COVID-19
Abstract
BACKGROUND. Coronavirus Disease 2019 (COVID-19) remains a global health emergency with limited treatment options, lagging vaccine rates, and inadequate healthcare resources in the face of an ongoing calamity. The disease is characterized by immune dysregulation and cytokine storm. Cyclosporine A (CSA) is a calcineurin inhibitor that modulates cytokine production and may have direct antiviral properties against coronaviruses. METHODS. To test whether a short course of CSA was safe in COVID-19 patients, we treated 10 hospitalized, oxygen requiring, non-critically ill patients with CSA (starting dose of 9mg/kg/day). We evaluated patients for clinical response and adverse events and measured serum cytokines and chemokines associated with COVID-19 hyper-inflammation and conducted gene-expression analyses. RESULTS. Five subjects experienced adverse events, none were serious; transaminitis was most common. No subject required intensive care unit (ICU)-level care and all patients were discharged alive. CSA treatment was associated with significant reductions in serum cytokines and chemokines important in COVID-19 hyper-inflammation, including CXCL10. Following CSA administration, we also observed a significant reduction in type I interferon gene expression signatures and other transcriptional profiles associated with exacerbated hyper-inflammation in the peripheral blood cells of these patients. CONCLUSIONS. Short courses of CSA appear safe and feasible in COVID-19 patients requiring oxygen and may be a useful adjunct in resource-limited health care settings. TRIAL REGISTRATION. This trial was registered on ClinicalTrials.gov (IND#149997, ClinicalTrials.gov identifier: NCT04412785). FUNDING. This study was internally funded by the Center for Cellular Immunotherapies
Authors
Emily A. Blumberg, Julia Han Noll, Pablo Tebas, Joseph A. Fraietta, Ian Frank, Amy E. Marshall, Anne Chew, Elizabeth A. Veloso, Alison Carulli, Walter Rogal, Avery L. Gaymon, Aliza H. Schmidt, Tiffany Barnette, Renee Jurek, Rene Martins, Briana M. Hudson, Kalyan Chavda, Christina M. Bailey, Sarah E. Church, Hooman Noorchashm, Wei-Ting Hwang, Carl H. June, Elizabeth O. Hexner
Abstract
BACKGROUND. Limited information is available on the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID). METHODS. This observational cohort study examined the immunogenicity of SARS-CoV-2 mRNA vaccines in adult patients with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, or psoriatic disease, with or without maintenance immunosuppressive therapies. Antibody and T cell responses to SARS-COV-2, including neutralization against SARS-CoV-2 variants were determined before and after 1 and 2 vaccine doses. RESULTS. We prospectively followed 150 subjects, 26 healthy controls, 9 IMID patients on no treatment, 44 on anti-TNF, 16 on anti-TNF with methotrexate/azathioprine (MTX/AZA), 10 on anti-IL-23, 28 on anti-IL-12/23, 9 on anti-IL-17, and 8 on MTX/AZA. Antibody and T cell responses to SARS-CoV-2 were detected in all participants, increasing from dose 1 to dose 2 and declining 3 months later, with greater attrition in IMID patients compared to healthy controls. Antibody levels and neutralization efficacy against variants of concern were substantially lower in anti-TNF treated patients than in healthy controls and were undetectable against Omicron by 3 months after dose 2. CONCLUSIONS. Our findings support the need for a third dose of mRNA vaccine and for continued monitoring of immunity in these patient groups. FUNDING. Funded by a donation from Juan and Stefania Speck and by Canadian Institutes of Health (CIHR) /COVID-Immunity Task Force (CITF) grants VR-1 172711 and VS1-175545 (T.H.W. and A.C.G); CIHR FDN-143250 (T.H.W.), GA2- 177716 (V.C., A.C.G., T.H.W.), GA1-177703 (A.C.G.) and the CIHR rapid response network to SARS-CoV-2 variants, CoVaRR-Net (to A.C.G.).
