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Article: COVID-19 neutralizing antibodies predict disease severity and survival.

medRxiv : the preprint server for health sciences

2020

Abstract: ... antibody responses in 113 COVID-19 patients and found that severe cases resulting in intubation or death exhibited ... the importance of neutralizing humoral immunity on disease progression and the need to develop broadly protective ... potency was a predictor of survival. In addition to neutralization of wild-type SARS-CoV-2, patient sera ...

Abstract	COVID-19 exhibits variable symptom severity ranging from asymptomatic to life-threatening, yet the relationship between severity and the humoral immune response is poorly understood. We examined antibody responses in 113 COVID-19 patients and found that severe cases resulting in intubation or death exhibited increased inflammatory markers, lymphopenia, and high anti-RBD antibody levels. While anti-RBD IgG levels generally correlated with neutralization titer, quantitation of neutralization potency revealed that high potency was a predictor of survival. In addition to neutralization of wild-type SARS-CoV-2, patient sera were also able to neutralize the recently emerged SARS-CoV-2 mutant D614G, suggesting protection from reinfection by this strain. However, SARS-CoV-2 sera was unable to cross-neutralize a highly-homologous pre-emergent bat coronavirus, WIV1-CoV, that has not yet crossed the species barrier. These results highlight the importance of neutralizing humoral immunity on disease progression and the need to develop broadly protective interventions to prevent future coronavirus pandemics.
Keywords	covid19
Language	English
Publishing date	2020-10-20
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.10.15.20213512
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Article ; Online: COVID-19 Neutralizing Antibodies Predict Disease Severity and Survival

SSRN Electronic Journal ; ISSN 1556-5068

2020

Keywords	covid19
Language	English
Publisher	Elsevier BV
Publishing country	us
Document type	Article ; Online
DOI	10.2139/ssrn.3720298
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Article ; Online: COVID-19 neutralizing antibodies predict disease severity and survival

medRxiv

Abstract	COVID-19 exhibits variable symptom severity ranging from asymptomatic to life-threatening, yet the relationship between severity and the humoral immune response is poorly understood. We examined antibody responses in 113 COVID-19 patients and found that severe cases resulting in intubation or death exhibited increased inflammatory markers, lymphopenia, and high anti-RBD antibody levels. While anti-RBD IgG levels generally correlated with neutralization titer, quantitation of neutralization potency revealed that high potency was a predictor of survival. In addition to neutralization of wild-type SARS-CoV-2, patient sera were also able to neutralize the recently emerged SARS-CoV-2 mutant D614G, suggesting protection from reinfection by this strain. However, SARS-CoV-2 sera was unable to cross-neutralize a highly-homologous pre-emergent bat coronavirus, WIV1-CoV, that has not yet crossed the species barrier. These results highlight the importance of neutralizing humoral immunity on disease progression and the need to develop broadly protective interventions to prevent future coronavirus pandemics.
Keywords	covid19
Language	English
Publishing date	2020-10-20
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2020.10.15.20213512
Database	COVID19

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Article ; Online: COVID-19-neutralizing antibodies predict disease severity and survival.

Cell

2020 Volume 184, Issue 2, Page(s) 476–488.e11

Abstract: ... understood. We examined antibody responses in 113 COVID-19 patients and found that severe cases resulting ... Coronavirus disease 2019 (COVID-19) exhibits variable symptom severity ranging from asymptomatic ... These results highlight the importance of neutralizing humoral immunity on disease progression and the need ...

Abstract	Coronavirus disease 2019 (COVID-19) exhibits variable symptom severity ranging from asymptomatic to life-threatening, yet the relationship between severity and the humoral immune response is poorly understood. We examined antibody responses in 113 COVID-19 patients and found that severe cases resulting in intubation or death exhibited increased inflammatory markers, lymphopenia, pro-inflammatory cytokines, and high anti-receptor binding domain (RBD) antibody levels. Although anti-RBD immunoglobulin G (IgG) levels generally correlated with neutralization titer, quantitation of neutralization potency revealed that high potency was a predictor of survival. In addition to neutralization of wild-type SARS-CoV-2, patient sera were also able to neutralize the recently emerged SARS-CoV-2 mutant D614G, suggesting cross-protection from reinfection by either strain. However, SARS-CoV-2 sera generally lacked cross-neutralization to a highly homologous pre-emergent bat coronavirus, WIV1-CoV, which has not yet crossed the species barrier. These results highlight the importance of neutralizing humoral immunity on disease progression and the need to develop broadly protective interventions to prevent future coronavirus pandemics.
MeSH term(s)	Adult ; Antibodies, Neutralizing/analysis ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/analysis ; Antibodies, Viral/blood ; Biomarkers/analysis ; Biomarkers/blood ; COVID-19/blood ; COVID-19/epidemiology ; COVID-19/immunology ; COVID-19/physiopathology ; Comorbidity ; Coronavirus/classification ; Coronavirus/physiology ; Cross Reactions ; Cytokines/blood ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Immunoglobulin A/analysis ; Immunoglobulin G/blood ; Immunoglobulin G/immunology ; Immunoglobulin M/blood ; Immunoglobulin M/immunology ; Male ; Massachusetts/epidemiology ; Middle Aged ; Protein Domains ; SARS-CoV-2/chemistry ; SARS-CoV-2/physiology ; Severity of Illness Index ; Spike Glycoprotein, Coronavirus/chemistry ; Survival Analysis ; Treatment Outcome
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Biomarkers ; Cytokines ; Immunoglobulin A ; Immunoglobulin G ; Immunoglobulin M ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2020-12-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2020.12.015
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Article ; Online: Testing fractional doses of COVID-19 vaccines.

