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.
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
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)
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
BACKGROUND. Although traditional lipid parameters and coronary imaging techniques are valuable for cardiovascular disease (CVD) risk prediction, better diagnostic tests are still needed. METHODS. In a prospective, observational study, 795 subjects had extensive cardiometabolic profiling, including emerging biomarkers, such as apolipoprotein E (ApoE)-containing HDL-cholesterol. Coronary artery calcium (CAC) score was assessed in the entire cohort, and quantitative coronary computed tomography angiographic (CCTA) characterization (Medis, Qangio) of total (TB), non-calcified (NCB) and fibrous plaque burden (FB) was performed in a sub-cohort (n=300) of patients stratified by concentration of ApoE-HDL-C. Total and HDL-containing apolipoprotein C-III (ApoC-III) were also measured. RESULTS. Most patients had a clinical diagnosis of coronary artery disease (CAD) (n=80.4% of 795), with mean age of 59 years, male (57%) and about half on statin treatment. The low ApoE-HDL-C group had more severe stenosis (11% vs. 2%, overall P<0.001), with higher CAC as compared to high ApoE-HDL-C. On quantitative CCTA, high ApoE-HDL-C group had lower NCB (β=-0.24, P=0.0001), which tended to be significant in fully adjusted model (β=-0.32, P=0.001) and altered by ApoC-III in HDL levels. Low ApoE-HDL-C was significantly associated with LDL particle number (β=0.31; P=0.0001). Finally, when stratified by FB, ApoC-III in HDL showed a more robust predictive value of CAD over ApoE-HDL-C (AUC: 0.705, P=0.0001) in a fully adjusted model. CONCLUSIONS. ApoE-containing HDL-C showed a significant association with early coronary plaque characteristics and is affected by the presence of ApoC-III, indicating that low ApoE-HDL-C and high ApoC-III may be important markers of CVD severity. CLINICAL TRIAL REGISTRATION. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01621594. FUNDING. This work was supported by the National Heart, Lung and Blood Institute (NHLBI) at the National Institutes of Health Intramural Research Program. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Alexander V. Sorokin, Nidhi Patel, Khaled M. Abdelrahman, Clarence Ling, Mart Reimund, Giorgio Graziano, Maureen Sampson, Martin Playford, Amit K. Dey, Aarthi Reddy, Heather L. Teague, Michael Stagliano, Marcelo Amar, Marcus Y. Chen, Nehal Mehta, Alan T. Remaley
BACKGROUND. COVID-19 is a global pandemic caused by the novel coronavirus SARS-CoV-2. Some clinical features of severe COVID-19 represent blood vessel damage induced by activation of host immune responses, initiated by the virus. We hypothesized that autoantibodies against angiotensin converting enzyme-2 (ACE2), the SARS-CoV-2 receptor expressed on vascular endothelium, are generated during COVID-19, and are of mechanistic importance. METHODS. The study was done in an opportunity sample of 118 COVID-19 inpatients. Autoantibodies recognizing ACE2 were detected by ELISA. Binding properties of anti-ACE2 IgM from patients were analyzed via biolayer interferometry. The effects of anti-ACE2 IgM on complement activation and endothelial function were demonstrated in a tissue-engineered pulmonary microvessel model. RESULTS. Anti-ACE2 IgM (but not IgG) were associated with severe COVID-19, found in 18/66 (27.2%) patients with severe disease compared to 2/52 (3.8%) of patients with moderate disease (OR 9.38, 95% CI 2.38-42.0; p=0.0009, Fisher’s exact test). Anti-ACE2 IgM were rare (2/50) in non-COVID-19 ventilated patients with ARDS. Unexpectedly, ACE2-reactive IgM in COVID-19 do not undergo class-switching to IgG, and have apparent KD values of 5.6-21.7nM, indicating that they are T-independent. Anti-ACE2 IgM activated complement and initiated complement-binding and functional changes in endothelial cells in microvessels, suggesting that they contribute to the angiocentric pathology of COVID-19. CONCLUSIONS. Our results identify anti-ACE2 IgM as a mechanism-based biomarker strongly associated with severe clinical outcomes in SARS-CoV-2 infection, which has therapeutic implications. We anticipate that additional IgM responses may identify other COVID-19 subgroups with severe disease, and potentially other serious pandemic illnesses.
