COVID-19 article collection
We are pleased to feature all COVID-19-related articles published in JCI Insight.
The editors of JCI and JCI Insight have revised the editorial process to address the impact of the COVID-19 pandemic on the global research community. Highlights:
- The editors may choose to be more lenient regarding revision requests if the requested experiments do not fundamentally change the conclusions
- The editors may overrule requests from reviewers that the editorial board deems to be beyond the scope of reasonable revision
- If additional studies are required, the editors want to ensure that authors have adequate time to perform the work
The most recent COVID-19 articles are shown below. For all articles, click here
Related articles
Abstract
Abs that neutralize SARS-CoV-2 are thought to provide the most immediate and effective treatment for those severely afflicted by this virus. Because coronavirus potentially diversifies by mutation, broadly neutralizing Abs are especially sought. Here, we report a possibly novel approach to rapid generation of potent broadly neutralizing human anti–SARS-CoV-2 Abs. We isolated SARS-CoV-2 spike protein–specific memory B cells by panning from the blood of convalescent subjects after infection with SARS-CoV-2 and sequenced and expressed Ig genes from individual B cells as human mAbs. All of 43 human mAbs generated in this way neutralized SARS-CoV-2. Eighteen of the forty-three human mAbs exhibited half-maximal inhibitory concentrations (IC50) of 6.7 × 10–12 M to 6.7 × 10–15 M for spike-pseudotyped virus. Seven of the human mAbs also neutralized (with IC50 < 6.7 × 10–12 M) viruses pseudotyped with mutant spike proteins (including receptor-binding domain mutants and the S1 C-terminal D614G mutant). Neutralization of the Wuhan Hu-1 founder strain and of some variants decreased when coding sequences were reverted to germline, suggesting that potency of neutralization was acquired by somatic hypermutation and selection of B cells. These results indicate that infection with SARS-CoV-2 evokes high-affinity B cell responses, some products of which are broadly neutralizing and others highly strain specific. We also identify variants that would potentially resist immunity evoked by infection with the Wuhan Hu-1 founder strain or by vaccines developed with products of that strain, suggesting evolutionary courses that SARS-CoV-2 could take.
Authors
Mayara Garcia de Mattos Barbosa, Hui Liu, Daniel Huynh, Greg Shelley, Evan T. Keller, Brian T. Emmer, Emily Sherman, David Ginsburg, Andrew A. Kennedy, Andrew W. Tai, Christiane Wobus, Carmen Mirabeli, Thomas M. Lanigan, Milagros Samaniego, Wenzhao Meng, Aaron M. Rosenfeld, Eline T. Luning Prak, Jeffrey L. Platt, Marilia Cascalho
Abstract
BACKGROUND Estimates of seroprevalence to SARS-CoV-2 vary widely and may influence vaccination response. We ascertained IgG levels across a single US metropolitan site, Chicago, from June 2020 through December 2020.METHODS Participants (n = 7935) were recruited through electronic advertising and received materials for a self-sampled dried-blood spot assay through the mail or a minimal contact in-person method. IgG against the receptor-binding domain of SARS-CoV-2 was measured using an established highly sensitive and highly specific assay.RESULTS Overall seroprevalence was 17.9%, with no significant difference between method of contact. Only 2.5% of participants reported having had a diagnosis of COVID-19 based on virus detection, consistent with a 7-fold greater exposure to SARS-CoV-2 measured by serology than that detected by viral testing. The range of IgG level observed in seropositive participants from this community survey overlapped with the range of IgG levels associated with COVID-19 cases having a documented positive PCR test. From a subset of those who participated in repeat testing, half of seropositive individuals retained detectable antibodies for 3 to 4 months.CONCLUSION Quantitative IgG measurements with a highly specific and sensitive assay indicated more widespread exposure to SARS-CoV-2 than observed by viral testing. The range of IgG concentrations produced from these asymptomatic exposures was similar to IgG levels occurring after documented nonhospitalized COVID-19, which were considerably lower than those produced from hospitalized COVID-19 cases. The differing ranges of IgG response, coupled with the rate of decay of antibodies, may influence response to subsequent viral exposure and vaccine.Funding National Science Foundation grant 2035114, NIH grant 3UL1TR001422-06S4, NIH National Center for Advancing Translational Sciences grants UL1 TR001422 and UL1 TR002389, Dixon Family Foundation, Northwestern University Cancer Center (NIH grant P30 CA060553), and Walder Foundation’s Chicago Coronavirus Assessment Network.
