Publications by authors named "Taia T Wang"

50 Publications

Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity.

Sci Transl Med 2022 Jan 18:eabm7853. Epub 2022 Jan 18.

Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA, 94305, USA.

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 IgG antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by mRNA SARS-CoV-2 vaccines were instead highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. To study the biology 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 COVID-19 patients induced inflammatory cytokine production and robust infiltration of the lung by immune cells. By contrast, vaccine-elicited IgG did not promote an inflammatory lung response. Together, these results show that IgG-FcγR interactions are able to regulate inflammation in the lung and may define distinct lung activities associated with the IgG that are associated with severe COVID-19 and protection against infection with SARS-CoV-2.
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http://dx.doi.org/10.1126/scitranslmed.abm7853DOI Listing
January 2022

Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium.

Nat Rev Cardiol 2022 Jan 13. Epub 2022 Jan 13.

Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and D-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.
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http://dx.doi.org/10.1038/s41569-021-00665-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8757397PMC
January 2022

Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudoviruses.

Sci Transl Med 2022 Jan 13:eabn7842. Epub 2022 Jan 13.

J. Craig Venter Institute, La Jolla, CA, 92037 and Rockville, MD, 20850 USA.

Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that possess 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 pre-existing 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 wildtype (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.
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http://dx.doi.org/10.1126/scitranslmed.abn7842DOI Listing
January 2022

New-onset IgG autoantibodies in hospitalized patients with COVID-19.

Nat Commun 2021 09 14;12(1):5417. Epub 2021 Sep 14.

Department of Medicine, Division of Primary Care and Population Health, Stanford University School of Medicine, Stanford, CA, USA.

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.
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http://dx.doi.org/10.1038/s41467-021-25509-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440763PMC
September 2021

Illuminating the Fc dependence of SARS-CoV-2 neutralization.

Immunity 2021 09 25;54(9):1912-1914. Epub 2021 Aug 25.

Department of Medicine, Division of Infectious Diseases, Stanford University, Stanford, CA, USA; Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA. Electronic address:

Monoclonal antibodies show efficacy in treating COVID-19, but the functional requirements for protection are unclear. In this issue of Immunity, Ullah et al. (2021) develop a stable SARS-CoV-2 reporter virus and use bioluminescence imaging to longitudinally monitor infection and assess neutralizing monoclonal antibody interventions in mice. They find that antibody-mediated protection depends on the Fc domain and Fc-gamma receptor-expressing immune cells.
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http://dx.doi.org/10.1016/j.immuni.2021.08.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384580PMC
September 2021

An aberrant inflammatory response in severe COVID-19.

Cell Host Microbe 2021 07;29(7):1043-1047

Department of Medicine, Division of Infectious Diseases, Stanford University, Stanford, CA, USA; Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA. Electronic address:

Severe COVID-19 arises from the convergence of inadequate pre-existing immunity and a host response that damages, rather than repairs, tissues. We outline clinical presentations of COVID-19 that are likely driven by dysregulated host immunity, discuss potential mechanisms underlying pathological responses, and highlight important areas for basic research on this topic.
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http://dx.doi.org/10.1016/j.chom.2021.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279571PMC
July 2021

Structurally and functionally distinct early antibody responses predict COVID-19 disease trajectory and mRNA vaccine response.

bioRxiv 2021 Dec 27. Epub 2021 Dec 27.

A damaging inflammatory response is strongly implicated in the pathogenesis of severe COVID-19 but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated, anti-SARS-CoV-2 IgG predicted progression from mild, to more severe COVID-19. In contrast to the antibody structures that predicted disease progression, antibodies that were elicited by mRNA SARS-CoV-2 vaccines were low in Fc afucosylation and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. To study the biology afucosylated IgG immune complexes, we developed an model which revealed that human IgG-FcγR interactions can regulate inflammation in the lung. Afucosylated IgG immune complexes induced inflammatory cytokine production and robust infiltration of the lung by immune cells. By contrast, vaccine elicited IgG did not promote an inflammatory lung response. Here, we show that IgG-FcγR interactions can regulate inflammation in the lung and define distinct lung activities associated with the IgG that predict severe COVID-19 and protection against SARS-CoV-2.

One Sentence Summary: Divergent early antibody responses predict COVID-19 disease trajectory and mRNA vaccine response and are functionally distinct .
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http://dx.doi.org/10.1101/2021.05.25.445649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168384PMC
December 2021

Immunity after SARS-CoV-2 infections.

Nat Immunol 2021 05;22(5):539-540

Department of Medicine, Division of Infectious Diseases, Stanford University, Stanford, CA, USA.

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http://dx.doi.org/10.1038/s41590-021-00923-3DOI Listing
May 2021

Engineering luminescent biosensors for point-of-care SARS-CoV-2 antibody detection.

Nat Biotechnol 2021 08 25;39(8):928-935. Epub 2021 Mar 25.

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.