Livia Casciola-Rosen, David R. Thiemann, Felipe Andrade, Maria I. Trejo-Zambrano, Elissa K. Leonard, Jamie B. Spangler, Nicole E. Skinner, Justin Bailey, Srinivasan Yegnasubramanian, Rulin Wang, Ajay M. Vaghasia, Anuj Gupta, Andrea L. Cox, Stuart C. Ray, Raleigh M. Linville, Zhaobin Guo, Peter C. Searson, Carolyn E. Machamer, Stephen Desiderio, Lauren M. Sauer, Oliver Laeyendecker, Brian T. Garibaldi, Li Gao, Mahendra Damarla, Paul M. Hassoun, Jody E. Hooper, Christopher A. Mecoli, Lisa Christopher-Stine, Laura Gutierrez-Alamillo, Qingyuan Yang, David Hines, William A. Clarke, Richard E. Rothman, Andrew Pekosz, Katherine Z.J. Fenstermacher, Zitong Wang, Scott L. Zeger, Antony Rosen
BACKGROUND. SARS-CoV-2 infections are frequently milder in children than adults, suggesting that immune responses may vary with age. However, information is limited regarding SARS-CoV-2 immune responses in young children. METHODS. We compared Receptor Binding Domain binding antibody (RBDAb) titers and SARS-CoV-2 neutralizing antibody titers measured by pseudovirus neutralizing antibody assay (PsVNA) in serum specimens obtained from children aged 0-4 years, 5-17 years, and in adults aged 18-62 years at the time of enrollment in a prospective longitudinal household study of SARS-CoV-2 infection. RESULTS. Among 56 participants seropositive at enrollment, children aged 0-4 years had >10-fold higher RBDAb titers than adults (416 vs. 31, P<0.0001), and the highest RBDAb titers in 11/12 households with seropositive children and adults. Children aged 0-4 years had only 2-fold higher neutralizing Ab than adults, resulting in higher binding to neutralizing (B/N) Ab ratios compared to adults (2.36 vs. 0.35 for ID50, P=0.0002). CONCLUSIONS. These findings suggest that young children mount robust antibody responses to SARS-CoV-2 following community infections. Additionally, these results support using neutralizing Ab to measure the immunogenicity of COVID-19 vaccines in children aged 0-4 years. FUNDING. Supported by CDC Award 75D30120C08737
Ruth A. Karron, Maria Garcia Quesada, Elizabeth A. Schappell, Stephen D. Schmidt, Maria Deloria Knoll, Marissa K. Hetrich, Vic Veguilla, Nicole A. Doria-Rose, Fatimah S. Dawood
BACKGROUND. Potent synthetic opioids, such as fentanyl, are increasingly abused, resulting in unprecedented numbers of fatalities from respiratory depression. Treatment with the high-affinity mu-opioid receptor partial agonist buprenorphine may prevent fatalities by reducing binding of potent opioids to the opioid receptor, limiting respiratory depression. METHODS. To characterize buprenorphine-fentanyl interaction at the level of the mu-opioid receptor in two populations (opioid-naïve individuals and chronic users of high-dose opioids), the effects of escalating intravenous fentanyl doses with range 0.075-0.35 mg/70kg (opioid-naïve) and 0.25-0.70 mg/70 kg (chronic opioid users) on iso-hypercapnic ventilation at 2-3 background doses of buprenorphine (target plasma concentrations range: 0.2-5 ng/mL) were quantified using receptor association/dissociation models combined with biophase distribution models. RESULTS. Buprenorphine produced mild respiratory depression, while high doses of fentanyl caused pronounced respiratory depression and apnea in both populations. When combined with fentanyl, buprenorphine produced a receptor binding-dependent reduction of fentanyl-induced respiratory depression in both populations. In chronic opioid users, at buprenorphine plasma concentrations ≥2 ng/mL, a protective effect against high-dose fentanyl was observed. CONCLUSION. Overall, the results indicate that when buprenorphine mu-opioid receptor occupancy is sufficiently high, fentanyl is unable to activate the mu-opioid receptor and consequently will not cause further respiratory depression in addition to the mild respiratory effects of buprenorphine. TRIAL REGISTRATION. Trialregister.nl, number NL7028 (https://www.trialregister.nl/trial/7028) FUNDING. Indivior Inc., North Chesterfield, VA.
