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Journal Article•DOI•

Rapid generation of neutralizing antibody responses in COVID-19 patients

Mehul S. Suthar1, Mehul S. Suthar2, Matthew G. Zimmerman2, Matthew G. Zimmerman1, Robert C. Kauffman1, Grace Mantus1, Susanne L. Linderman1, William H. Hudson1, Abigail Vanderheiden2, Abigail Vanderheiden1, Lindsay E. Nyhoff1, Carl W. Davis1, Oluwaseyi Adekunle1, Maurizio Affer1, Melanie A. Sherman3, Stacian Reynolds3, Hans Verkerke1, David Alter1, Jeannette Guarner1, Janetta Bryksin1, Michael Horwath1, Connie M. Arthur1, Natia Saakadze1, Geoffrey H. Smith1, Srilatha Edupuganti1, Erin M. Scherer1, Kieffer Hellmeister1, Andrew Cheng1, Juliet A. Morales1, Andrew S. Neish1, Sean R. Stowell1, Filipp Frank1, Eric A. Ortlund1, Evan J. Anderson1, Vineet D. Menachery4, Nadine Rouphael1, Aneesh K. Mehta1, David S. Stephens1, Rafi Ahmed1, John D. Roback1, Jens Wrammert1 •
Emory University1, Yerkes National Primate Research Center2, Emory Healthcare3, University of Texas Medical Branch4
23 Jun 2020-Vol. 1, Iss: 3, pp 100040-100040
TL;DR: A cross-sectional study of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in a cohort of 44 hospitalized COVID-19 patients, which has implications for understanding protective immunity against SARS-CoV-2, therapeutic use of immune plasma, and development of much-needed vaccines.
Abstract: Summary SARS-CoV-2, the virus responsible for COVID-19, is causing a devastating worldwide pandemic, and there is a pressing need to understand the development, specificity, and neutralizing potency of humoral immune responses during acute infection. We report a cross-sectional study of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in a cohort of 44 hospitalized COVID-19 patients. RBD-specific IgG responses are detectable in all patients 6 days after PCR confirmation. Isotype switching to IgG occurs rapidly, primarily to IgG1 and IgG3. Using a clinical SARS-CoV-2 isolate, neutralizing antibody titers are detectable in all patients by 6 days after PCR confirmation and correlate with RBD-specific binding IgG titers. The RBD-specific binding data were further validated in a clinical setting with 231 PCR-confirmed COVID-19 patient samples. These findings have implications for understanding protective immunity against SARS-CoV-2, therapeutic use of immune plasma, and development of much-needed vaccines.
Citations
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Journal Article•DOI•
Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.

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Jennifer M. Dan1, Jennifer M. Dan2, Jose Mateus2, Yu Kato2, Kathryn M. Hastie2, Esther Dawen Yu2, Caterina E. Faliti2, Alba Grifoni2, Sydney I. Ramirez1, Sydney I. Ramirez2, Sonya Haupt2, April Frazier2, Catherine Nakao2, Vamseedhar Rayaprolu2, Stephen A. Rawlings1, Bjoern Peters2, Bjoern Peters1, Florian Krammer3, Viviana Simon3, Erica Ollmann Saphire2, Erica Ollmann Saphire1, Davey M. Smith1, Daniela Weiskopf2, Alessandro Sette2, Alessandro Sette1, Shane Crotty2, Shane Crotty1 •
University of California, San Diego1, La Jolla Institute for Allergy and Immunology2, Icahn School of Medicine at Mount Sinai3
05 Feb 2021-Science
TL;DR: This article analyzed multiple compartments of circulating immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months after infection.
Abstract: Understanding immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for improving diagnostics and vaccines and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥6 months after infection. Immunoglobulin G (IgG) to the spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month after symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3 to 5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.

1,980 citations

Journal Article•DOI•
Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding.

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Tyler N. Starr1, Allison J. Greaney2, Allison J. Greaney1, Sarah K Hilton1, Sarah K Hilton2, Daniel Ellis2, Katharine H.D. Crawford2, Katharine H.D. Crawford1, Adam S. Dingens1, Mary Jane Navarro2, John E. Bowen2, M. Alejandra Tortorici2, Alexandra C. Walls2, Neil P. King2, David Veesler2, Jesse D. Bloom1, Jesse D. Bloom3, Jesse D. Bloom2 •
Fred Hutchinson Cancer Research Center1, University of Washington2, Howard Hughes Medical Institute3
03 Sep 2020-Cell
TL;DR: It is found that a substantial number of mutations to the RBD are well tolerated or even enhance ACE2 binding, including at ACE2 interface residues that vary across SARS-related coronaviruses.

1,517 citations

Cites background from "Rapid generation of neutralizing an..."

