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1.
Cell Reports Medicine ; : 100640, 2022.
Article in English | ScienceDirect | ID: covidwho-1819630

ABSTRACT

Summary SARS-CoV-2-specific CD4+ T cells are likely important in immunity against COVID-19, but our understanding of CD4+ longitudinal dynamics following infection, and specific features that correlate with the maintenance of neutralizing antibodies, remains limited. Here, we characterize SARS-CoV-2-specific CD4+ T cells in a longitudinal cohort of 109 COVID-19 outpatients enrolled during acute infection. The quality of the SARS-CoV-2-specific CD4+ response shifts from cells producing IFNγ to TNFα from five days to four months post-enrollment, with IFNγ-IL21-TNFα+ CD4+ T cells the predominant population detected at later timepoints. Greater percentages of IFNγ-IL21-TNFα+ CD4+ T cells on day 28 correlate with SARS-CoV-2 neutralizing antibodies measured seven months post-infection (⍴=0.4, P=0.01). mRNA vaccination following SARS-CoV-2 infection boosts both IFNγ and TNFα producing, spike protein-specific CD4+ T cells. These data suggest that SARS-CoV-2-specific, TNFα-producing CD4+ T cells may play an important role in antibody maintenance following COVID-19.

2.
Viruses ; 14(3)2022 03 07.
Article in English | MEDLINE | ID: covidwho-1732249

ABSTRACT

Glycosylation is the most common form of post-translational modification of proteins, critically affecting their structure and function. Using liquid chromatography and mass spectrometry for high-resolution site-specific quantification of glycopeptides coupled with high-throughput artificial intelligence-powered data processing, we analyzed differential protein glycoisoform distributions of 597 abundant serum glycopeptides and nonglycosylated peptides in 50 individuals who had been seriously ill with COVID-19 and in 22 individuals who had recovered after an asymptomatic course of COVID-19. As additional comparison reference phenotypes, we included 12 individuals with a history of infection with a common cold coronavirus, 16 patients with bacterial sepsis, and 15 healthy subjects without history of coronavirus exposure. We found statistically significant differences, at FDR < 0.05, for normalized abundances of 374 of the 597 peptides and glycopeptides interrogated between symptomatic and asymptomatic COVID-19 patients. Similar statistically significant differences were seen when comparing symptomatic COVID-19 patients to healthy controls (350 differentially abundant peptides and glycopeptides) and common cold coronavirus seropositive subjects (353 differentially abundant peptides and glycopeptides). Among healthy controls and sepsis patients, 326 peptides and glycopeptides were found to be differentially abundant, of which 277 overlapped with biomarkers that showed differential expression between symptomatic COVID-19 cases and healthy controls. Among symptomatic COVID-19 cases and sepsis patients, 101 glycopeptide and peptide biomarkers were found to be statistically significantly abundant. Using both supervised and unsupervised machine learning techniques, we found specific glycoprotein profiles to be strongly predictive of symptomatic COVID-19 infection. LASSO-regularized multivariable logistic regression and K-means clustering yielded accuracies of 100% in an independent test set and of 96% overall, respectively. Our findings are consistent with the interpretation that a majority of glycoprotein modifications observed which are shared among symptomatic COVID-19 and sepsis patients likely represent a generic consequence of a severe systemic immune and inflammatory state. However, there are glycoisoform changes that are specific and particular to severe COVID-19 infection. These may be representative of either COVID-19-specific consequences or susceptibility to or predisposition for a severe course of the disease. Our findings support the potential value of glycoproteomic biomarkers in the biomedical understanding and, potentially, the clinical management of serious acute infectious conditions.


