Severe COVID-19 disease is associated with dysregulation of the myeloid compartment during acute infection. Survivors frequently experience long-lasting sequelae but little is known about the eventual persistence of this immune alteration. Herein, we evaluated Toll-like receptor-induced cytokine responses in a cohort of mild to critical patients during acute or convalescent phases (n=97). In the acute phase, we observed impaired cytokine production by monocytes in the most severe patients. This capacity was globally restored in convalescent patients. Yet, we observed increased responsiveness to TLR1/2 ligation in patients that recovered from severe disease, indicating that these cells display distinct functional properties at the different stages of the disease. We identified a specific transcriptomic and epigenomic state in monocytes from acute severe patients that can account for their functional refractoriness. The molecular profile of monocytes from recovering patients was distinct and characterized by increased chromatin accessibility at AP1 and MAF loci. These results demonstrate that severe COVID-19 infection has a profound impact on the differentiation status and function of circulating monocytes both during the acute and the convalescent phases in a completely distinct manner. This could have important implications for our understanding of short and long-term COVID19-related morbidity.
Elisa Brauns, Abdulkader Azouz, David Grimaldi, Hanxi Xiao, Séverine Thomas, Muriel Nguyen, Véronique Olislagers, Ines Vu Duc, Carmen Orte Cano, Véronique Del Marmol, Pieter Pannus, Frédérick Libert, Sven Saussez, Nicolas Dauby, Jishnu Das, Arnaud Marchant, Stanislas Goriely
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
Transplant recipients exhibit an impaired protective immunity after SARS-CoV-2 vaccination, potentially caused by mycophenolate (MPA) immunosuppression. Recent data from autoimmune patients suggest that temporary MPA hold might significantly improve booster vaccination outcomes. We applied a fourth dose of SARS-CoV-2 vaccine to 29 kidney transplant recipients during temporary (5 weeks) MPA (n=28)/azathioprine (n=1) hold, who had not mounted a humoral immune-response to previous vaccinations. Seroconversion until day 32 after vaccination was observed in 76% of patients, associated with acquisition of virus neutralizing capacity. Interestingly, 21/25 (84%) CNI-treated patients responded, but only 1/4 Belatacept-treated patients. In line with humoral responses, counts and relative frequencies of spike receptor binding domain (RBD) specific B cells were significantly increased on day 7 after vaccination, with an increase in RBD specific CD27++CD38+ plasmablasts. Whereas overall proportions of spike-reactive CD4+ T cells remained unaltered after the fourth dose, frequencies were positively correlated with specific IgG levels. Importantly, antigen-specific proliferating Ki67+ and in vivo activated PD1+ T cells significantly increased after re-vaccination during MPA hold, whereas cytokine production and memory differentiation remained unaffected. In summary, antimetabolite hold augmented all arms of immunity during booster vaccination. These data suggest further studies of MMF hold in KTR.
Eva Schrezenmeier, Hector Rincon-Arevalo, Annika Jens, Ana-Luisa Stefanski, Charlotte Hammett, Bilgin Osmanodja, Nadine Koch, Bianca Zukunft, Julia Beck, Michael Oellerich, Vanessa Pross, Carolin Stahl, Mira Choi, Friederike Bachmann, Lutz Liefeldt, Petra Glander, Ekkehard Schütz, Kirsten Bornemann-Kolatzki, Covadonga López del Moral, Hubert Schrezenmeier, Carolin Ludwig, Bernd Jahrsdörfer, Kai-Uwe Eckardt, Nils Lachmann, Katja Kotsch, Thomas Dörner, Fabian Halleck, Arne Sattler, Klemens Budde
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. 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
Most therapeutic monoclonal antibodies target the receptor-binding domain (RBD) of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Unfortunately, the RBD is a hot spot for mutations in SARS-CoV-2 variants, which will lead to loss of the neutralizing function of current therapeutic monoclonal antibodies. Universal monoclonal antibodies for different variants are necessary. We identified monoclonal antibodies that recognized the S2 region of the spike protein, which is identical in different variants. The monoclonal antibodies could neutralize SARS-CoV-2 infection and protect animals from SARS-CoV-2 challenge. After cloning the variable region of the light chain and heavy chain, the variable region sequences were humanized to select a high-affinity humanized monoclonal antibody (hMab5.17). hMab5.17 protected animals from SARS-CoV-2 challenge and neutralized SARS-CoV-2 variant infection. We further identified the linear epitope of the monoclonal antibody, which is not mutated in any variant of concern (VOC). These data suggest that a monoclonal antibody recognizing the S2 region of the spike protein will be a potential universal therapeutic monoclonal antibody for COVID-19.