Authors
Roya M. Dayam, Jaclyn C. Law, Rogier L. Goetgebuer, Gary Y.C. Chao, Kento T. Abe, Mitchell Sutton, Naomi Finkelstein, Joanne M. Stempak, Daniel Pereira, David Croitoru, Lily Acheampong, Saima Rizwan, Klaudia Rymaszewski, Raquel Milgrom, Darshini Ganatra, Nathalia V. Batista, Melanie Girard, Irene Lau, Ryan Law, Michelle W. Cheung, Bhavisha Rathod, Julia Kitaygorodsky, Reuben Samson, Queenie Hu, W. Rod Hardy, Nigil Haroon, Robert D. Inman, Vincent Piguet, Vinod Chandran, Mark S. Silverberg, Anne-Claude Gingras, Tania H. Watts
Abstract
Respiratory failure in COVID-19 is characterized by widespread disruption of the lung’s alveolar gas exchange interface. To elucidate determinants of alveolar lung damage, we performed epithelial and immune cell profiling in lungs from 24 COVID-19 autopsies and 43 uninfected organ donors ages 18-92 years. We found marked loss of type 2 alveolar epithelial (T2AE) cells and increased peri-alveolar lymphocyte cytotoxicity in all fatal COVID-19 cases, even at early stages before typical patterns of acute lung injury are histologically apparent. In lungs from uninfected organ donors, there is also progressive loss of T2AE with increasing age which may increase susceptibility to COVID-19 mediated lung damage in older individuals. In the fatal COVID-19 cases, macrophage infiltration differed according to the histopathological pattern of lung injury. In cases with acute lung injury, we found accumulation of CD4+ macrophages that express distinctly high levels of T-cell activation and co-stimulation genes and strongly correlate with increased extent of alveolar epithelial cell depletion and CD8 T-cell cytotoxicity. Together, our results show that T2AE deficiency may underlie age-related COVID-19 risk and initiate alveolar injury shortly after infection; and we define immune cell mediators that may contribute to alveolar injury in distinct pathological stages of lethal COVID-19.
Authors
Michael Chait, Mine M. Yilmaz, Shanila Shakil, Amy W. Ku, Pranay Dogra, Thomas J. Connors, Peter A. Szabo, Joshua I. Gray, Steven B. Wells, Masaru Kubota, Rei Matsumoto, Maya M.L. Poon, Mark E. Snyder, Matthew R. Baldwin, Peter A. Sims, Anjali Saqi, Donna L. Farber, Stuart P. Weisberg
Abstract
SARS-CoV-2 has resulted in over 450 million confirmed cases since 2019. Although several vaccines have been certified by World Health Organization and are being vaccinated on a global scale, it has been reported that multiple SARS-CoV-2 variants can escape neutralisation by antibodies, resulting in vaccine breakthrough infections. Bacillus Calmette-Guérin (BCG) is known to induce heterologous protection based on trained immune responses. Here, we investigated whether BCG-induced trained immunity protected against SARS-CoV-2 challenge in the K18-hACE2 mouse model. Our data demonstrates that intravenous BCG vaccination induces robust trained innate immune responses and provides protection against wild-type SARS-CoV-2 as well as the B.1.617.1 and B.1.617.2 variants. Further studies suggest that myeloid cell differentiation and activation of the glycolysis pathway are associated with BCG-induced training immunity in the K18-hACE2 mice. Overall, our study provides the experimental evidence that establishes a causal relationship between intravenous BCG vaccination and protection against SARS-CoV-2 challenge.