Więcek, Witold / Ahuja, Amrita / Chaudhuri, Esha / Kremer, Michael / Simoes Gomes, Alexandre / Snyder, Christopher M / Tabarrok, Alex / Tan, Brandon Joel

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 8

Abstract: Due to the enormous economic, health, and social costs of the COVID-19 pandemic, there are high ... levels of protection, particularly against severe disease and death, while potentially expanding supply ... of some COVID-19 vaccines. While existing evidence is not dispositive, available clinical data ...

Abstract	Due to the enormous economic, health, and social costs of the COVID-19 pandemic, there are high expected social returns to investing in parallel in multiple approaches to accelerating vaccination. We argue there are high expected social returns to investigating the scope for lowering the dosage of some COVID-19 vaccines. While existing evidence is not dispositive, available clinical data on the immunogenicity of lower doses combined with evidence of a high correlation between neutralizing antibody response and vaccine efficacy suggests that half or even quarter doses of some vaccines could generate high levels of protection, particularly against severe disease and death, while potentially expanding supply by 450 million to 1.55 billion doses per month, based on supply projections for 2021. An epidemiological model suggests that, even if fractional doses are less effective than standard doses, vaccinating more people faster could substantially reduce total infections and deaths. The costs of further testing alternative doses are much lower than the expected public health and economic benefits. However, commercial incentives to generate evidence on fractional dosing are weak, suggesting that testing may not occur without public investment. Governments could support either experimental or observational evaluations of fractional dosing, for either primary or booster shots. Discussions with researchers and government officials in multiple countries where vaccines are scarce suggests strong interest in these approaches.
MeSH term(s)	COVID-19/immunology ; COVID-19/mortality ; COVID-19/prevention & control ; COVID-19/virology ; COVID-19 Vaccines/administration & dosage ; COVID-19 Vaccines/economics ; COVID-19 Vaccines/supply & distribution ; Developed Countries ; Developing Countries ; Drug Administration Schedule ; Humans ; Immunization, Secondary/economics ; Immunization, Secondary/methods ; Models, Statistical ; Off-Label Use ; SARS-CoV-2/drug effects ; SARS-CoV-2/immunology ; SARS-CoV-2/pathogenicity ; Survival Analysis ; Vaccination/economics ; Vaccination/methods
Chemical Substances	COVID-19 Vaccines
Language	English
Publishing date	2022-02-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2116932119
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Article ; Online: Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients.

Youngs, Jonathan / Provine, Nicholas M / Lim, Nicholas / Sharpe, Hannah R / Amini, Ali / Chen, Yi-Ling / Luo, Jian / Edmans, Matthew D / Zacharopoulou, Panagiota / Chen, Wentao / Sampson, Oliver / Paton, Robert / Hurt, William J / Duncan, David A / McNaughton, Anna L / Miao, Vincent N / Leaver, Susannah / Wyncoll, Duncan L A / Ball, Jonathan /

Hopkins, Philip / Skelly, Donal T / Barnes, Eleanor / Dunachie, Susanna / Ogg, Graham / Lambe, Teresa / Pavord, Ian / Shalek, Alex K / Thompson, Craig P / Xue, Luzheng / Macallan, Derek C / Goulder, Philip / Klenerman, Paul / Bicanic, Tihana

PLoS pathogens

2021 Volume 17, Issue 9, Page(s) e1009804

Abstract: ... responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection ... who survive to broad pro-inflammatory responses in fatal COVID-19 -a feature not observed in severe influenza ... activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08-18.2 ...

