAbs demonstrated no enhancement of infection. In a Syrian Golden hamster proof-of concept wildtype SARS-CoV-2 infection model, animals treated with VIR-7831 had less weight loss, and significantly decreased total viral load and infectious virus levels in the lung compared to a control mAb. Taken together, these data indicate that VIR-7831 and VIR-7832 are promising new agents in the fight against COVID-19.
- Published
- 2021
31. Association between Vascular Inflammation and Inflammation in Adipose Tissue, Spleen, and Bone Marrow in Patients with Psoriasis
- Author
-
Amanda Kvist-Hansen, Martin Krakauer, Kristoffer Mads Aaris Henningsen, Christine Becker, Hannah Kaiser, Xing Wang, Claus Zachariae, Peter Riis Hansen, Lone Skov, and Peter Michael Gørtz
- Subjects
Pathology ,medicine.medical_specialty ,18F-FDG-PET/CT ,Adipose tissue ,Spleen ,Inflammation ,F-FDG-PET/CT ,030204 cardiovascular system & hematology ,General Biochemistry, Genetics and Molecular Biology ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,cardiovascular disease ,medicine.artery ,Psoriasis ,medicine ,vascular inflammation ,lcsh:Science ,Vascular inflammation ,Ecology, Evolution, Behavior and Systematics ,Aorta ,medicine.diagnostic_test ,business.industry ,Communication ,Paleontology ,psoriasis ,Cardiovascular disease ,medicine.disease ,adipose tissue ,medicine.anatomical_structure ,Space and Planetary Science ,Positron emission tomography ,lcsh:Q ,Bone marrow ,medicine.symptom ,business ,Body mass index - Abstract
Psoriasis is associated with atherosclerotic cardiovascular disease (CVD) with significant overlap of inflammatory pathways. A link between vascular inflammation and inflammation in multiple adipose tissue types, spleen, and bone marrow may exist. Therefore, we investigated these associations using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in patients with psoriasis (n = 83) where half had established CVD. Carotid ultrasound imaging was also performed. Inflammation was measured by FDG uptake in the aorta, visceral- (VAT), subcutaneous- (SAT), and pericardial (PAT) adipose tissues, and spleen and bone marrow, respectively. Vascular inflammation was associated with FDG uptakes in all adipose tissues, including VAT (β = 0.26; p < 0.001), SAT (β = 0.28; p < 0.001), PAT (β = 0.24; p < 0.001), spleen (β = 1.35; p = 0.001), and bone marrow (β = 1.14; p < 0.001). Adjustments for age, sex, body mass index, and high sensitivity C-reactive protein did not change the results. These associations were generally preserved in the patients without prior CVD. No associations were observed between vascular inflammation and carotid intima-media thickness or presence of carotid plaques, respectively. The results suggest an inflammatory link between vascular and adipose tissues, spleen, and bone marrow in patients with psoriasis.
