COVID-19
Abstract
We are reporting on a phase IIa study which aimed to determine the intubation rate, survival, viral clearance, and the development of endogenous antibodies in patients with COVID-19 pneumonia treated with convalescent plasma (CCP) containing high levels of neutralizing anti-SARS-CoV-2 antibodies. All 51 treated patients had COVID-19 pneumonia by radiographic and laboratory evaluation. Fresh or frozen CCP from donors with high titers of neutralizing antibodies was administered. The non-mechanically ventilated patients (n=36) had an intubation rate of 13.9% and a day-30 survival of 88.9%. The overall survival for a comparative group based on network data was 72.5% (1625/2241). Patients had rates of negative nasopharyngeal swab on day +10 and +30 of 43.8% and 73% respectively. Patients mechanically ventilated had a day-30 mortality of 46.7%; the mortality for a comparative group based on network data was 71% (369/520). All evaluable patients were found to have neutralizing antibodies on day +3 (n=47), and all but 1 had antibodies on day +30 and +60. The only adverse event was a mild rash. We are concluding that in this study of patients with COVID-19 pneumonia, CCP was safe and conferred transfer of antibodies while preserving endogenous immune response.
Authors
Michele L. Donato, Steven Park, Melissa Baker, Robert Korngold, Alison Morawski, Xue Geng, Ming Tan, Andrew Ip, Stuart Goldberg, Scott D. Rowley, Kar F. Chow, Emily Brown, Joshua Zenreich, Phyllis McKiernan, Kathryn Buttner, Anna Ullrich, Laura Long, Rena Feinman, Andrea Ricourt, Marlo Kemp, Mariefel Vendivil, Hyung C. Suh, Bindu Balani, Cristina Cicogna, Rani Sebti, Abdulla Al-Khan, Steven J. Sperber, Samit Desai, Stacey L. Fanning, Danit Arad, Ronaldo C. Go, Elizabeth Tam, Keith Rose, Sean Sadikot, David S. Siegel, Martin Gutierrez, Tatyana Feldman, Andre Goy, Andrew Pecora, Noa Biran, Lori A. Leslie, Alfred Gillio, Sarah Timmapuri, Michele S. Boonstra, Sam Singer, Sukhdeep Kaur, Ernest Richards, David S. Perlin
Abstract
The development of prophylactic and therapeutic agents for coronavirus disease 2019 (COVID-19) is a current global health priority. Here, we investigated the presence of cross-neutralizing antibodies against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) in dromedary camels that were Middle East respiratory syndrome (MERS)-CoV-seropositive but MERS-CoV-free. The tested 229 dromedaries had anti-MERS-CoV camel antibodies with variable cross-reactivity patterns against SARS-CoV-2 proteins, including the S trimer, M, N, and E proteins. Using SARS-CoV-2 competitive immunofluorescence immunoassays and pseudovirus neutralization assays, we found medium-to-high titers of cross-neutralizing antibodies against SARS-CoV-2 in these animals. Through linear B cell epitope mapping using phage immunoprecipitation sequencing and a SARS-CoV-2 peptide/proteome microarray, we identified a large repertoire of betacoronavirus cross-reactive antibody specificities in these dromedaries and demonstrated that the SARS-CoV-2-specific VHH antibody repertoire is qualitatively diverse. This analysis revealed not only several SARS-CoV-2 epitopes that are highly immunogenic in humans, including a neutralizing epitope, but also epitopes exclusively targeted by camel antibodies. The identified SARS-CoV-2 cross-neutralizing camel antibodies are not proposed as a potential treatment for COVID-19. Rather, their presence in non-immunized camels supports the development of SARS-CoV-2 hyperimmune camels, which could be a prominent source of therapeutic agents for the prevention and treatment of COVID-19.