Authors
Alexis R. Demonbreun, Thomas W. McDade, Lorenzo Pesce, Lauren A. Vaught, Nina L. Reiser, Elena Bogdanovic, Matthew P. Velez, Ryan R. Hsieh, Lacy M. Simons, Rana Saber, Daniel T. Ryan, Michael G. Ison, Judd F. Hultquist, John T. Wilkins, Richard T. D’Aquila, Brian Mustanski, Elizabeth M. McNally
Abstract
The early COVID-19 pandemic was characterized by rapid global spread. In Maryland and Washington, DC, United States, more than 2500 cases were reported within 3 weeks of the first COVID-19 detection in March 2020. We aimed to use genomic sequencing to understand the initial spread of SARS-CoV-2 — the virus that causes COVID-19 — in the region. We analyzed 620 samples collected from the Johns Hopkins Health System during March 11–31, 2020, comprising 28.6% of the total cases in Maryland and Washington, DC. From these samples, we generated 114 complete viral genomes. Analysis of these genomes alongside a subsampling of over 1000 previously published sequences showed that the diversity in this region rivaled global SARS-CoV-2 genetic diversity at that time and that the sequences belong to all of the major globally circulating lineages, suggesting multiple introductions into the region. We also analyzed these regional SARS-CoV-2 genomes alongside detailed clinical metadata and found that clinically severe cases had viral genomes belonging to all major viral lineages. We conclude that efforts to control local spread of the virus were likely confounded by the number of introductions into the region early in the epidemic and the interconnectedness of the region as a whole.
Authors
Peter M. Thielen, Shirlee Wohl, Thomas Mehoke, Srividya Ramakrishnan, Melanie Kirsche, Oluwaseun Falade-Nwulia, Nídia S. Trovão, Amanda Ernlund, Craig Howser, Norah Sadowski, C. Paul Morris, Mark Hopkins, Matthew Schwartz, Yunfan Fan, Victoria Gniazdowski, Justin Lessler, Lauren Sauer, Michael C. Schatz, Jared D. Evans, Stuart C. Ray, Winston Timp, Heba H. Mostafa
Abstract
Preexisting cross-reactivity to SARS-CoV-2 occurs in the absence of prior viral exposure. However, this has been difficult to quantify at the population level due to a lack of reliably defined seroreactivity thresholds. Using an orthogonal antibody testing approach, we estimated that about 0.6% of nontriaged adults from the greater Vancouver, Canada, area between May 17 and June 19, 2020, showed clear evidence of a prior SARS-CoV-2 infection, after adjusting for false-positive and false-negative test results. Using a highly sensitive multiplex assay and positive/negative thresholds established in infants in whom maternal antibodies have waned, we determined that more than 90% of uninfected adults showed antibody reactivity against the spike protein, receptor-binding domain (RBD), N-terminal domain (NTD), or the nucleocapsid (N) protein from SARS-CoV-2. This seroreactivity was evenly distributed across age and sex, correlated with circulating coronaviruses’ reactivity, and was partially outcompeted by soluble circulating coronaviruses’ spike. Using a custom SARS-CoV-2 peptide mapping array, we found that this antibody reactivity broadly mapped to spike and to conserved nonstructural viral proteins. We conclude that most adults display preexisting antibody cross-reactivity against SARS-CoV-2, which further supports investigation of how this may impact the clinical severity of COVID-19 or SARS-CoV-2 vaccine responses.