- Published
- 2021
32. Statin Therapy and Vascular Inflammation Detected by Positron Emission Tomography/Computed Tomography in Patients with Psoriasis
- Author
-
Christine Becker, Kristoffer Mads Aaris Henningsen, Hannah Kaiser, Lone Skov, Xing Wang, Amanda Kvist-Hansen, Peter Riis Hansen, Martin Krakauer, and Peter Michael Gørtz
- Subjects
medicine.medical_specialty ,Dermatology ,statins ,Fluorodeoxyglucose F18 ,Psoriasis ,Positron Emission Tomography Computed Tomography ,Medicine ,Humans ,vascular inflammation ,In patient ,Positron Emission Tomography-Computed Tomography ,Inflammation ,18f-fdg-pet/ct ,business.industry ,Vascular inflammation ,General Medicine ,psoriasis ,medicine.disease ,Positron-Emission Tomography ,RL1-803 ,Fdg pet ct ,Statin therapy ,Radiology ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Radiopharmaceuticals ,business - Published
- 2021
33. Lectins enhance SARS-CoV-2 infection and influence neutralizing antibodies
- Author
-
Florian A, Lempp, Leah B, Soriaga, Martin, Montiel-Ruiz, Fabio, Benigni, Julia, Noack, Young-Jun, Park, Siro, Bianchi, Alexandra C, Walls, John E, Bowen, Jiayi, Zhou, Hannah, Kaiser, Anshu, Joshi, Maria, Agostini, Marcel, Meury, Exequiel, Dellota, Stefano, Jaconi, Elisabetta, Cameroni, Javier, Martinez-Picado, Júlia, Vergara-Alert, Nuria, Izquierdo-Useros, Herbert W, Virgin, Antonio, Lanzavecchia, David, Veesler, Lisa A, Purcell, Amalio, Telenti, and Davide, Corti
- Subjects
SARS-CoV-2 ,Sialic Acid Binding Ig-like Lectin 1 ,Receptors, Cell Surface ,Antibodies, Neutralizing ,Membrane Fusion ,Cell Line ,Cell Fusion ,Cricetinae ,Lectins ,Spike Glycoprotein, Coronavirus ,Animals ,Humans ,Female ,Lectins, C-Type ,Angiotensin-Converting Enzyme 2 ,Cell Adhesion Molecules - Abstract
SARS-CoV-2 infection-which involves both cell attachment and membrane fusion-relies on the angiotensin-converting enzyme 2 (ACE2) receptor, which is paradoxically found at low levels in the respiratory tract(1-3), suggesting that there may be additional mechanisms facilitating infection. Here we show that C-type lectin receptors, DC-SIGN, L-SIGN and the sialic acid-binding immunoglobulin-like lectin 1 (SIGLEC1) function as attachment receptors by enhancing ACE2-mediated infection and modulating the neutralizing activity of different classes of spike-specific antibodies. Antibodies to the amino-terminal domain or to the conserved site at the base of the receptor-binding domain, while poorly neutralizing infection of ACE2-overexpressing cells, effectively block lectin-facilitated infection. Conversely, antibodies to the receptor binding motif, while potently neutralizing infection of ACE2-overexpressing cells, poorly neutralize infection of cells expressing DC-SIGN or L-SIGN and trigger fusogenic rearrangement of the spike, promoting cell-to-cell fusion. Collectively, these findings identify a lectin-dependent pathway that enhances ACE2-dependent infection by SARS-CoV-2 and reveal distinct mechanisms of neutralization by different classes of spike-specific antibodies.
- Published
- 2021
34. Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms
- Author
-
Ha V. Dang, Andrea Minola, Michael A. Schmid, Cindy Ng, Rana Abdelnabi, Matthew McCallum, David Veesler, Heather Tucker, Alessia Peter, Michael S. Diamond, Katja Culap, Josh Dillen, Nicole Sprugasci, Jiayi Zhou, Martin Montiel-Ruiz, Hannah Kaiser, James Brett Case, M. Alejandra Tortorici, Roberto Spreafico, Marcel Meury, Siro Bianchi, Herbert W. Virgin, Jason A. Wojcechowskyj, Elisabetta Cameroni, John E. Bowen, Agostino Riva, Fabio Benigni, G. Snell, Massimo Galli, Barbara Guarino, Martina Beltramello, Colin Havenar-Daughton, Matteo Samuele Pizzuto, Stefano Jaconi, Davide Corti, Anna De Marco, Arianna Gabrieli, Rita E. Chen, Florian A. Lempp, Laura E. Rosen, Shi Yan Caroline Foo, Elvin J. Lauron, Katja Fink, Nadine Czudnochowski, Dora Pinto, Johan Neyts, and Fabrizia Zatta
- Subjects