Wan-Ling Wu, Chen-Yi Chiang, Szu-Chia Lai, Chia-Yi Yu, Yu-Ling Huang, Hung-Chun Liao, Ching-Len Liao, Hsin-Wei Chen, Shih-Jen Liu
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines pose as the most effective approach for mitigating COVID-19 pandemic. High-degree efficacy of SARS-CoV-2 vaccines in clinical trials indicates that vaccination invariably induces an adaptive immune response in vaccine recipients. However, the emergence of breakthrough infections in vaccinated individuals suggest that the breadth and magnitude vaccine-induced adaptive immune response may varies. We assessed vaccine-induced SARS-CoV-2 T-cell response in twenty-one vaccinated individuals and found that SARS-CoV-2 specific T-cells were invariably detected in all individuals. However, the magnitude and breadth of SARS-CoV-2 specific T-cell response varied. Vaccination induced mainly a CD4+ T-cell dominant SARS-CoV-2 specific immune response and the frequencies of SARS-CoV-2 specific T-cell varied across vaccinated individuals. To gain insights into whether SARS-CoV-2 vaccines can induce a long-lived T-cell immune response we investigated differentiation states and cytokine profiles to identify immune features associated with superior recall function and longevity. We identified distinct hierarchically organized differentiation states and cytokine expression patterns. SARS-CoV-2 specific CD4+ T-cells were polyfunctional and produced high levels of IL-2, which could be associated with superior longevity. Stratifying the vaccinated individuals based on the breadth and magnitude of vaccine-induced SARS-CoV-2 response identified two distinct response groups: individuals with high abundance vs low abundance of SARS-CoV-2 T-cells. The fractions of TNF-a and IL-2 producing SARS-CoV-2 T-cells were the main determinants distinguishing high vs low responders. Lastly, we identified the majority of vaccine-induced SARS-CoV-2 T-cells were reactive against conserved regions of mutant S-protein, suggesting that vaccine-induced SARS-CoV-2 T-cells could provide continued protection against emerging variants-of-concern.
Li Li, Muharrem Muftuoglu, Shaoheng Liang, Mahesh Basyal, Jiangxing LV, Mehmet E. Akdogan, Ken Chen, Michael Andreeff, Simrit Parmar
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
Cytomegalovirus (CMV) is a globally ubiquitous pathogen with a seroprevalence of approximately 50% in the UK. CMV infection induces expansion of immunosenescent T cell and NK cell populations with these cells demonstrating lower responsiveness to activation and reduced functionality upon infection and vaccination. In this study, we found that CMV+ participants had normal T cell responses after single dose or homologous vaccination with the viral vector ChAdOx1. In contrast, CMV seropositivity was associated with a loss of T cell IFN-γ secretion following heterologous ChAd-MVA viral vector vaccination. Analysis of participants receiving a single dose of ChAdOx1 demonstrates that T cells from CMV+ donors have a more terminally differentiated profile of CD57+PD1+ CD4+ T cells and CD8+ T cells expressing less IL-2Rα (CD25), and fewer polyfunctional CD4+ T cells 14 days post-vaccination. NK cells from CMV-seropositive individuals also have a reduced activation profile. Overall, our data suggest that although CMV infection enhances immunosenescence of T and NK populations, it does not affect antigen-specific T cell IFN-γ secretion or antibody IgG production after vaccination with the current ChAdOx1 nCoV-19 vaccination regimen in the UK.
Hannah R. Sharpe, Nicholas M. Provine, Georgina S. Bowyer, Pedro Moreira Folegatti, Sandra Belij-Rammerstorfer, Amy Flaxman, Rebecca Makinson, Adrian V.S. Hill, Katie J. Ewer, Andrew J. Pollard, Paul Klenerman, Sarah Gilbert, Teresa Lambe
Duration of protection from SARS-CoV-2 infection in people with HIV (PWH) following vaccination is unclear. In a sub-study of the phase 2/3 the COV002 trial (NCT04400838), 54 HIV positive male participants on antiretroviral therapy (undetectable viral loads, CD4+ T cells >350 cells/ul) received two doses of ChAdOx1 nCoV-19 (AZD1222) 4-6 weeks apart and were followed for 6 months. Responses to vaccination were determined by serology (IgG ELISA and MesoScale Discovery (MSD)), neutralisation, ACE-2 inhibition, gamma interferon ELISpot, activation-induced marker (AIM) assay and T cell proliferation. We show that 6 months after vaccination the majority of measurable immune responses were greater than pre-vaccination baseline, but with evidence of a decline in both humoral and cell mediated immunity. There was, however, no significant difference compared to a cohort of HIV-uninfected individuals vaccinated with the same regimen. Responses to the variants of concern were detectable, although were lower than wild type. Pre-existing cross-reactive T cell responses to SARS-CoV-2 spike were associated with greater post-vaccine immunity and correlated with prior exposure to beta coronaviruses. These data support the on-going policy to vaccinate PWH against SARS-CoV-2, and underpin the need for long-term monitoring of responses after vaccination.
Ane Ogbe, Matthew Pace, Mustapha Bittaye, Timothy Tipoe, Sandra Adele, Jasmini Alagaratnam, Parvinder K. Aley, M. Azim Ansari, Anna Bara, Samantha Broadhead, Anthony Brown, Helen Brown, Federica Cappuccini, Paola Cinardo, Wanwisa Dejnirattisai, Katie Ewer, Henry Fok, Pedro M. Folegatti, Jamie Fowler, Leila Godfrey, Anna L. Goodman, Bethany Jackson, Daniel Jenkin, Mathew Jones, Stephanie Longet, Rebecca A. Makinson, Natalie G. Marchevsky, Moncy Mathew, Andrea Mazzella, Yama F. Mujadidi, Lucia Parolini, Claire Petersen, Emma Plested, Katrina Pollock, Thurkka Rajeswaran, Maheshi N. Ramasamy, Sarah Rhead, Hannah Robinson, Nicola Robinson, Helen Sanders, Sonia Serrano Fandos, Tom Tipton, Anele Waters, Panagiota Zacharopoulou, Eleanor Barnes, Susanna Dunachie, Philip Goulder, Paul Klenerman, Gavin R. Screaton, Alan Winston, Adrian V.S. Hill, Sarah C. Gilbert, Miles Carroll, Andrew J. Pollard, Sarah Fidler, Julie Fox, Teresa Lambe, John Frater
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