Authors
Lotfi Chouchane, Jean-Charles Grivel, Elmoubasher Farag, Igor Pavlovski, Selma Maacha, Abbirami Sathappan, Hamad Al-Romaihi, Sirin Abuaqel, Manar Ata, Aouatef Ismail Chouchane, Sami Remadi, Najeeb M. Halabi, Arash Rafii, Mohammed Al-Thani, Nico Marr, Murugan Subramanian, Jingxuan Shan
Abstract
Convalescent plasma with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) antibodies (CCP) may hold promise as treatment for Coronavirus Disease 2019 (COVID-19). We compared the mortality and clinical outcome of patients with COVID-19 who received 200mL of CCP with a Spike protein IgG titer ≥1:2,430 (median 1:47,385) within 72 hours of admission to propensity score-matched controls cared for at a medical center in the Bronx, between April 13 to May 4, 2020. Matching criteria for controls were age, sex, body mass index, race, ethnicity, comorbidities, week of admission, oxygen requirement, D-dimer, lymphocyte counts, corticosteroids, and anticoagulation use. There was no difference in mortality or oxygenation between CCP recipients and controls at day 28. When stratified by age, compared to matched controls, CCP recipients <65 years had 4-fold lower mortality and 4-fold lower deterioration in oxygenation or mortality at day 28. For CCP recipients, pre-transfusion Spike protein IgG, IgM and IgA titers were associated with mortality at day 28 in univariate analyses. No adverse effects of CCP were observed. Our results suggest CCP may be beneficial for hospitalized patients <65 years, but data from controlled trials is needed to validate this finding and establish the effect of ageing on CCP efficacy.
Authors
Hyun ah Yoon, Rachel Bartash, Inessa Gendlina, Johanna Rivera, Antonio Nakouzi, Robert H. Bortz III, Ariel S. Wirchnianski, Monika Paroder, Karen Fehn, Leana Serrano-Rahman, Rachelle Babb, Uzma N. Sarwar, Denise Haslwanter, Ethan Laudermilch, Catalina Florez, M. Eugenia Dieterle, Rohit K. Jangra, J. Maximilian Fels, Karen Tong, Margarette C. Mariano, Olivia Vergnolle, George I. Georgiev, Natalia G. Herrera, Ryan J. Malonis, Jose A. Quiroz, Nicholas C. Morano, Gregory J. Krause, Joseph M. Sweeney, Kelsie Cowman, Stephanie A. Allen, Jayabhargav Annam, Ariella Applebaum, Daniel Barboto, Ahmed Khokhar, Brianna J. Lally, Audrey Lee, Max Lee, Avinash Malaviya, Reise Sample, Xiuyi A. Yang, Yang Li, Rafael E. Ruiz, Raja Thota, Jason Barnhill, Doctor Y. Goldstein, Joan Uehlinger, Scott J. Garforth, Steven C. Almo, Jonathan R. Lai, Morayma Reyes Gil, Amy S. Fox, Kartik Chandran, Tao Wang, Johanna P. Daily, Liise-anne Pirofski
Effective virus-neutralizing activities in antisera from the first wave of severe COVID-19 survivors
Abstract
The pandemic of Coronavirus Disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become one of the worst public health crises. However, knowledge about the dynamics of antibody responses in COVID-19 patients is still poorly understood. In this study, we performed serological study with serum specimens collected at the acute and the convalescent phases from 104 severe COVID-19 patients who were the first wave of COVID-19 cases in Wuhan, China. Our findings uncovered that neutralizing antibodies to SARS-CoV-2 are persistent at least for more than 6 months in severe COVID-19 patients, despite that immunoglobulin G (IgG) levels against receptor binding domain (RBD) and nucleocapsid protein (N) IgG declined from the acute to the convalescent phase. Moreover, we demonstrate that the level of RBD-IgG is capable of correlating with SARS-CoV-2-neutralizing activities in COVID-19 serum. In summary, our findings identify the magnitude, functionality and longevity of antibody responses in COVID-19 patients, which sheds light on better understanding of humoral immune response to COVID-19, and would be beneficial for developing vaccines.
Authors
Yang Han, Peipei Liu, Yang Qiu, Jie Zhou, Ying Liu, Xujuan Hu, Qingyu Yang, Rui Huang, Xinyue Wen, Hao Song, Pengcheng Yu, Mengjie Yang, Jing Zhang, William J. Liu, Ke Peng, Guizhen Wu, Dingyu Zhang, Xi Zhou, Ying Wu
Abstract
Background: Mitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined. Methods: We measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. ICU admission, intubation, vasopressor and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristics and area under-the-curve assessment were used to compare MT-DNA levels to established and emerging inflammatory markers of COVID-19. Results: Circulating MT-DNA levels were highly elevated in patients who eventually died, required ICU admission, intubation, vasopressor use or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA is an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels have a similar or superior area-under-the curve when compared against clinically-established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy. Conclusions: These results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes. Funding: This project was supported by Washington University Institute of Clinical Translational Sciences COVID-19 Research Program. Sample procurement and patient outcome data collection was supported by the Washington University ICTS NIH grant UL1TR002345.