Authors
Bao-Zhong Zhang, Huiping Shuai, Hua-rui Gong, Jing-Chu Hu, Bingpeng Yan, Terrence Tsz-Tai Yuen, Ye-Fan Hu, Chaemin Yoon, Xiao-Lei Wang, Yuxin Hou, Xuansheng Lin, Xiner Huang, Renhao Li, Yee Man Au-Yeung, Wenjun Li, Bingjie Hu, Yue Chai, Ming Yue, Jian-Piao Cai, Guang Sheng Ling, Ivan Fan-Ngai Hung, Kwok-Yung Yuen, Jasper Fuk-Woo Chan, Jian-Dong Huang, Hin Chu
Abstract
BACKGROUND. Measuring the immune response to SARS-CoV-2 enables assessment of past infection and protective immunity. SARS-CoV-2 infection induces humoral and T-cell responses, but these responses vary with disease severity and individual characteristics. METHODS. A T-cell receptor (TCR) immunosequencing assay was conducted using small-volume blood samples from 302 individuals recovered from COVID-19. Correlations between the magnitude of the T-cell response and neutralizing antibody (nAb) titers or indicators of disease severity were evaluated. Sensitivity of T-cell testing was assessed and compared to serologic testing. RESULTS. SARS-CoV-2–specific T-cell responses were significantly correlated with nAb titers and clinical indicators of disease severity, including hospitalization, fever, and difficulty breathing. Despite modest declines in depth and breadth of T-cell responses during convalescence, high sensitivity was observed until at least 6 months after infection, with overall sensitivity ~5% greater than serology tests for identifying prior SARS-CoV-2 infection. Improved performance of T-cell testing was most apparent in recovered, non-hospitalized individuals sampled >150 days after initial illness, suggesting greater sensitivity than serology at later timepoints and in individuals with less severe disease. T-cell testing identified SARS-CoV-2 infection in 68% (55/81) of samples with undetectable nAb titers (<1:40) and in 37% (13/35) of samples negative by 3 antibody assays. CONCLUSION. These results support TCR-based testing as a scalable, reliable measure of past SARS-CoV-2 infection with clinical value beyond serology. FUNDING. Adaptive Biotechnologies, Frederick National Laboratory for Cancer Research, National Institutes of Allergy and Infectious Diseases, Fred Hutchinson Joel Meyers Endowment; Fast Grants, American Society for Transplantation and Cell Therapy.
Authors
Rebecca Elyanow, Thomas M. Snyder, Sudeb C. Dalai, Rachel M. Gittelman, Jim Boonyaratanakornkit, Anna Wald, Stacy Selke, Mark H. Wener, Chihiro Morishima, Alexander L. Greninger, Michael Gale Jr., Tien-Ying Hsiang, Lichen Jing, Michael R. Holbrook, Ian M. Kaplan, H. Jabran Zahid, Damon H. May, Jonathan M. Carlson, Lance Baldo, Thomas Manley, Harlan S. Robins, David M. Koelle
Abstract
T cells play a prominent role in orchestrating the adaptive immune response to viral diseases and are a key component in understanding variability in SARS-CoV-2 infection severity and immunity. How the T cell response to SARS-CoV-2 infection and vaccination relates to clinical presentation, other components of the immune response, and subsequent immunity remains poorly understood. A population-based swab survey of the municipality of Vo’, Italy, conducted after the initial SARS-CoV-2 outbreak, uncovered a high frequency of asymptomatic infected individuals and their role in transmission. We sampled the T-cell receptor repertoire structure of the entire Vo’ population 2 months after the initial survey and followed up positive cases at 9 and 15 months post infection. We found that 97.0% (98/101) of cases had elevated levels of T-cell receptors associated with SARS-CoV-2 antigens at 2 months. T-cell frequency (depth) was increased in individuals with more severe disease. Both depth and diversity (breadth) of the T-cell receptor repertoire were also positively associated with neutralizing antibody titers, driven mostly by helper CD4+ T cells directed towards antigens from spike protein. At the later time points, detection of SARS-CoV-2 associated T cells remained high, with 90.7% (78/96) and 86.2% (25/29) of individuals having detectable signal at 9 and 15 months, respectively. Notably, at 9 months, T-cell signal was detectable in 84.6% (22/26) of cases who were initially asymptomatic. Forty-three individuals had been vaccinated by month fifteen, all presenting with a positive T-cell signal and showing a significant increase in T cells, specifically directed against spike protein. Taken together, these results demonstrate the central role of the T-cell response in mounting a comprehensive immune defense against SARS-CoV-2 that persists out to 15 months.