  • ...Mutational Constraint of Antibody Epitopes The RBD is the dominant target of neutralizing antibodies to SARS-CoV-2 (Brouwer et al., 2020; Cao et al., 2020; Ju et al., 2020; Pinto et al., 2020; Premkumar et al., 2020; Rogers et al., 2020; Suthar et al., 2020; Yuan et al., 2020a; Zhang et al., 2020; Zost et al., 2020)....

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Journal Article•DOI•
Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity.

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Carolyn Rydyznski Moderbacher1, Sydney I. Ramirez1, Sydney I. Ramirez2, Jennifer M. Dan1, Jennifer M. Dan2, Alba Grifoni1, Kathryn M. Hastie1, Daniela Weiskopf1, Simon Bélanger1, Robert K. Abbott1, Christina K. Kim1, Jinyong Choi1, Yu Kato1, Eleanor G. Crotty1, Cheryl Kim1, Stephen A. Rawlings2, Jose Mateus1, Longping V. Tse3, April Frazier1, Ralph S. Baric3, Bjoern Peters1, Jason A. Greenbaum1, Erica Ollmann Saphire1, Erica Ollmann Saphire2, Davey M. Smith2, Alessandro Sette1, Alessandro Sette2, Shane Crotty1, Shane Crotty2 •
La Jolla Institute for Allergy and Immunology1, University of California, San Diego2, University of North Carolina at Chapel Hill3
12 Nov 2020-Cell
TL;DR: A combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects suggested roles for both CD4 plus T cells in protective immunity in COVID-19.

1,298 citations

Cites background or result from "Rapid generation of neutralizing an..."

  • ...S IgG and IgA responses were robust in most COVID-19 cases (25/28 acute, 15/15 convalescent S IgG; Figures 1E and S1E) (27/28 acute, 14/15 convalescent S IgA; Figures 1F and S1F), though 17% of cases had relatively low titers (within 3-fold of the LOD)....

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  • ...The black dotted line indicates LOD; the green dotted line Cell 183, 996–1012, November 12, 2020 1005 (legend on next page) ll OPEN ACCESS 1006 Cell 183, 996–1012, November 12, 2020 Article ll OPEN ACCESSArticle naive CD8+ T cell percentage was not simply an effect of acute COVID-19....

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  • ...The black dotted line indicates LOD; the green dotted line demarcatesmarginal responses as determined by unexposed donor responses....

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  • ...The dotted line indicates LOD....

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  • ...Statistics in (D) n of (E) CD40L+IFNg+ or (F) CD40L+IL-2+ after stimulation with SARS-CoV-2 OVID-19 samples (n = 11). th SARS-CoV-2 or CMV peptide pools in unexposed (n = 15), acute COVID-19 k dotted line delineates background signal as determined by the unexposed T cells (blue dots) overlaid on total CD4+T cells (black dots). convalescent COVID-19 (n = 15) samples that had a positive total CD4+ AIM , or the total non-antigen-specific CXCR5+ CD4+ T cells in unexposed controls d CCR6 staining in total cTFH (CXCR5 +CD4+ cells) in unexposed donors or S- ls out of total CD4+ T cells in acute or convalescent samples or non-antigenactive AIM+ cells out of total CD4+ T cells in acute donors (n = 26 samples) or line indicates LOD; the green dotted line demarcates marginal responses as o or more peptide pools were not run due to cell numbers....

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Journal Article•DOI•
Adaptive immunity to SARS-CoV-2 and COVID-19.

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Alessandro Sette1, Alessandro Sette2, Shane Crotty2, Shane Crotty1•
University of California, San Diego1, La Jolla Institute for Allergy and Immunology2
18 Feb 2021-Cell
TL;DR: In this article, a picture has begun to emerge that reveals that CD4+ T cells, CD8+ Tcells, and neutralizing antibodies all contribute to control SARS-CoV-2 in both non-hospitalized and hospitalized cases of COVID-19.

1,092 citations

Journal Article•DOI•
COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives.