Subject(s)
COVID-19 , Artificial Intelligence , COVID-19/diagnosis , Chromatography, Liquid/methods , Glycopeptides/analysis , Glycopeptides/chemistry , Glycopeptides/metabolism , Glycoproteins , Humans
3.
Sci Transl Med ; 14(634): eabn7842, 2022 03 02.
Article in English | MEDLINE | ID: covidwho-1723505

ABSTRACT

Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that have mutations associated with increased transmission and antibody escape have arisen over the course of the current pandemic. Although the current vaccines have largely been effective against past variants, the number of mutations found on the Omicron (B.1.1.529) spike protein appear to diminish the protection conferred by preexisting immunity. Using vesicular stomatitis virus (VSV) pseudoparticles expressing the spike protein of several SARS-CoV-2 variants, we evaluated the magnitude and breadth of the neutralizing antibody response over time in individuals after infection and in mRNA-vaccinated individuals. We observed that boosting increases the magnitude of the antibody response to wild-type (D614), Beta, Delta, and Omicron variants; however, the Omicron variant was the most resistant to neutralization. We further observed that vaccinated healthy adults had robust and broad antibody responses, whereas responses may have been reduced in vaccinated pregnant women, underscoring the importance of learning how to maximize mRNA vaccine responses in pregnant populations. Findings from this study show substantial heterogeneity in the magnitude and breadth of responses after infection and mRNA vaccination and may support the addition of more conserved viral antigens to existing SARS-CoV-2 vaccines.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 , Adult , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/immunology , Female , Humans , Pregnancy , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/prevention & control , Pregnancy Complications, Infectious/virology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/immunology , /immunology
4.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-328540

ABSTRACT

The great majority of SARS-CoV-2 infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunologic outcomes in SARS-CoV-2-infected patients. Leveraging longitudinal samples and data from a clinical trial in SARS-CoV-2 infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients within the first 2 weeks of symptom onset. We identify early immune signatures, including plasma RIG-I levels, early interferon signaling, and related cytokines (CXCL10, MCP1, MCP-2 and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2 specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer–BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine learning models using 7-10 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset.

5.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327138

ABSTRACT

SARS–CoV–2–specific CD4 + T cells are likely important in immunity against COVID–19, but our understanding of CD4 + longitudinal dynamics following infection, and specific features that correlate with the maintenance of neutralizing antibodies, remains limited. We characterized SARS–CoV–2–specific CD4 + T cells in a longitudinal cohort of 109 COVID–19 outpatients. The quality of the SARS–CoV–2–specific CD4 + response shifted from cells producing IFNγ to TNFα from five days to four months post–enrollment, with IFNγ − IL21 − TNFα + CD4 + T cells the predominant population detected at later timepoints. Greater percentages of IFNγ − IL21 − TNFα + CD4 + T cells on day 28 correlated with SARS–CoV–2 neutralizing antibodies measured seven months post–infection (ρ=0.4, P=0.01). mRNA vaccination following SARS–CoV–2 infection boosted both IFNγ and TNFα producing, spike protein–specific CD4 + T cells. These data suggest that SARS–CoV–2–specific, TNFα–producing CD4 + T cells may play an important role in antibody maintenance following COVID–19.

6.
Sci Transl Med ; 14(635): eabm7853, 2022 03 09.
Article in English | MEDLINE | ID: covidwho-1630954

ABSTRACT

A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated immunoglobulin G (IgG) antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. To study the biology of afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG-Fc-gamma receptor (FcγR) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from patients with COVID-19 induced inflammatory cytokine production and robust infiltration of the lung by immune cells. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by messenger RNA SARS-CoV-2 vaccines were highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. Vaccine-elicited IgG did not promote an inflammatory lung response. These results show that human IgG-FcγR interactions regulate inflammation in the lung and define distinct lung activities mediated by the IgG that are associated with protection against, or progression to, severe COVID-19.


Subject(s)
COVID-19 , Antibodies, Neutralizing , Antibodies, Viral , Antibody Formation , COVID-19 Vaccines , Humans , Prospective Studies , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
7.
Nat Commun ; 12(1): 5417, 2021 09 14.
Article in English | MEDLINE | ID: covidwho-1410404

ABSTRACT

COVID-19 is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. Here we develop three protein arrays to measure IgG autoantibodies associated with connective tissue diseases, anti-cytokine antibodies, and anti-viral antibody responses in serum from 147 hospitalized COVID-19 patients. Autoantibodies are identified in approximately 50% of patients but in less than 15% of healthy controls. When present, autoantibodies largely target autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes. A subset of autoantibodies targeting traditional autoantigens or cytokines develop de novo following SARS-CoV-2 infection. Autoantibodies track with longitudinal development of IgG antibodies recognizing SARS-CoV-2 structural proteins and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins.