Authors
Rachel M. Gittelman, Enrico Lavezzo, Thomas M. Snyder, H. Jabran Zahid, Cara L. Carty, Rebecca Elyanow, Sudeb C. Dalai, Ilan Kirsch, Lance Baldo, Laura Manuto, Elisa Franchin, Claudia Del Vecchio, Monia Pacenti, Caterina Boldrin, Margherita Cattai, Francesca Saluzzo, Andrea Padoan, Mario Plebani, Fabio Simeoni, Jessica Bordini, Nicola I. Lorè, Dejan Lazarević, Daniela Maria Cirillo, Paolo Ghia, Stefano Toppo, Jonathan M. Carlson, Harlan S. Robins, Andrea Crisanti, Giovanni Tonon
Abstract
Studying temporal gene expression shifts during disease progression provides important insights into the biological mechanisms that distinguish adaptive and maladaptive responses. Existing tools for the analysis of time course transcriptomic data are not designed to optimally identify distinct temporal patterns when analyzing dynamic differentially expressed genes (DDEGs). Moreover, there are not enough methods to assess and visualize the temporal progression of biological pathways mapped from time course transcriptomic data sets. In this study, we developed an open-source R package TrendCatcher (https://github.com/jaleesr/TrendCatcher), which applies the smoothing spline ANOVA model and break point searching strategy, to identify and visualize distinct dynamic transcriptional gene signatures and biological processes from longitudinal data sets. We used TrendCatcher to perform a systematic temporal analysis of COVID-19 peripheral blood transcriptomes, including bulk and single-cell RNA-Seq time course data. TrendCatcher uncovered the early and persistent activation of neutrophils and coagulation pathways, as well as impaired type I IFN (IFN-I) signaling in circulating cells as a hallmark of patients who progressed to severe COVID-19, whereas no such patterns were identified in individuals receiving SARS-CoV-2 vaccinations or patients with mild COVID-19. These results underscore the importance of systematic temporal analysis to identify early biomarkers and possible pathogenic therapeutic targets.
Authors
Xinge Wang, Mark A. Sanborn, Yang Dai, Jalees Rehman
Abstract
BACKGROUND. Breakthrough SARS-CoV-2 infections in vaccinated individuals have been previously associated with suboptimal humoral immunity. However, less is known about breakthrough infections with the Omicron variant. METHODS. We analyzed SARS-CoV-2 specific antibody and cellular responses in healthy vaccine recipients who experienced breakthrough infections a median of 50 days after receiving a booster mRNA vaccine with an ACE2 binding inhibition assay and an ELISpot assay respectively.Results: We found high levels of antibodies that inhibited vaccine strain spike protein binding to ACE2 but lower levels that inhibited Omicron variant spike protein binding to ACE2 in four boosted vaccine recipients prior to infection. The levels of antibodies that inhibited vaccine strain and Omicron spike protein binding after breakthrough in 18 boosted vaccine recipients were similar to levels seen in COVID-19 negative boosted vaccine recipients. In contrast, boosted vaccine recipients had significantly stronger T cells responses to both vaccine strain and Omicron variant spike proteins at the time of breakthrough. CONCLUSIONS. Our data suggest that breakthrough infections with the Omicron variant can occur despite robust immune responses to the vaccine strain spike protein. FUNDING. This work was supported by the Johns Hopkins COVID-19 Vaccine-related Research Fund and by funds from the National Institute of Allergy and Infectious Disease intramural program as well as awards from the National Cancer Institute (U54CA260491) and the National Institutes of Allergy and Infectious Disease (K08AI156021 and U01AI138897)
Authors
Bezawit A. Woldemeskel, Caroline C. Garliss, Tihitina Y. Aytenfisu, Trevor S. Johnston, Evan J. Beck, Arbor G. Dykema, Nicole Frumento, Desiree A. Wright, Andrew H. Yang, Alexander I. Damanakis, Oliver Laeyendecker, Andrea L. Cox, Heba H. Mostafa, Andrew H. Karaba, Joel N. Blankson