0301 basic medicine ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,viruses ,Protein domain ,Mutant ,Amino Acid Motifs ,Pneumonia, Viral ,Immunology ,CHO Cells ,Biology ,Peptidyl-Dipeptidase A ,Antibodies, Viral ,Epitope ,03 medical and health sciences ,Betacoronavirus ,0302 clinical medicine ,Cricetulus ,Protein Domains ,Cricetinae ,Animals ,Humans ,Pandemics ,Research Articles ,Multidisciplinary ,Immunodominant Epitopes ,SARS-CoV-2 ,Chinese hamster ovary cell ,R-Articles ,HEK 293 cells ,fungi ,Cryoelectron Microscopy ,COVID-19 ,Biochem ,biology.organism_classification ,Virology ,Antibodies, Neutralizing ,Microscopy, Electron ,030104 developmental biology ,HEK293 Cells ,Spike Glycoprotein, Coronavirus ,biology.protein ,Angiotensin-Converting Enzyme 2 ,Antibody ,Coronavirus Infections ,030217 neurology & neurosurgery ,Research Article - Abstract
A strong cocktail against SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by the trimeric spike protein that decorates the virus and binds the ACE2 receptor. Antibodies against the spike that neutralize viral infection have potential as therapeutics. Tortorici et al. describe two very potent antibodies, S2E12 and S2M11. Electron microscopy structures characterized the binding and showed that S2E12 traps the spike in a conformation that cannot bind ACE2. Both antibodies protected hamsters against SARS-CoV-2 challenge and may be useful in antibody cocktails to combat the virus and prevent the development of resistance. Science, this issue p. 950, A potent antibody cocktail blocks attachment of SARS-CoV-2 to the host receptor and activates a protective immune response., Efficient therapeutic options are needed to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has caused more than 922,000 fatalities as of 13 September 2020. We report the isolation and characterization of two ultrapotent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that protect hamsters against SARS-CoV-2 challenge. Cryo–electron microscopy structures show that S2E12 and S2M11 competitively block angiotensin-converting enzyme 2 (ACE2) attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Antibody cocktails that include S2M11, S2E12, or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions. Our results pave the way to implement antibody cocktails for prophylaxis or therapy, circumventing or limiting the emergence of viral escape mutants.
- Published
- 2020
35. Availability, prices and affordability of essential medicines for treatment of diabetes and hypertension in private pharmacies in Zambia
- Author
-
Warren Mukelabai Simangolwa, Andrea Hannah Kaiser, Birger C Forsberg, Lindsey Hehman, and Jesper Sundewall
- Subjects
Cross-sectional study ,Economics ,Social Sciences ,Blood Pressure ,030204 cardiovascular system & hematology ,Pharmacists ,Biochemistry ,Vascular Medicine ,Essential medicines ,Health Services Accessibility ,Geographical Locations ,0302 clinical medicine ,Endocrinology ,Per capita ,Medicine and Health Sciences ,Salaries ,Insulin ,Public and Occupational Health ,030212 general & internal medicine ,Medical Personnel ,health care economics and organizations ,Extreme poverty ,Multidisciplinary ,Standard treatment ,Commerce ,Drugs ,Socioeconomic Aspects of Health ,Professions ,Hypertension ,Costs and Cost Analysis ,Medicine ,Private Sector ,Drugs, Essential ,Research Article ,Endocrine Disorders ,Science ,MEDLINE ,Zambia ,Pharmacy ,03 medical and health sciences ,Environmental health ,Diabetes Mellitus ,Humans ,Hypoglycemic Agents ,Antihypertensive Agents ,Pharmacology ,Diabetic Endocrinology ,Pharmacies ,business.industry ,Biology and Life Sciences ,Hormones ,Health Care ,Cross-Sectional Studies ,Metabolic Disorders ,Labor Economics ,People and Places ,Africa ,Household income ,Population Groupings ,business ,Antihypertensives - Abstract