Authors
Davide Scozzi, Marlene Cano, Lina Ma, Dequan Zhou, Ji Hong Zhu, Jane A. O’Halloran, Charles W. Goss, Adriana M. Rauseo, Zhiyi Liu, Sanjaya Kumar Sahu, Valentina Peritore, Monica Rocco, Alberto Ricci, Rachele Amodeo, Laura Aimati, Mohsen Ibrahim, Ramsey R. Hachem, Daniel Kreisel, Philip A. Mudd, Hrishikesh S. Kulkarni, Andrew E. Gelman
Abstract
The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coupled with a lack of therapeutics, has paralyzed the globe. Although significant effort has been invested in identifying antibodies that block infection, the ability of antibodies to target infected cells through Fc interactions may be vital to eliminate the virus. To explore the role of Fc activity in SARS-CoV-2 immunity, the functional potential of a cross–SARS-reactive antibody, CR3022, was assessed. CR3022 was able to broadly drive antibody effector functions, providing critical immune clearance at entry and upon egress. Using selectively engineered Fc variants, no protection was observed after administration of WT IgG1 in mice or hamsters. Conversely, the functionally enhanced Fc variant resulted in increased pathology in both the mouse and hamster models, causing weight loss in mice and enhanced viral replication and weight loss in the more susceptible hamster model, highlighting the pathological functions of Fc-enhancing mutations. These data point to the critical need for strategic Fc engineering for the treatment of SARS-CoV-2 infection.
Authors
Caroline Atyeo, Matthew D. Slein, Stephanie Fischinger, John Burke, Alexandra Schäfer, Sarah R. Leist, Natalia A. Kuzmina, Chad Mire, Anna Honko, Rebecca Johnson, Nadia Storm, Matthew Bernett, Pei Tong, Teng Zuo, Junrui Lin, Adam Zuiani, Caitlyn Linde, Todd Suscovich, Duane R. Wesemann, Anthony Griffiths, John R. Desjarlais, Boris D. Juelg, Jaap Goudsmit, Alexander Bukreyev, Ralph Baric, Galit Alter
Abstract
Extra-pulmonary manifestations of COVID-19 are associated with a much higher mortality rate. Yet, little is known about the pathogenesis of systemic complications of COVID-19. Here, we create a murine model of SARS-CoV-2 induced severe systemic toxicity and multi-organ involvement by expressing the human ACE2 transgene in multiple tissues via viral delivery followed by systemic administration of SARS-CoV-2. The animals develop a profound phenotype within 7 days with severe weight loss, morbidity and failure to thrive. We demonstrate there is metabolic suppression of oxidative phosphorylation and the tri-carboxylic acid (TCA) cycle in multiple organs with neutrophilia, lymphopenia and splenic atrophy mirroring human COVID-19 phenotypes. Animals had a significantly lower heart rate and electron microscopy demonstrated myofibrillar disarray and myocardial edema, a common pathogenic cardiac phenotype in human COVID-19. We perform metabolomic profiling of peripheral blood and identify a panel of TCA cycle metabolites that serve as biomarkers of depressed oxidative phosphorylation. Finally, we observed that SARS-CoV-2 induces epigenetic changes of DNA methylation, that affects expression of immune response genes and could in part contribute to COVID-19 pathogenesis. Our model suggests that SARS-CoV-2 induced metabolic reprogramming and epigenetic changes in internal organs could contribute to systemic toxicity and lethality in COVID-19.
Authors
Shen Li, Feiyang Ma, Tomohiro Yokota, Gustavo Garcia Jr., Amelia Palermo, Yijie Wang, Colin Farrell, Yu-Chen Wang, Rimao Wu, Zhiqiang Zhou, Calvin Pan, Marco Morselli, Michael A. Teitell, Sergey Ryazantsev, Gregory A. Fishbein, Johanna ten Hoeve, Valerie A. Arboleda, Joshua Bloom, Barbara J. Dillon, Matteo Pellegrini, Aldons J. Lusis, Thomas G. Graeber, Vaithilingaraja Arumugaswami, Arjun Deb
Abstract
Immune and inflammatory responses to SARS-CoV-2 contribute to disease severity of COVID-19. However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity, and assessed type-I IFN-, type-II IFN-, and NF-κB-dependent whole blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and non-hematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type-I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients’ first samples revealed 12 biomarkers (CCL2, IL-15, sST2, NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and two additional biomarkers (lactoferrin, CXCL9) that were significantly associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.