Abstract	Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49-14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08-18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 -a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.
MeSH term(s)	Antibodies, Neutralizing/immunology ; Antibodies, Viral/immunology ; Antigens, CD/immunology ; Antigens, Differentiation, T-Lymphocyte/immunology ; B-Lymphocytes/immunology ; Biomarkers/blood ; Blood Proteins/metabolism ; COVID-19/immunology ; COVID-19/mortality ; Cohort Studies ; Critical Illness/mortality ; Female ; Humans ; Immunophenotyping ; Influenza, Human/immunology ; Lectins, C-Type/immunology ; Lymphocyte Activation ; Male ; Middle Aged ; Mucosal-Associated Invariant T Cells/immunology ; Patient Acuity
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Antigens, CD ; Antigens, Differentiation, T-Lymphocyte ; Biomarkers ; Blood Proteins ; CD69 antigen ; Lectins, C-Type
Language	English
Publishing date	2021-09-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1009804
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Multi-phasic gene profiling using candidate gene approach predict the capacity of specific antibody production and maintenance following COVID-19 vaccination in Japanese population.

Takemoto, Yuki / Tanimine, Naoki / Yoshinaka, Hisaaki / Tanaka, Yuka / Takafuta, Toshiro / Sugiyama, Aya / Tanaka, Junko / Ohdan, Hideki

Frontiers in immunology

2023 Volume 14, Page(s) 1217206

Abstract: ... effective in preventing infection and reducing the severity of coronavirus disease (COVID-19 ... interaction, and B cell survival. We measured total anti-SARS-Cov2 spike IgG antibody titers and analyzed ... on antibody production after COVID-19 vaccination.: Methods: In total 236 healthcare workers ...

Abstract	Background: Vaccination against severe acute respiratory syndrome coronavirus type 2 is highly effective in preventing infection and reducing the severity of coronavirus disease (COVID-19). However, acquired humoral immunity wanes within six months. Focusing on the different tempo of acquisition and attenuation of specific antibody titers in individuals, we investigated the impact of genetic polymorphisms on antibody production after COVID-19 vaccination. Methods: In total 236 healthcare workers from a Japanese municipal hospital, who received two doses of the vaccine were recruited. We employed a candidate gene approach to identify the target genetic polymorphisms affecting antibody production after vaccination. DNA samples from the study populations were genotyped for 33 polymorphisms in 15 distinct candidate genes encoding proteins involved in antigen-presenting cell activation, T cell activation, T-B interaction, and B cell survival. We measured total anti-SARS-Cov2 spike IgG antibody titers and analyzed the association with genetic polymorphisms at several time points after vaccination using an unbiased statistical method, and stepwise logistic regression following multivariate regression. Results: Significant associations were observed between seven SNPs in Conclusions: The candidate gene approach successfully showed shifting responsible gene profiles and initial and boosting effect mainly related to the priming phase into antibody maintenance including B cell survival, which traces the phase of immune reactions. These gene profiles provide valuable information for further investigation of humoral immunity against COVID-19 and for building a strategy for personalized vaccine schedules.
MeSH term(s)	Humans ; Antibody Formation/genetics ; COVID-19 Vaccines ; CTLA-4 Antigen ; East Asian People ; NLR Family, Pyrin Domain-Containing 3 Protein ; COVID-19/genetics ; COVID-19/prevention & control ; Vaccination ; Antibodies, Neutralizing ; Polymorphism, Single Nucleotide
Chemical Substances	COVID-19 Vaccines ; CTLA-4 Antigen ; NLR Family, Pyrin Domain-Containing 3 Protein ; Antibodies, Neutralizing
Language	English
Publishing date	2023-07-26
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1217206
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Article ; Online: Peripheral Plasma Cells Associated with Mortality Benefit in Severe COVID-19: A Marker of Disease Resolution.

Boulanger, Mary / Molina, Emily / Wang, Kunbo / Kickler, Thomas / Xu, Yanxun / Garibaldi, Brian T

The American journal of medicine

2021 Volume 134, Issue 8, Page(s) 1029–1033

Abstract: ... blood, though may produce virus-neutralizing antibodies in COVID-19 later in the course of an infection ... adjusting for known covariates associated with disease severity in COVID-19. Further investigation is ... Background: Cytokines seen in severe coronavirus disease 2019 (COVID-19) are associated ...