Objectives To explore availability, prices and affordability of essential medicines for diabetes and hypertension treatment in private pharmacies in three provinces of Zambia. Methods A cross-sectional survey was conducted in 99 pharmacies across three Zambian provinces. Methods were based on a standardized methodology by the World Health Organization and Health Action International. Availability was analysed as mean availability per pharmacy and individual medicine. Median prices were compared to international reference prices and differences in price between medicine forms (original brand or generic product) were computed. Affordability was assessed as number of days’ salaries required to purchase a standard treatment course using the absolute poverty line and mean per capita provincial household income as standard. An analysis identifying medicines considered both available and affordable was conducted. Results Two antidiabetics and nine antihypertensives had high-level availability (≥80%) in all provinces; availability levels for the remaining surveyed antidiabetics and antihypertensives were largely found below 50%. Availability further varied markedly across medicines and medicine forms. Prices for most medicines were higher than international reference prices and great price variations were found between pharmacies, medicines and medicine forms. Compared to original brand products, purchase of generics was associated with price savings for patients between 21.54% and 96.47%. No medicine was affordable against the absolute poverty line and only between four and eleven using mean per capita provincial incomes. Seven generics in Copperbelt/Lusaka and two in Central province were highly available and affordable. Conclusions The study showed that the majority of surveyed antidiabetic and antihypertensive medicines was inadequately available (
- Published
- 2019
36. Coronary Artery Disease Assessed by Computed Tomography in Patients with Psoriasis: A Systematic Review and Meta-Analysis
- Author
-
Hannah Kaiser, Jawdat Abdulla, Peter Riis Hansen, Kristoffer Mads Aaris Henningsen, and Lone Skov
- Subjects
medicine.medical_specialty ,Computed Tomography Angiography ,Dermatology ,Disease ,Coronary Artery Disease ,Coronary artery disease ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Psoriasis ,medicine ,Prevalence ,Humans ,In patient ,Subclinical infection ,business.industry ,medicine.disease ,Coronary Vessels ,Coronary Calcium Score ,030220 oncology & carcinogenesis ,Meta-analysis ,Relative risk ,Case-Control Studies ,Calcium ,business - Abstract
Background: Patients with psoriasis have an increased risk of coronary artery disease (CAD) but data on coronary calcium score (CCS) and cardiac computed tomography angiography (CCTA) are inconsistent. Objectives: The present study quantitatively summarizes the literature data on the prevalence and burden of CAD in patients with psoriasis compared with controls using CCS and CCTA. Methods: A systematic review and meta-analysis was conducted. The search included all studies examining CAD prevalence and burden detected by CCS with or without CCTA in patients with psoriasis without prior CAD compared with controls, between the year 2000 and May 30, 2018. Results: Fourteen eligible studies provided data on 1,427 patients with psoriasis and 9,670 controls. Pooled data provided the estimated risk ratio (RR) of CAD and weighted mean differences of CCS in psoriasis patients versus controls. Meta-analysis of the prevalence and burden of CCS showed that patients with psoriasis had an increased risk of CAD (RR 1.14, 95% CI 1.04–1.26; p = 0.004), and for more severe CAD (CCS >100) the risk was further increased (RR 1.71, 95% CI 1.28–2.30; p < 0.001) compared with controls. Weighted mean difference for CCS was significantly higher in patients with psoriasis (12.74, 95% CI 10.70–14.78; p < 0.001). The risk of high-risk coronary plaques identified by CCTA was also significantly higher in psoriasis patients compared with controls (RR 1.77, 95% CI 1.37–2.28; p < 0.001). Conclusions: Patients with psoriasis have a higher prevalence of subclinical CAD, a higher burden of the disease, and more high-risk coronary plaques compared with controls without psoriasis.