Authors
Michael S. Abers, Ottavia M. Delmonte, Emily E. Ricotta, Jonathan Fintzi, Danielle Fink, Adriana A. de Jesus, Kol A. Zarember, Sara Alehashemi, Vasileios Oikonomou, Jigar V. Desai, Scott W. Canna, Bita Shakoory, Kerry Dobbs, Luisa Imberti, Alessandra Sottini, Eugenia Quiros-Roldan, Francesco Castelli, Camillo Rossi, Duilio Brugnoni, Andrea Biondi, Laura R. Bettini, Mariella D’Angio’, Paolo Bonfanti, Riccardo Castagnoli, Daniela Montagna, Amelia Licari, Gian Luigi Marseglia, Emily Gliniewicz, Elana R. Shaw, Dana Kahle, Andre T. Rastegar, Michael A Stack, Katherine Myint-Hpu, Susan L. Levinson, Mark J. DiNubile, Daniel W. Chertow, Peter Burbelo, Jeffrey I. Cohen, Katherine R. Calvo, John S. Tsang, Helen C. Su, John I. Gallin, Douglas B. Kuhns, Raphaela Goldbach-Mansky, Michail S Lionakis, Luigi D Notarangelo
Abstract
We remain largely without effective prophylactic/therapeutic interventions for COVID-19. Although many human COVID-19 clinical trials are ongoing, there remains a deficiency of supportive preclinical drug efficacy studies to help guide decisions. Here we assessed the prophylactic/therapeutic efficacy of hydroxychloroquine (HCQ), a drug of interest for COVID-19 management, in two animal disease models. The standard human malaria HCQ prophylaxis (6.5 mg/kg given weekly) and treatment (6.5 mg/kg) did not significantly benefit clinical outcome nor reduce SARS-CoV-2 replication/shedding in the upper and lower respiratory tract in the rhesus macaque disease model. Similarly, when used for prophylaxis or treatment neither the standard human malaria dose (6.5 mg/kg) nor a high dose (50 mg/kg) of HCQ had any beneficial effect on clinical disease or SARS-CoV-2 kinetics (replication/shedding) in the Syrian hamster disease model. Results from these two preclinical animal models may prove helpful in guiding clinical use of HCQ for prophylaxis/treatment of COVID-19.
Authors
Kyle Rosenke, Michael A. Jarvis, Friederike Feldmann, Benjamin Schwarz, Atsushi Okumura, Jamie Lovaglio, Greg Saturday, Patrick W. Hanley, Kimberly Meade-White, Brandi N. Williamson, Frederick A. Hansen, Lizette Pérez-Pérez, Shanna Leventhal, Tsing-Lee Tang-Huau, Julie Callison, Elaine Haddock, Kaitlin A. Stromberg, Graham Sewell, Dana Scott, Catharine M. Bosio, David W. Hawman, Emmie de Wit, Heinz Feldmann
Abstract
Rapid and specific antibody testing is crucial for improved understanding, control, and treatment of COVID-19 pathogenesis. Herein, we describe and apply a rapid, sensitive, and accurate virus neutralization assay for SARS-CoV-2 antibodies. The new assay is based on an HIV-1 lentiviral vector that contains a secreted intron Gaussia luciferase or secreted Nano-luciferase reporter cassette, pseudotyped with the SARS-CoV-2 spike (S) glycoprotein, and is validated with a plaque reduction assay using an authentic, infectious SARS-CoV-2 strain. The new assay was used to evaluate SARS-CoV-2 antibodies in serum from individuals with a broad range of COVID-19 symptoms, including intensive care unit (ICU) patients, health care workers (HCWs), and convalescent plasma donors. The highest neutralizing antibody titers were observed among ICU patients, followed by general hospitalized patients, HCWs and convalescent plasma donors. Our study highlights a wide phenotypic variation in human antibody responses against SARS-CoV-2, and demonstrates the efficacy of a novel lentivirus pseudotype assay for high-throughput serological surveys of neutralizing antibody titers in large cohorts.
Authors
Cong Zeng, John P. Evans, Rebecca Pearson, Panke Qu, Yi-Min Zheng, Richard T. Robinson, Luanne Hall-Stoodley, Jacob S. Yount, Sonal Pannu, Rama K. Mallampalli, Linda Saif, Eugene Oltz, Gerard Lozanski, Shan-Lu Liu
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