Abstract	Background: Cytokines seen in severe coronavirus disease 2019 (COVID-19) are associated with proliferation, differentiation, and survival of plasma cells. Plasma cells are not routinely found in peripheral blood, though may produce virus-neutralizing antibodies in COVID-19 later in the course of an infection. Methods: Using the Johns Hopkins COVID-19 Precision Medicine Analytics Platform Registry, we identified hospitalized adult patients with confirmed severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and stratified by presence of plasma cells and World Health Organization (WHO) disease severity. To identify plasma cells, we employed a sensitive flow cytometric screening method for highly fluorescent lymphocytes and confirmed these microscopically. Cox regression models were used to evaluate time to death and time to clinical improvement by the presence of plasma cells in patients with severe disease. Results: Of 2301 hospitalized patients with confirmed infection, 371 had plasma cells identified. Patients with plasma cells were more likely to have severe disease, though 86.6% developed plasma cells after onset of severe disease. In patients with severe disease, after adjusting for age, sex, body mass index, race, and other covariates associated with disease severity, patients with plasma cells had a reduced hazard of death (adjusted hazard ratio: 0.57; 95% confidence interval: 0.38-0.87; P value: .008). There was no significant association with the presence of plasma cells and time to clinical improvement. Conclusions: Patients with severe disease who have detectable plasma cells in the peripheral blood have improved mortality despite adjusting for known covariates associated with disease severity in COVID-19. Further investigation is warranted to understand the role of plasma cells in the immune response to COVID-19.
MeSH term(s)	Antibodies, Neutralizing/immunology ; COVID-19/blood ; COVID-19/mortality ; COVID-19/physiopathology ; Female ; Humans ; Immunity, Cellular ; Male ; Mass Screening/methods ; Middle Aged ; Mortality ; Plasma Cells/immunology ; Plasma Cells/pathology ; Predictive Value of Tests ; Prognosis ; SARS-CoV-2 ; Severity of Illness Index ; Survival Analysis ; United States/epidemiology
Chemical Substances	Antibodies, Neutralizing
Language	English
Publishing date	2021-03-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80015-6
ISSN	1555-7162 ; 1873-2178 ; 0002-9343 ; 1548-2766
ISSN (online)	1555-7162 ; 1873-2178
ISSN	0002-9343 ; 1548-2766
DOI	10.1016/j.amjmed.2021.01.040
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Article: Identification and mechanistic basis of non-ACE2 blocking neutralizing antibodies from COVID-19 patients with deep RNA sequencing and molecular dynamics simulations.

Fredericks, Alger M / East, Kyle W / Shi, Yuanjun / Liu, Jinchan / Maschietto, Federica / Ayala, Alfred / Cioffi, William G / Cohen, Maya / Fairbrother, William G / Lefort, Craig T / Nau, Gerard J / Levy, Mitchell M / Wang, Jimin / Batista, Victor S / Lisi, George P / Monaghan, Sean F

Frontiers in molecular biosciences

2022 Volume 9, Page(s) 1080964

Abstract: ... million reads) of peripheral blood as a diagnostic tool for predicting the severity of the disease and ... identified. Patients who survived severe COVID-19 had significantly more of a Class 3 antibody (C135) to SARS ... neutralizing antibodies (NAbs) from fully recovered patients has been explored in several early stages of novel drugs ...

Abstract	Variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continue to cause disease and impair the effectiveness of treatments. The therapeutic potential of convergent neutralizing antibodies (NAbs) from fully recovered patients has been explored in several early stages of novel drugs. Here, we identified initially elicited NAbs (Ig Heavy, Ig lambda, Ig kappa) in response to COVID-19 infection in patients admitted to the intensive care unit at a single center with deep RNA sequencing (>100 million reads) of peripheral blood as a diagnostic tool for predicting the severity of the disease and as a means to pinpoint specific compensatory NAb treatments. Clinical data were prospectively collected at multiple time points during ICU admission, and amino acid sequences for the NAb CDR3 segments were identified. Patients who survived severe COVID-19 had significantly more of a Class 3 antibody (C135) to SARS-CoV-2 compared to non-survivors (15059.4 vs. 1412.7,
Language	English
Publishing date	2022-12-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2022.1080964
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Article ; Online: Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients.

Jonathan Youngs / Nicholas M Provine / Nicholas Lim / Hannah R Sharpe / Ali Amini / Yi-Ling Chen / Jian Luo / Matthew D Edmans / Panagiota Zacharopoulou / Wentao Chen / Oliver Sampson / Robert Paton / William J Hurt / David A Duncan / Anna L McNaughton / Vincent N Miao / Susannah Leaver / Duncan L A Wyncoll / Jonathan Ball /

Philip Hopkins / Oxford Immunology Network Covid-19 response T cell Consortium / Oxford Protective T cell Immunology for COVID-19 (OPTIC) Clinical team / Donal T Skelly / Eleanor Barnes / Susanna Dunachie / Graham Ogg / Teresa Lambe / Ian Pavord / Alex K Shalek / Craig P Thompson / Luzheng Xue / Derek C Macallan / Philip Goulder / Paul Klenerman / Tihana Bicanic

PLoS Pathogens, Vol 17, Iss 9, p e

2021 Volume 1009804

Abstract	Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49-14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08-18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 -a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	610 ; 616
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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