- Published
- 2019
37. In vitro and in vivo characterization of VIR-2218, an investigational RNAi therapeutic targeting hepatitis B virus
- Author
-
Yesseinia Anglero-Rodriguez, Florian Lempp, Abigail Liebow, Tuyen Nguyen, Sarah LeBlanc, Charalambos Kaittanis, Joseph Barry, Adam Castoreno, Jonathan Gall, Hannah Kaiser, Christy Hebner, Stuart Milstein, Vasant Jadhav, and Anna Bakardjiev
- Subjects
Hepatology - Published
- 2020
38. A Single Pair of Serotonergic Neurons Counteracts Serotonergic Inhibition of Ethanol Attraction in Drosophila
- Author
-
Andrea Hannah Kaiser, Jianzheng He, Henrike Scholz, Li Xu, Yvonne Ritze, Nikolaus Gräber, and Laura Schläger
- Subjects
0301 basic medicine ,Olfactory system ,Light ,lcsh:Medicine ,Biochemistry ,Animals, Genetically Modified ,0302 clinical medicine ,Cognition ,Animal Cells ,Drosophila Proteins ,lcsh:Science ,Serotonin transporter ,Serotonin Plasma Membrane Transport Proteins ,Neurons ,Light Pulses ,Multidisciplinary ,Microscopy, Confocal ,Organic Compounds ,Drosophila Melanogaster ,Physics ,Electromagnetic Radiation ,Brain ,Neurochemistry ,Olfactory Pathways ,Neurotransmitters ,Animal Models ,Attraction ,Smell ,Insects ,Chemistry ,Physical Sciences ,Drosophila ,Drosophila melanogaster ,Cellular Types ,Serotonergic Neurons ,Research Article ,Biogenic Amines ,Serotonin ,Visible Light ,Synaptic cleft ,Arthropoda ,Decision Making ,Biology ,Serotonergic ,Research and Analysis Methods ,Olfactory Receptor Neurons ,03 medical and health sciences ,Model Organisms ,ddc:570 ,Humans ,Animals ,Ethanol ,Organic Chemistry ,lcsh:R ,Chemical Compounds ,Organisms ,Correction ,Biology and Life Sciences ,Afferent Neurons ,Cell Biology ,biology.organism_classification ,Invertebrates ,030104 developmental biology ,Cellular Neuroscience ,Alcohols ,Odorants ,biology.protein ,Cognitive Science ,lcsh:Q ,Neuroscience ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Attraction to ethanol is common in both flies and humans, but the neuromodulatory mechanisms underlying this innate attraction are not well understood. Here, we dissect the function of the key regulator of serotonin signaling-the serotonin transporter-in innate olfactory attraction to ethanol in Drosophila melanogaster. We generated a mutated version of the serotonin transporter that prolongs serotonin signaling in the synaptic cleft and is targeted via the Gal4 system to different sets of serotonergic neurons. We identified four serotonergic neurons that inhibit the olfactory attraction to ethanol and two additional neurons that counteract this inhibition by strengthening olfactory information. Our results reveal that compensation can occur on the circuit level and that serotonin has a bidirectional function in modulating the innate attraction to ethanol. Given the evolutionarily conserved nature of the serotonin transporter and serotonin, the bidirectional serotonergic mechanisms delineate a basic principle for how random behavior is switched into targeted approach behavior.
- Published
- 2016
39. Age-dependent effects of UCP2 deficiency on experimental acute pancreatitis in mice
- Author
-
Robert Jaster, Burkhard Krüger, Olaf Wolkenhauer, Horst Nizze, Saleh M. Ibrahim, Falko Lange, Brit Fitzner, Hannah Kaiser, Georg Fuellen, Sarah Müller, and Cristin N. Bock
- Subjects
Male ,Aging ,Physiology ,lcsh:Medicine ,medicine.disease_cause ,Pathology and Laboratory Medicine ,Severity of Illness Index ,Biochemistry ,Ion Channels ,Mice ,Medicine and Health Sciences ,Trypsin ,Uncoupling Protein 2 ,lcsh:Science ,Lung ,Ceruletide ,Mice, Knockout ,Multidisciplinary ,biology ,Pancreatitis, Acute Necrotizing ,Elastase ,Age Factors ,Animal Models ,Glutathione ,medicine.anatomical_structure ,Myeloperoxidase ,Acute pancreatitis ,Female ,Anatomy ,Pancreas ,Research Article ,medicine.medical_specialty ,Histopathology ,Endocrine System ,Mouse Models ,Gastroenterology and Hepatology ,Research and Analysis Methods ,Mitochondrial Proteins ,Model Organisms ,Diagnostic Medicine ,Internal medicine ,Acinar cell ,medicine ,Animals ,Peroxidase ,lcsh:R ,Biology and Life Sciences ,Proteins ,medicine.disease ,Mice, Inbred C57BL ,Endocrinology ,Pancreatitis ,Anatomical Pathology ,biology.protein ,lcsh:Q ,alpha-Amylases ,Reactive Oxygen Species ,Physiological Processes ,Organism Development ,Oxidative stress ,Biomarkers ,Developmental Biology - Abstract