Authors
Abdelilah Majdoubi, Christina Michalski, Sarah E. O’Connell, Sarah Dada, Sandeep Narpala, Jean Gelinas, Disha Mehta, Claire Cheung, Dirk F.H. Winkler, Manjula Basappa, Aaron C. Liu, Matthias Görges, Vilte E. Barakauskas, Mike Irvine, Jennifer Mehalko, Dominic Esposito, Inna Sekirov, Agatha N. Jassem, David M. Goldfarb, Steven Pelech, Daniel C. Douek, Adrian B. McDermott, Pascal M. Lavoie
Abstract
INTRODUCTION The clinical course of coronavirus 2019 (COVID-19) is heterogeneous, ranging from mild to severe multiorgan failure and death. In this study, we analyzed cell-free DNA (cfDNA) as a biomarker of injury to define the sources of tissue injury that contribute to such different trajectories.METHODS We conducted a multicenter prospective cohort study to enroll patients with COVID-19 and collect plasma samples. Plasma cfDNA was subject to bisulfite sequencing. A library of tissue-specific DNA methylation signatures was used to analyze sequence reads to quantitate cfDNA from different tissue types. We then determined the correlation of tissue-specific cfDNA measures to COVID-19 outcomes. Similar analyses were performed for healthy controls and a comparator group of patients with respiratory syncytial virus and influenza.RESULTS We found markedly elevated levels and divergent tissue sources of cfDNA in COVID-19 patients compared with patients who had influenza and/or respiratory syncytial virus and with healthy controls. The major sources of cfDNA in COVID-19 were hematopoietic cells, vascular endothelium, hepatocytes, adipocytes, kidney, heart, and lung. cfDNA levels positively correlated with COVID-19 disease severity, C-reactive protein, and D-dimer. cfDNA profile at admission identified patients who subsequently required intensive care or died during hospitalization. Furthermore, the increased cfDNA in COVID-19 patients generated excessive mitochondrial ROS (mtROS) in renal tubular cells in a concentration-dependent manner. This mtROS production was inhibited by a TLR9-specific antagonist.CONCLUSION cfDNA maps tissue injury that predicts COVID-19 outcomes and may mechanistically propagate COVID-19–induced tissue injury.FUNDING Intramural Targeted Anti–COVID-19 grant, NIH.
Authors
Temesgen E. Andargie, Naoko Tsuji, Fayaz Seifuddin, Moon Kyoo Jang, Peter S.T. Yuen, Hyesik Kong, Ilker Tunc, Komudi Singh, Ananth Charya, Kenneth Wilkins, Steven Nathan, Andrea Cox, Mehdi Pirooznia, Robert A. Star, Sean Agbor-Enoh
Abstract
Comorbid medical illnesses, such as obesity and diabetes, are associated with more severe COVID-19, hospitalization, and death. However, the role of the immune system in mediating these clinical outcomes has not been determined. We used multiparameter flow cytometry and systems serology to comprehensively profile the functions of T cells and antibodies targeting spike, nucleocapsid, and envelope proteins in a convalescent cohort of COVID-19 subjects who were either hospitalized (n = 20) or not hospitalized (n = 40). To avoid confounding, subjects were matched by age, sex, ethnicity, and date of symptom onset. Surprisingly, we found that the magnitude and functional breadth of virus-specific CD4+ T cell and antibody responses were consistently higher among hospitalized subjects, particularly those with medical comorbidities. However, an integrated analysis identified more coordination between polyfunctional CD4+ T cells and antibodies targeting the S1 domain of spike among subjects who were not hospitalized. These data reveal a functionally diverse and coordinated response between T cells and antibodies targeting SARS-CoV-2, which is reduced in the presence of comorbid illnesses that are known risk factors for severe COVID-19.
Authors
Krystle K.Q. Yu, Stephanie Fischinger, Malisa T. Smith, Caroline Atyeo, Deniz Cizmeci, Caitlin R. Wolf, Erik D. Layton, Jennifer K. Logue, Melissa S. Aguilar, Kiel Shuey, Carolin Loos, Jingyou Yu, Nicholas Franko, Robert Y. Choi, Anna Wald, Dan H. Barouch, David M. Koelle, Douglas Lauffenburger, Helen Y. Chu, Galit Alter, Chetan Seshadri
Abstract