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Masataka Nishiga1, Dao Wen Wang2, Yaling Han, David B. Lewis3, Joseph C. Wu3, Joseph C. Wu1 •
Cardiovascular Institute of the South1, Huazhong University of Science and Technology2, Stanford University3
01 Sep 2020-Nature Reviews Cardiology
TL;DR: The interaction between the viral spike protein and angiotensin-converting enzyme 2, which triggers entry of the virus into host cells, is likely to be involved in the cardiovascular manifestations of COVID-19.
Abstract: Coronavirus disease 2019 (COVID-19), caused by a strain of coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic that has affected the lives of billions of individuals. Extensive studies have revealed that SARS-CoV-2 shares many biological features with SARS-CoV, the zoonotic virus that caused the 2002 outbreak of severe acute respiratory syndrome, including the system of cell entry, which is triggered by binding of the viral spike protein to angiotensin-converting enzyme 2. Clinical studies have also reported an association between COVID-19 and cardiovascular disease. Pre-existing cardiovascular disease seems to be linked with worse outcomes and increased risk of death in patients with COVID-19, whereas COVID-19 itself can also induce myocardial injury, arrhythmia, acute coronary syndrome and venous thromboembolism. Potential drug-disease interactions affecting patients with COVID-19 and comorbid cardiovascular diseases are also becoming a serious concern. In this Review, we summarize the current understanding of COVID-19 from basic mechanisms to clinical perspectives, focusing on the interaction between COVID-19 and the cardiovascular system. By combining our knowledge of the biological features of the virus with clinical findings, we can improve our understanding of the potential mechanisms underlying COVID-19, paving the way towards the development of preventative and therapeutic solutions.

927 citations

References
More filters
Journal Article•DOI•
SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

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Markus Hoffmann1, Hannah Kleine-Weber1, Simon Schroeder2, Nadine Krüger3, Tanja Herrler, Sandra Erichsen4, Tobias S. Schiergens5, Georg Herrler3, Nai Huei Wu3, Andreas Nitsche6, Marcel A. Müller2, Christian Drosten2, Christian Drosten7, Stefan Pöhlmann1 •
German Primate Center1, Humboldt University of Berlin2, University of Veterinary Medicine Vienna3, Paracelsus Private Medical University of Salzburg4, Ludwig Maximilian University of Munich5, Robert Koch Institute6, Charité7
16 Apr 2020-Cell
TL;DR: It is demonstrated that SARS-CoV-2 uses the SARS -CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming, and it is shown that the sera from convalescent SARS patients cross-neutralized Sars-2-S-driven entry.

15,362 citations

Journal Article•DOI•
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.

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Daniel Wrapp1, Nianshuang Wang1, Kizzmekia S. Corbett2, Jory A. Goldsmith1, Ching-Lin Hsieh1, Olubukola M. Abiona2, Barney S. Graham2, Jason S. McLellan1 •
University of Texas at Austin1, National Institutes of Health2
13 Mar 2020-Science
TL;DR: The authors show that this protein binds at least 10 times more tightly than the corresponding spike protein of severe acute respiratory syndrome (SARS)–CoV to their common host cell receptor, and test several published SARS-CoV RBD-specific monoclonal antibodies found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs.
Abstract: The outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we determined a 3.5-angstrom-resolution cryo-electron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophysical and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Additionally, we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.

7,324 citations

Journal Article•DOI•
Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein.

[...]

Alexandra C. Walls1, Young-Jun Park1, M. Alejandra Tortorici2, M. Alejandra Tortorici1, Abigail Wall3, Andrew T. McGuire3, Andrew T. McGuire1, David Veesler1 •
University of Washington1, Pasteur Institute2, Fred Hutchinson Cancer Research Center3
16 Apr 2020-Cell
TL;DR: It is demonstrating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination, and it is shown that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of Sars- coV- 2 S and SARS S bind with similar affinities to human ACE2, correlating with the efficient spread of SATS among humans.

7,219 citations

Additional excerpts

  • ...Recent studies have shown that the SARS-CoV-2 RBD interacts with the ACE2 receptor for cellular attachment.(5,6,10) Sequence analysis of the RBD shows extensive homology in this region to SARS (73%)....

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Journal Article•DOI•
Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2.

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Qihui Wang1, Yanfang Zhang1, Lili Wu1, Sheng Niu1, Sheng Niu2, Chunli Song3, Chunli Song1, Zengyuan Zhang1, Guangwen Lu4, Chengpeng Qiao1, Yu Hu5, Yu Hu1, Kwok-Yung Yuen6, Qisheng Wang1, Huan Zhou1, Jinghua Yan, Jianxun Qi1 •
Chinese Academy of Sciences1, Shanxi Agricultural University2, Anhui University3, Sichuan University4, University of Science and Technology of China5, University of Hong Kong6
14 May 2020-Cell
TL;DR: The crystal structure of the C-terminal domain of SARS-CoV-2 (SARS- coV- 2-CTD) spike (S) protein in complex with human ACE2 (hACE2) is presented, which reveals a hACE2-binding mode similar overall to that observed for SARS -CoV.

2,334 citations

Additional excerpts

  • ...Recent studies have shown that the SARS-CoV-2 RBD interacts with the ACE2 receptor for cellular attachment.(5,6,10) Sequence analysis of the RBD shows extensive homology in this region to SARS (73%)....

