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
Severe acute lung injury has few treatment options and a high mortality rate. Upon injury, neutrophils infiltrate the lungs and form neutrophil extracellular traps (NETs), damaging the lungs and driving an exacerbated immune response. Unfortunately, no drug preventing NET formation has completed clinical development. Here, we report that disulfiram —an FDA-approved drug for alcohol use disorder— dramatically reduced NETs, increased survival, improved blood oxygenation, and reduced lung edema in a transfusion-related acute lung injury (TRALI) mouse model. We then tested whether disulfiram could confer protection in the context of SARS-CoV-2 infection, as NETs are elevated in patients with severe COVID-19. In SARS-CoV-2-infected golden hamsters, disulfiram reduced NETs and perivascular fibrosis in the lungs, and downregulated innate immune and complement/coagulation pathways, suggesting that it could be beneficial for COVID-19 patients. In conclusion, an existing FDA-approved drug can block NET formation and improve disease course in two rodent models of lung injury for which treatment options are limited.
Jose M. Adrover, Lucia Carrau, Juliane Daßler-Plenker, Yaron Bram, Vasuretha Chandar, Sean Houghton, David Redmond, Joseph R. Merrill, Margaret Shevik, Benjamin R. tenOever, Scott K. Lyons, Robert E. Schwartz, Mikala Egeblad
Benchmarks for protective immunity from infection or severe disease after SARS-CoV-2 vaccination are still being defined. Here we characterized virus neutralizing and ELISA antibody levels, cellular immune responses, and viral variants in 4 separate groups: Healthy control participants weeks (early) or months (late) following vaccination in comparison to symptomatic SARS-CoV-2 infections after partial or full mRNA vaccination. During the study time, most symptomatic breakthrough infections were caused by the SARS-CoV-2 Alpha variant. Neutralizing antibody levels in the healthy controls were sustained over time against the vaccine parent virus, but decreased against the Alpha variant, whereas IgG titers and T cell responses against the parent virus and Alpha variant declined over time in healthy controls. Both partially and fully vaccinated patients with symptomatic infections had lower virus neutralizing antibody levels against parent virus than the healthy controls, similar IgG antibody titers and similar virus-specific T cell responses measured by IFN-γ. Compared to healthy controls, neutralization activity against the Alpha variant was lower in the partially vaccinated infected patients and tended toward lower in the fully vaccinated infected patients. In this cohort of breakthrough infections, parent virus neutralization was the superior predictor of breakthrough infections with the Alpha variant of SARS-CoV-2.
Han-Sol Park, Janna R. Shapiro, Ioannis Sitaras, Bezawit A. Woldemeskel, Caroline Garliss, Amanda Dziedzic, Jaiprasath Sachithanandham, Anne E. Jedlicka, Christopher A. Caputo, Kimberly E. Rousseau, Manjusha Thakar, San Suwanmanee, Pricila Hauk, Lateef Aliyu, Natalia I. Majewska, Sushmita Koley, Bela Patel, Patrick Broderick, Giselle Mosnaim, Sonya L. Heath, Emily S. Spivak, Aarthi Shenoy, Evan M. Bloch, Thomas J. Gniadek, Shmuel Shoham, Arturo Casadevall, Daniel Hanley, Andrea L. Cox, Oliver Laeyendecker, Michael Betenbaugh, Steven M. Cramer, Heba H. Mostafa, Andrew Pekosz, Joel N. Blankson, Sabra L. Klein, Aaron A.R. Tobian, David Sullivan, Kelly A. Gebo
Why Multisystem Inflammatory Syndrome in Children (MIS-C) develops after SARS-CoV-2 infection in a subset of children is unknown. We hypothesized that aberrant virus52 specific T-cell responses contribute to MIS-C pathogenesis. We quantified SARS-CoV-2 reactive T-cells, serologic responses against major viral proteins, and cytokine responses from plasma and peripheral blood mononuclear cells in children with convalescent COVID-19, acute MIS-C, and healthy controls. Children with MIS-C had significantly lower virus-specific CD4+ and CD8+ T-cell responses to major SARS-CoV-2 antigens compared with children convalescing from COVID-19. Further, T-cell responses in participants with MIS-C were similar to or lower than those in healthy controls. Serologic responses against spike receptor binding domain (RBD), full-length spike, and nucleocapsid were similar among convalescent COVID-19 and MIS-C, suggesting functional B cell responses. Cytokine profiling demonstrated predominant Th1 polarization of CD4+ T-cells from children with convalescent COVID-19 and MIS-C, although cytokine production was reduced in MIS-C. Our findings support a role for constrained induction of anti-SARS-CoV-2-specific T-cells in the pathogenesis of MIS-C.