Erik Olofsen, Marijke Hyke Algera, Laurence Moss, Robert L. Dobbins, Geert J. Groeneveld, Monique van Velzen, Marieke Niesters, Albert Dahan, Celine M. Laffont
BACKGROUND. The value of the soluble receptor for advanced glycation end-products (sRAGE) as a biomarker in COVID-19 is not well understood. We tested the association between plasma sRAGE and illness severity, viral burden, and clinical outcomes in non-mechanically ventilated hospitalized COVID-19 patients. METHODS. Baseline sRAGE was measured among participants enrolled in the ACTIV-3/TICO trial of bamlanivimab for hospitalized COVID-19. Spearman rank correlation was used to assess the relationship between sRAGE and other plasma biomarkers, including viral nucleocapsid antigen. Fine-Gray models adjusted for baseline supplemental oxygen requirement, antigen level, positive endogenous antibody response, gender, age, body mass index, diabetes mellitus, renal impairment, and log2-transformed IL-6 level were used to assess the association between baseline sRAGE and time to sustained recovery. Cox regression adjusted for the same factors was used to assess the association between sRAGE and mortality. RESULTS. Among 277 participants, baseline sRAGE was strongly correlated with viral plasma antigen concentration (ρ = 0.57). There was a weaker correlation between sRAGE and biomarkers of systemic inflammation such as IL-6 (ρ = 0.36) and CRP (ρ = 0.20). Participants with plasma sRAGE in the highest quartile had a significantly lower rate of sustained recovery (adjusted recovery rate ratio 0.64 [95% CI 0.43-0.90]) and a higher unadjusted risk of death (HR 4.70 [95% CI 2.01-10.99]) compared with participants in the lower quartiles. CONCLUSIONS. Elevated plasma sRAGE in hospitalized, non-ventilated patients with COVID-19 was an indicator of both clinical illness severity and plasma viral load and was associated with a lower likelihood of sustained recovery. These novel results indicate that plasma sRAGE may be a promising biomarker for COVID-19 prognostication and clinical trial enrichment.
Katherine D. Wick, Lianne Siegel, James D. Neaton, Cathryn Oldmixon, Jens Lundgren, Robin L. Dewar, H. Clifford Lane, B. Taylor Thompson, Michael A. Matthay
BACKGROUND. Gut decontamination (GD) can decrease the incidence and severity of acute graft-versus-host-disease (aGVHD) in murine models of allogeneic hematopoietic cell transplantation (HCT). In this pilot study, we examined the impact of GD on the gut microbiome composition and incidence of aGVHD in HCT patients. METHODS. We randomized 20 pediatric patients undergoing allogeneic HCT to receive (GD) or not receive (no-GD) oral vancomycin-polymyxin B from day -5 through neutrophil engraftment. We evaluated shotgun metagenomic sequencing of serial stool samples to compare the composition and diversity of the gut microbiome between study arms. We assessed clinical outcomes in the 2 arms and performed strain-specific analyses of pathogens that caused bloodstream infections (BSI). RESULTS. The two arms did not differ in the predefined primary outcome of Shannon diversity of the gut microbiome at two weeks post-HCT (Genus, p=0.8; Species, p=0.44) or aGVHD incidence (p=0.58). Immune reconstitution of T-cell and B-cell subsets was similar between groups. Five patients in the no-GD arm had eight BSI episodes vs one episode in the GD arm (p=0.09). The BSI-causing pathogens were traceable to the gut in seven of eight BSI episodes in the no-GD arm, including Staphylococcus species. CONCLUSIONS. While GD did not differentially impact Shannon diversity or clinical outcomes, our findings suggest that GD may protect against gut-derived BSI in HCT patients by decreasing the prevalence or abundance of gut pathogens. TRIAL REGISTRATION. ClinicalTrials.gov NCT02641236 FUNDING. NIH, Damon Runyon Cancer Research Foundation, V Foundation, Sloan Foundation, Emerson Collective, Stanford MCHRI.