Abstract
Shortness of breath, chest pain, and palpitations occur as post-acute sequelae of COVID-19 (PASC), but whether symptoms are associated with echocardiographic abnormalities, cardiac biomarkers, or markers of systemic inflammation remains unknown. In a cross-sectional analysis, we assessed symptoms, performed echocardiograms, and measured biomarkers among adults >8 weeks after confirmed SARS-CoV-2 infection. We modeled associations between symptoms and baseline characteristics, echocardiographic findings, and biomarkers using logistic regression. We enrolled 102 participants at a median 7.2 months (IQR 4.1-9.1) following COVID-19 onset; 47 individuals reported dyspnea, chest pain, or palpitations. Median age was 52 years (range 24-86) and 41% were women. Female sex, hospitalization, IgG antibody to SARS-CoV-2 receptor binding domain and C-reactive protein were associated with symptoms. Regarding echocardiographic findings, 4/47 (9%) with symptoms had pericardial effusions compared to 0/55 without symptoms (p=0.038); those with effusions had a median 4 symptoms compared to 1 without (p<0.001). There was no strong evidence for a relationship between symptoms and echocardiographic functional parameters or other biomarkers. Among adults >8 weeks after SARS-CoV-2 infection, SARS-CoV-2 RBD antibodies, markers of inflammation and, possibly, pericardial effusions are associated with cardiopulmonary symptoms. Investigation into inflammation as a mechanism underlying PASC is warranted.
Authors
Matthew S. Durstenfeld, Michael J. Peluso, J. Daniel Kelly, Sithu Win, Shreya Swaminathan, Danny Li, Victor M. Arechiga, Victor Antonio Zepeda, Kaiwen Sun, Shirley J. Shao, Christopher Hill, Mireya I. Arreguin, Scott Lu, Rebecca Hoh, Viva W. Tai, Ahmed Chenna, Brandon C. Yee, John W. Winslow, Christos J. Petropoulos, John Kornak, Timothy J. Henrich, Jeffrey N. Martin, Steven G. Deeks, Priscilla Y. Hsue
Immunogenic epitope panel for accurate detection of non-cross-reactive T cell response to SARS-CoV-2
Abstract
The ongoing COVID-19 pandemic calls for more effective diagnostic tools. T cell response assessment serves as an independent indicator of prior COVID-19 exposure while also contributing to a more comprehensive characterization of SARS-CoV-2 immunity. In this study, we systematically assessed the immunogenicity of 118 epitopes with immune cells collected from multiple cohorts of vaccinated, convalescent, healthy unexposed, and SARS-CoV-2 exposed donors. We identified 75 immunogenic epitopes, 24 of which were immunodominant. We further confirmed HLA restriction for 49 epitopes, and described association with more than one HLA allele for 14 of these. Exclusion of two cross-reactive epitopes that generated a response in pre-pandemic samples, left us with a 73-epitope set that offered excellent diagnostic specificity without losing sensitivity compared to full-length antigens, which evoked a robust cross-reactive response. We subsequently incorporated this set of epitopes into an in vitro diagnostic ‘Corona-T-test’ which achieved a diagnostic accuracy of 95% in a clinical trial. In a cohort of asymptomatic seronegative individuals with a history of prolonged SARS-CoV-2 exposure, we observed a complete absence of T cell response to our epitope panel. In combination with strong reactivity to full-length antigens, this suggests that a cross-reactive response might protect these individuals.
Authors
Aleksei Titov, Regina Shaykhutdinova, Olga V. Shcherbakova, Yana V. Serdyuk, Savely A. Sheetikov, Ksenia V. Zornikova, Alexandra V. Maleeva, Alexandra Khmelevskaya, Dmitry V. Dianov, Naina T. Shakirova, Dmitry B. Malko, Maxim Shkurnikov, Stepan Nersisyan, Alexander Tonevitsky, Ekaterina Khamaganova, Anton V. Ershov, Elena Y. Osipova, Ruslan V. Nikolaev, Dmitry E. Pershin, Viktoria A. Vedmedskia, Mikhail Maschan, Victoria R. Ginanova, Grigory A. Efimov
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