Vidisha Singh, Veronica Obregon-Perko, Stacey A. Lapp, Anna M. Horner, Alyssa Brooks, Lisa Macoy, Laila Hussaini, Austin Lu, Theda Gibson, Guido Silvestri, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Evan J. Anderson, Christina A. Rostad, Ann Chahroudi
BACKGROUND. Vaccine-elicited adaptive immunity is a prerequisite for control of SARS-CoV-2 infection. Multiple sclerosis (MS) disease-modifying therapies (DMTs) differentially target humoral and cellular immunity. A comprehensive comparison of MS DMTs on SARS-CoV-2 vaccine-specific immunity is needed, including quantitative and functional B and T cell responses. METHODS. Spike-specific antibody and T cell responses were measured before and following SARS-CoV-2 vaccination in a cohort of 80 subjects, including healthy controls and MS patients in six DMT groups: untreated, glatiramer acetate (GA), dimethyl fumarate (DMF), natalizumab (NTZ), sphingosine-1-phosphate (S1P) receptor modulators, and anti-CD20 monoclonal antibodies. Anti-spike antibody responses were quantified by Luminex assay, high-resolution spike epitope reactivity was mapped by VirScan, and pseudovirus neutralization was assessed. Spike-specific CD4+ and CD8+ T cell responses were characterized by activation-induced marker (AIM) expression, cytokine production, and tetramer analysis. RESULTS. Anti-spike IgG levels were similar between healthy controls, untreated MS, GA, DMF, and NTZ patients, but were significantly reduced in anti-CD20 and S1P-treated patients. Anti-spike seropositivity in anti-CD20 patients was significantly correlated with CD19+ B cell levels and inversely correlated with cumulative treatment duration. Spike epitope reactivity and pseudovirus neutralization was reduced in anti-CD20 and S1P patients, directly correlating with reduced spike receptor binding domain (RBD) IgG levels. Spike-specific CD4+ and CD8+ T cell reactivity remained robust across all groups except in S1P-treated patients in whom post-vaccine CD4+ T cell responses were attenuated. CONCLUSIONS. These findings from a large MS cohort exposed to a wide spectrum of MS immunotherapies have important implications for treatment-specific COVID-19 clinical guidelines. FUNDING. This work was supported by grants from the NIH 1K08NS107619 (JJS), NMSS TA- 1903-33713 (JJS), K08NS096117 (MRW), Westridge Foundation (MRW), Chan Zuckerberg Biohub (JLD), R01AI159260 (JAH), R01NS092835 (SSZ), R01AI131624 (SSZ), R21NS108159 (SSZ), NMSS RG1701-26628 (SSZ), and the Maisin Foundation (SSZ).
Joseph J. Sabatino Jr, Kristen Mittl, William M. Rowles, Kira McPolin, Jayant V. Rajan, Matthew T. Laurie, Colin R. Zamecnik, Ravi Dandekar, Bonny D. Alvarenga, Rita P. Loudermilk, Chloe Gerungan, Collin M. Spencer, Sharon A. Sagan, Danillo G. Augusto, Jessa R. Alexander, Joseph L. DeRisi, Jill A. Hollenbach, Michael R. Wilson, Scott S. Zamvil, Riley Bove
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