Christopher J. Severyn, Benjamin A. Siranosian, Sandra Tian-Jiao Kong, Angel Moreno, Michelle M. Li, Nan Chen, Christine N. Duncan, Steven P. Margossian, Leslie E. Lehmann, Shan Sun, Tessa M. Andermann, Olga Birbrayer, Sophie Silverstein, Soomin Kim, Niaz Banaei, Jerome Ritz, Anthony A. Fodor, Wendy B. London, Ami S. Bhatt, Jennifer S. Whangbo
BACKGROUND. There is a need to support the diagnosis of anaphylaxis by objective markers. miRNAs are promising non-coding RNA species that may serve as serological biomarkers, but their use in diagnosing anaphylaxis has not been systematically studied. We aimed to comprehensively investigate serum biomarker profiles (proteins, lipids, and miRNAs) to support the diagnosis of anaphylaxis. METHODS. Adult patients admitted to the emergency room with a diagnosis of anaphylaxis (< 3 hours) were included. Blood samples were taken upon emergency room arrival and one month later. RESULTS. Next-generation sequencing of 18 samples (6 anaphylaxis patients in acute and non-acute condition, respectively, and 6 healthy controls) identified hsa-miR-451a to be elevated during anaphylaxis and verified by RT-qPCR in the remaining cohort. The random forest classifier enabled us to classify anaphylaxis with high accuracy using a composite model. We identified tryptase, 9α,11β-PGF2, apolipoprotein A1, and hsa-miR-451a as serological biomarkers of anaphylaxis. These predictors qualified as serological biomarkers individually but performed better in combination. CONCLUSION. Unexpectedly, hsa-miR-451a was identified as the most relevant biomarker in our data set. We were also able to distinguish between patients with a history of anaphylaxis and healthy individuals with higher accuracy than any other available model. Future studies will need to verify miRNA biomarker utility in real-life clinical settings. FUNDING. This work is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) as part of the clinical research unit (CRU339): Food allergy and tolerance (FOOD@) and a grant to MW (Wo541-16-2); project numbers (409525714, 428094283, 428447634, 264921598).
Wojciech Francuzik, Kristijan Pažur, Magdalena Dalke, Sabine Dölle-Bierke, Magda Babina, Margitta Worm
BACKGROUND After the initial surge in COVID-19 cases, large numbers of patients were discharged from a hospital without assessment of recovery. Now, an increasing number of patients report postacute neurological sequelae, known as “long COVID” — even those without specific neurological manifestations in the acute phase.METHODS Dynamic brain changes are crucial for a better understanding and early prevention of “long COVID.” Here, we explored the cross-sectional and longitudinal consequences of COVID-19 on the brain in 34 discharged patients without neurological manifestations. Gray matter morphology, cerebral blood flow (CBF), and volumes of white matter tracts were investigated using advanced magnetic resonance imaging techniques to explore dynamic brain changes from 3 to 10 months after discharge.RESULTS Overall, the differences of cortical thickness were dynamic and finally returned to the baseline. For cortical CBF, hypoperfusion in severe cases observed at 3 months tended to recover at 10 months. Subcortical nuclei and white matter differences between groups and within subjects showed various trends, including recoverable and long-term unrecovered differences. After a 10-month recovery period, a reduced volume of nuclei in severe cases was still more extensive and profound than that in mild cases.CONCLUSION Our study provides objective neuroimaging evidence for the coexistence of recoverable and long-term unrecovered changes in 10-month effects of COVID-19 on the brain. The remaining potential abnormalities still deserve public attention, which is critically important for a better understanding of “long COVID” and early clinical guidance toward complete recovery.FUNDING National Natural Science Foundation of China.
Tian Tian, Jinfeng Wu, Tao Chen, Jia Li, Su Yan, Yiran Zhou, Xiaolong Peng, Yuanhao Li, Ning Zheng, Aoling Cai, Qin Ning, Hongbing Xiang, Fuqiang Xu, Yuanyuan Qin, Wenzhen Zhu, Jie Wang
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