Subject(s)
Autoantibodies/immunology , COVID-19/immunology , Immunoglobulin G/immunology , SARS-CoV-2/immunology , Aged , Antibodies, Antinuclear/blood , Antibodies, Antinuclear/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Autoantibodies/blood , Autoantigens/immunology , Connective Tissue Diseases/immunology , Cytokines/immunology , Female , Hospitalization , Humans , Immunoglobulin G/blood , Male , Middle Aged , SARS-CoV-2/pathogenicity , Viral Proteins/immunology
8.
Sci Immunol ; 6(61)2021 07 01.
Article in English | MEDLINE | ID: covidwho-1295163

ABSTRACT

A central feature of the SARS-CoV-2 pandemic is that some individuals become severely ill or die, whereas others have only a mild disease course or are asymptomatic. Here we report development of an improved multimeric αß T cell staining reagent platform, with each maxi-ferritin "spheromer" displaying 12 peptide-MHC complexes. Spheromers stain specific T cells more efficiently than peptide-MHC tetramers and capture a broader portion of the sequence repertoire for a given peptide-MHC. Analyzing the response in unexposed individuals, we find that T cells recognizing peptides conserved amongst coronaviruses are more abundant and tend to have a "memory" phenotype, compared to those unique to SARS-CoV-2. Significantly, CD8+ T cells with these conserved specificities are much more abundant in COVID-19 patients with mild disease versus those with a more severe illness, suggesting a protective role.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Severity of Illness Index , CD8-Positive T-Lymphocytes/pathology , COVID-19/pathology , Female , Humans , Male
9.
Nat Immunol ; 22(1): 67-73, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065904

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 infections can cause coronavirus disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life-threatening pneumonia and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature, including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that patients with severe COVID-19 produced a unique serologic signature, including an increased likelihood of IgG1 with afucosylated Fc glycans. This Fc modification on severe acute respiratory syndrome coronavirus 2 IgGs enhanced interactions with the activating Fcγ receptor FcγRIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including interleukin-6 and tumor necrosis factor. These results show that disease severity in COVID-19 correlates with the presence of proinflammatory IgG Fc structures, including afucosylated IgG1.


Subject(s)
COVID-19/immunology , Cytokines/immunology , Immunoglobulin G/immunology , Receptors, IgG/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Aged , COVID-19/metabolism , COVID-19/virology , Child , Cytokines/metabolism , Female , Glycosylation , Humans , Immunoglobulin G/metabolism , Interleukin-6 , Male , Middle Aged , Receptors, IgG/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Severity of Illness Index , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolism
10.
Adv Drug Deliv Rev ; 172: 314-338, 2021 05.
Article in English | MEDLINE | ID: covidwho-1039241

ABSTRACT

The ongoing SARS-CoV-2 pandemic has led to the focused application of resources and scientific expertise toward the goal of developing investigational vaccines to prevent COVID-19. The highly collaborative global efforts by private industry, governments and non-governmental organizations have resulted in a number of SARS-CoV-2 vaccine candidates moving to Phase III trials in a period of only months since the start of the pandemic. In this review, we provide an overview of the preclinical and clinical data on SARS-CoV-2 vaccines that are currently in Phase III clinical trials and in few cases authorized for emergency use. We further discuss relevant vaccine platforms and provide a discussion of SARS-CoV-2 antigens that may be targeted to increase the breadth and durability of vaccine responses.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Clinical Trials, Phase III as Topic/methods , SARS-CoV-2/drug effects , Animals , COVID-19/epidemiology , COVID-19/immunology , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Drug Evaluation, Preclinical/methods , Drug Evaluation, Preclinical/trends , Humans , Protein Structure, Secondary , Protein Structure, Tertiary , SARS-CoV-2/chemistry , SARS-CoV-2/immunology
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