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  • ...Antibody Responses against SARS-CoV-2 RBD in PCR-Confirmed Acutely Infected COVID-19 Patients (A) Structure of a SARS-CoV-2 spike protein (single monomer is shown) with the RBD highlighted in red.(6) (B) Sequence homology analysis of SARS-CoV-2 spike protein RBD compared to SARS, MERS, and seasonal alpha- and beta-CoVs....

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Journal Article•DOI•
Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma.

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Chenguang Shen1, Zhaoqin Wang1, Fang Zhao1, Yang Yang1, Jinxiu Li1, Jing Yuan1, Fuxiang Wang1, Delin Li2, Delin Li1, Minghui Yang1, Li Xing1, Jinli Wei1, Haixia Xiao2, Haixia Xiao1, Yan Yang1, Jiuxin Qu1, Ling Qing1, Li Chen1, Zhixiang Xu1, Ling Peng1, Yanjie Li1, Haixia Zheng1, Feng Chen1, Kun Huang1, Yujing Jiang1, Dongjing Liu1, Zheng Zhang1, Yingxia Liu1, Lei Liu1 •
Southern University of Science and Technology1, Chinese Academy of Sciences2
27 Mar 2020-JAMA
TL;DR: In this preliminary uncontrolled case series of 5 critically ill patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in their clinical status, and these observations require evaluation in clinical trials.
Abstract: Importance Coronavirus disease 2019 (COVID-19) is a pandemic with no specific therapeutic agents and substantial mortality. It is critical to find new treatments. Objective To determine whether convalescent plasma transfusion may be beneficial in the treatment of critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Design, Setting, and Participants Case series of 5 critically ill patients with laboratory-confirmed COVID-19 and acute respiratory distress syndrome (ARDS) who met the following criteria: severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment; Pao2/Fio2 Exposures Patients received transfusion with convalescent plasma with a SARS-CoV-2–specific antibody (IgG) binding titer greater than 1:1000 (end point dilution titer, by enzyme-linked immunosorbent assay [ELISA]) and a neutralization titer greater than 40 (end point dilution titer) that had been obtained from 5 patients who recovered from COVID-19. Convalescent plasma was administered between 10 and 22 days after admission. Main Outcomes and Measures Changes of body temperature, Sequential Organ Failure Assessment (SOFA) score (range 0-24, with higher scores indicating more severe illness), Pao2/Fio2, viral load, serum antibody titer, routine blood biochemical index, ARDS, and ventilatory and extracorporeal membrane oxygenation (ECMO) supports before and after convalescent plasma transfusion. Results All 5 patients (age range, 36-65 years; 2 women) were receiving mechanical ventilation at the time of treatment and all had received antiviral agents and methylprednisolone. Following plasma transfusion, body temperature normalized within 3 days in 4 of 5 patients, the SOFA score decreased, and Pao2/Fio2increased within 12 days (range, 172-276 before and 284-366 after). Viral loads also decreased and became negative within 12 days after the transfusion, and SARS-CoV-2–specific ELISA and neutralizing antibody titers increased following the transfusion (range, 40-60 before and 80-320 on day 7). ARDS resolved in 4 patients at 12 days after transfusion, and 3 patients were weaned from mechanical ventilation within 2 weeks of treatment. Of the 5 patients, 3 have been discharged from the hospital (length of stay: 53, 51, and 55 days), and 2 are in stable condition at 37 days after transfusion. Conclusions and Relevance In this preliminary uncontrolled case series of 5 critically ill patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in their clinical status. The limited sample size and study design preclude a definitive statement about the potential effectiveness of this treatment, and these observations require evaluation in clinical trials.

2,001 citations

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18 Jun 2020-Nature Medicine
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25 Jun 2020-Cell
Alba Grifoni, Daniela Weiskopf, Sydney I. Ramirez, Sydney I. Ramirez, Jose Mateus, Jennifer M. Dan, Jennifer M. Dan, Carolyn Rydyznski Moderbacher, Stephen A. Rawlings, Aaron Sutherland, Lakshmanane Premkumar, Ramesh Jadi, Daniel Marrama, Aravinda M. de Silva, April Frazier, Aaron F. Carlin, Jason A. Greenbaum, Bjoern Peters, Bjoern Peters, Florian Krammer, Davey M. Smith, Shane Crotty, Shane Crotty, Alessandro Sette, Alessandro Sette 
Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein.

[...]

16 Apr 2020-Cell
Alexandra C. Walls, Young-Jun Park, M. Alejandra Tortorici, M. Alejandra Tortorici, Abigail Wall, Andrew T. McGuire, Andrew T. McGuire, David Veesler 
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.

[...]

13 Mar 2020-Science
Daniel Wrapp, Nianshuang Wang, Kizzmekia S. Corbett, Jory A. Goldsmith, Ching-Lin Hsieh, Olubukola M. Abiona, Barney S. Graham, Jason S. McLellan