Here, we report on a phase IIa study to determine the intubation rate, survival, viral clearance, and development of endogenous Abs in patients with COVID-19 pneumonia treated with convalescent plasma (CCP) containing high levels of neutralizing anti–SARS-CoV-2 Abs. Radiographic and laboratory evaluation confirmed all 51 treated patients had COVID-19 pneumonia. Fresh or frozen CCP from donors with high titers of neutralizing Abs was administered. The nonmechanically ventilated patients (n = 36) had an intubation rate of 13.9% and a 30-day survival rate of 88.9%, and the overall survival rate for a comparative group based on network data was 72.5% (1625/2241). Patients had negative nasopharyngeal swab rates of 43.8% and 73.0% on days 10 and 30, respectively. Patients mechanically ventilated had a day-30 mortality rate of 46.7%; the mortality rate for a comparative group based on network data was 71.0% (369/520). All evaluable patients were found to have neutralizing Abs on day 3 (n = 47), and all but 1 patient had Abs on days 30 and 60. The only adverse event was a mild rash. In this study on patients with COVID-19 disease, we show therapeutic use of CCP was safe and conferred transfer of Abs, 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 Rowley, Kar Chow, Emily Brown, Joshua Zenreich, Phyllis McKiernan, Kathryn Buttner, Anna Ullrich, Laura Long, Rena Feinman, Andrea Ricourt, Marlo Kemp, Mariefel Vendivil, Hyung Suh, Bindu Balani, Cristina Cicogna, Rani Sebti, Abdulla Al-Khan, Steven Sperber, Samit Desai, Stacey Fanning, Danit Arad, Ronaldo Go, Elizabeth Tam, Keith Rose, Sean Sadikot, David Siegel, Martin Gutierrez, Tatyana Feldman, Andre Goy, Andrew Pecora, Noa Biran, Lori Leslie, Alfred Gillio, Sarah Timmapuri, Michele 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 coronavirus (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 and 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 nonimmunized 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 Abu Baker Abd Farag, Igor Pavlovski, Selma Maacha, Abbirami Sathappan, Hamad Eid Al-Romaihi, Sirin W.J. Abuaqel, Manar Mahmoud Ahmad Ata, Aouatef Ismail Chouchane, Sami Remadi, Najeeb Halabi, Arash Rafii, Mohammed H. Al-Thani, Nico Marr, Murugan Subramanian, Jingxuan Shan
Abstract
Four endemic human coronaviruses (HCoVs) are commonly associated with acute respiratory infection in humans. B cell responses to these “common cold” viruses remain incompletely understood. Here we report a comprehensive analysis of CoV-specific antibody repertoires in 231 children and 1168 adults using phage immunoprecipitation sequencing. Seroprevalence of antibodies against endemic HCoVs ranged between approximately 4% and 27% depending on the species and cohort. We identified at least 136 novel linear B cell epitopes. Antibody repertoires against endemic HCoVs were qualitatively different between children and adults in that anti-HCoV IgG specificities more frequently found among children targeted functionally important and structurally conserved regions of the spike, nucleocapsid, and matrix proteins. Moreover, antibody specificities targeting the highly conserved fusion peptide region and S2′ cleavage site of the spike protein were broadly cross-reactive with peptides of epidemic human and nonhuman coronaviruses. In contrast, an acidic tandem repeat in the N-terminal region of the Nsp3 subdomain of the HCoV-HKU1 polyprotein was the predominant target of antibody responses in adult donors. Our findings shed light on the dominant species-specific and pan-CoV target sites of human antibody responses to coronavirus infection, thereby providing important insights for the development of prophylactic or therapeutic monoclonal antibodies and vaccine design.
Authors
Taushif Khan, Mahbuba Rahman, Fatima Al Ali, Susie S. Y. Huang, Manar Ata, Qian Zhang, Paul Bastard, Zhiyong Liu, Emmanuelle Jouanguy, Vivien Béziat, Aurélie Cobat, Gheyath K. Nasrallah, Hadi M. Yassine, Maria K. Smatti, Amira Saeed, Isabelle Vandernoot, Jean-Christophe Goffard, Guillaume Smits, Isabelle Migeotte, Filomeen Haerynck, Isabelle Meyts, Laurent Abel, Jean-Laurent Casanova, Mohammad R. Hasan, Nico Marr
Abstract
Convalescent plasma with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) antibodies (CCP) may hold promise as a treatment for coronavirus disease 2019 (COVID-19). We compared the mortality and clinical outcome of patients with COVID-19 who received 200 mL of CCP with a spike protein IgG titer ≥ 1:2430 (median 1:47,385) within 72 hours of admission with propensity score–matched controls cared for at a medical center in the Bronx, between April 13 and 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, corticosteroid use, and anticoagulation use. There was no difference in mortality or oxygenation between CCP recipients and controls at day 28. When stratified by age, compared with matched controls, CCP recipients less than 65 years had 4-fold lower risk of mortality and 4-fold lower risk of deterioration in oxygenation or mortality at day 28. For CCP recipients, pretransfusion 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 less than 65 years, but data from controlled trials are needed to validate this finding and establish the effect of aging 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 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 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