Reactive oxygen species (ROS) have been implicated in the pathogenesis of acute pancreatitis (AP) for many years but experimental evidence is still limited. Uncoupling protein 2 (UCP2)-deficient mice are an accepted model of age-related oxidative stress. Here, we have analysed how UCP2 deficiency affects the severity of experimental AP in young and older mice (3 and 12 months old, respectively) triggered by up to 7 injections of the secretagogue cerulein (50 μg/kg body weight) at hourly intervals. Disease severity was assessed at time points from 3 hours to 7 days based on pancreatic histopathology, serum levels of alpha-amylase, intrapancreatic trypsin activation and levels of myeloperoxidase (MPO) in lung and pancreatic tissue. Furthermore, in vitro studies with pancreatic acini were performed. At an age of 3 months, UCP2-/- mice and wild-type (WT) C57BL/6 mice were virtually indistinguishable with respect to disease severity. In contrast, 12 months old UCP2-/- mice developed a more severe pancreatic damage than WT mice at late time points after the induction of AP (24 h and 7 days, respectively), suggesting retarded regeneration. Furthermore, a higher peak level of alpha-amylase activity and gradually increased MPO levels in pancreatic and lung tissue were observed in UCP2-/- mice. Interestingly, intrapancreatic trypsin activities (in vivo studies) and intraacinar trypsin and elastase activation in response to cerulein treatment (in vitro studies) were not enhanced but even diminished in the knockout strain. Finally, UCP2-/- mice displayed a diminished ratio of reduced and oxidized glutathione in serum but no increased ROS levels in pancreatic acini. Together, our data indicate an aggravating effect of UCP2 deficiency on the severity of experimental AP in older but not in young mice. We suggest that increased severity of AP in 12 months old UCP2-/- is caused by an imbalanced inflammatory response but is unrelated to acinar cell functions.
- Published
- 2013
40. UCP2 deficiency increases severity of acute pancreatitis in aged mice by aggravating inflammation and impairing regeneration
- Author
-
Hannah Kaiser, Sandra Brunotte, Sarah Müller, Burkhard Krüger, Horst Nizze, and Robert Jaster
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Regeneration (biology) ,Gastroenterology ,Inflammation ,medicine.disease ,Internal medicine ,medicine ,Acute pancreatitis ,medicine.symptom ,business - Published
- 2015
41. The impact of health insurance on maternal and reproductive health service utilization and financial protection in low- and lower middle-income countries: a systematic review of the evidence
- Author
-
Joseph Kazibwe, Phuong Bich Tran, Andrea Hannah Kaiser, Simon Peter Kasagga, Felix Masiye, Björn Ekman, and Jesper Sundewall
- Subjects
Health insurance ,Impact ,Low and lower middle-income countries ,Maternal and reproductive health ,Financial protection ,UHC ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background Low- and middle-income countries have committed to achieving universal health coverage (UHC) as a means to enhance access to services and improve financial protection. One of the key health financing reforms to achieve UHC is the introduction or expansion of health insurance to enhance access to basic health services, including maternal and reproductive health care. However, there is a paucity of evidence of the extent to which these reforms have had impact on the main policy objectives of enhancing service utilization and financial protection. The aim of this systematic review is to assess the existing evidence on the causal impact of health insurance on maternal and reproductive health service utilization and financial protection in low- and lower middle-income countries. Methods The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search included six databases: Medline, Embase, Web of Science, Cochrane, CINAHL, and Scopus as of 23rd May 2023. The keywords included health insurance, impact, utilisation, financial protection, and maternal and reproductive health. The search was followed by independent title and abstract screening and full text review by two reviewers using the Covidence software. Studies published in English since 2010, which reported on the impact of health insurance on maternal and reproductive health utilisation and or financial protection were included in the review. The ROBINS-I tool was used to assess the quality of the included studies. Results A total of 17 studies fulfilled the inclusion criteria. The majority of the studies (82.4%, n = 14) were nationally representative. Most studies found that health insurance had a significant positive impact on having at least four antenatal care (ANC) visits, delivery at a health facility and having a delivery assisted by a skilled attendant with average treatment effects ranging from 0.02 to 0.11, 0.03 to 0.34 and 0.03 to 0.23 respectively. There was no evidence that health insurance had increased postnatal care, access to contraception and financial protection for maternal and reproductive health services. Various maternal and reproductive health indicators were reported in studies. ANC had the greatest number of reported indicators (n = 10), followed by financial protection (n = 6), postnatal care (n = 5), and delivery care (n = 4). The overall quality of the evidence was moderate based on the risk of bias assessment. Conclusion The introduction or expansion of various types of health insurance can be a useful intervention to improve ANC (receiving at least four ANC visits) and delivery care (delivery at health facility and delivery assisted by skilled birth attendant) service utilization in low- and lower-middle-income countries. Implementation of health insurance could enable countries’ progress towards UHC and reduce maternal mortality. However, more research using rigorous impact evaluation methods is needed to investigate the causal impact of health insurance coverage on postnatal care utilization, contraceptive use and financial protection both in the general population and by socioeconomic status. Trial registration This study was registered with Prospero (CRD42021285776).
- Published
- 2024
- Full Text
- View/download PDF
42. Comorbidity in connection with psoriasis is more than psoriatic arthritis
- Author
-
Amanda Kvist-Hansen, Hannah Kaiser, Lone Skov, and Peter Riis Hansen
- Subjects
Depressive Disorder ,Cardiovascular Diseases ,Neoplasms ,Arthritis, Psoriatic ,Practice Guidelines as Topic ,Humans ,Psoriasis ,Comorbidity ,Renal Insufficiency, Chronic ,Inflammatory Bowel Diseases - Abstract
Psoriasis is a common chronic inflammatory disease which is associated with extensive comorbidity, including psoriatic arthritis, cardiovascular and cardiometabolic disease, inflammatory bowel disease, malignancy, chronic kidney disease and depression. Clinical guidelines have been developed to target some of these comorbid diseases in patients with psoriasis and should be used by the treating physician.
43. Availability, prices and affordability of essential medicines for treatment of diabetes and hypertension in private pharmacies in Zambia.
- Author
-
Andrea Hannah Kaiser, Lindsey Hehman, Birger Carl Forsberg, Warren Mukelabai Simangolwa, and Jesper Sundewall
- Subjects
Medicine ,Science - Abstract
OBJECTIVES:To explore availability, prices and affordability of essential medicines for diabetes and hypertension treatment in private pharmacies in three provinces of Zambia. METHODS:A cross-sectional survey was conducted in 99 pharmacies across three Zambian provinces. Methods were based on a standardized methodology by the World Health Organization and Health Action International. Availability was analysed as mean availability per pharmacy and individual medicine. Median prices were compared to international reference prices and differences in price between medicine forms (original brand or generic product) were computed. Affordability was assessed as number of days' salaries required to purchase a standard treatment course using the absolute poverty line and mean per capita provincial household income as standard. An analysis identifying medicines considered both available and affordable was conducted. RESULTS:Two antidiabetics and nine antihypertensives had high-level availability (≥80%) in all provinces; availability levels for the remaining surveyed antidiabetics and antihypertensives were largely found below 50%. Availability further varied markedly across medicines and medicine forms. Prices for most medicines were higher than international reference prices and great price variations were found between pharmacies, medicines and medicine forms. Compared to original brand products, purchase of generics was associated with price savings for patients between 21.54% and 96.47%. No medicine was affordable against the absolute poverty line and only between four and eleven using mean per capita provincial incomes. Seven generics in Copperbelt/Lusaka and two in Central province were highly available and affordable. CONCLUSIONS:The study showed that the majority of surveyed antidiabetic and antihypertensive medicines was inadequately available (
- Published
- 2019
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.