Current serology tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies mainly take the form of enzyme-linked immunosorbent assays, chemiluminescent microparticle immunoassays or lateral flow assays, which are either laborious, expensive or lacking sufficient sensitivity and scalability. Here we present the development and validation of a rapid, low-cost, solution-based assay to detect antibodies in serum, plasma, whole blood and to a lesser extent saliva, using rationally designed split luciferase antibody biosensors. This new assay, which generates quantitative results in 30 min, substantially reduces the complexity and improves the scalability of coronavirus disease 2019 (COVID-19) antibody tests. This assay is well-suited for point-of-care, broad population testing, and applications in low-resource settings, for monitoring host humoral responses to vaccination or viral infection.
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http://dx.doi.org/10.1038/s41587-021-00878-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355051PMC
August 2021

New-Onset IgG Autoantibodies in Hospitalized Patients with COVID-19.

medRxiv 2021 Jan 29. Epub 2021 Jan 29.

Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. We developed three different protein arrays to measure hallmark IgG autoantibodies associated with Connective Tissue Diseases (CTDs), Anti-Cytokine Antibodies (ACA), and anti-viral antibody responses in 147 hospitalized COVID-19 patients in three different centers. Autoantibodies were identified in approximately 50% of patients, but in <15% of healthy controls. When present, autoantibodies largely targeted autoantigens associated with rare disorders such as myositis, systemic sclerosis and CTD overlap syndromes. Anti-nuclear antibodies (ANA) were observed in ∼25% of patients. Patients with autoantibodies tended to demonstrate one or a few specificities whereas ACA were even more prevalent, and patients often had antibodies to multiple cytokines. Rare patients were identified with IgG antibodies against angiotensin converting enzyme-2 (ACE-2). A subset of autoantibodies and ACA developed following SARS-CoV-2 infection while others were transient. Autoantibodies tracked with longitudinal development of IgG antibodies that recognized SARS-CoV-2 structural proteins such as S1, S2, M, N and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. COVID-19 patients with one or more autoantibodies tended to have higher levels of antibodies against SARS-CoV-2 Nonstructural Protein 1 (NSP1) and Methyltransferase (ME). 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.
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http://dx.doi.org/10.1101/2021.01.27.21250559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852238PMC
January 2021

SARS-CoV-2 vaccines in advanced clinical trials: Where do we stand?

Adv Drug Deliv Rev 2021 05 20;172:314-338. Epub 2021 Jan 20.

Department of Medicine, Division of Infectious Diseases, Stanford University, Stanford, CA, USA; Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.addr.2021.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816567PMC
May 2021

Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome.

Sci Immunol 2020 12;5(54)

Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.

SARS-CoV-2-specific antibodies, particularly those preventing viral spike receptor binding domain (RBD) interaction with host angiotensin-converting enzyme 2 (ACE2) receptor, can neutralize the virus. It is, however, unknown which features of the serological response may affect clinical outcomes of COVID-19 patients. We analyzed 983 longitudinal plasma samples from 79 hospitalized COVID-19 patients and 175 SARS-CoV-2-infected outpatients and asymptomatic individuals. Within this cohort, 25 patients died of their illness. Higher ratios of IgG antibodies targeting S1 or RBD domains of spike compared to nucleocapsid antigen were seen in outpatients who had mild illness versus severely ill patients. Plasma antibody increases correlated with decreases in viral RNAemia, but antibody responses in acute illness were insufficient to predict inpatient outcomes. Pseudovirus neutralization assays and a scalable ELISA measuring antibodies blocking RBD-ACE2 interaction were well correlated with patient IgG titers to RBD. Outpatient and asymptomatic individuals' SARS-CoV-2 antibodies, including IgG, progressively decreased during observation up to five months post-infection.
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http://dx.doi.org/10.1126/sciimmunol.abe0240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857392PMC
December 2020

Proinflammatory IgG Fc structures in patients with severe COVID-19.

Nat Immunol 2021 01 9;22(1):67-73. Epub 2020 Nov 9.

Department of Medicine, Division of Infectious Diseases, Stanford University, Stanford, CA, USA.

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.
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http://dx.doi.org/10.1038/s41590-020-00828-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130642PMC
January 2021

Human B Cell Clonal Expansion and Convergent Antibody Responses to SARS-CoV-2.

Cell Host Microbe 2020 10 3;28(4):516-525.e5. Epub 2020 Sep 3.

Department of Pathology, Stanford University, Stanford, CA 94305, USA; Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA, 94305, USA. Electronic address:

B cells are critical for the production of antibodies and protective immunity to viruses. Here we show that patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) display early recruitment of B cells expressing a limited subset of IGHV genes, progressing to a highly polyclonal response of B cells with broader IGHV gene usage and extensive class switching to IgG and IgA subclasses with limited somatic hypermutation in the initial weeks of infection. We identify convergence of antibody sequences across SARS-CoV-2-infected patients, highlighting stereotyped naive responses to this virus. Notably, sequence-based detection in COVID-19 patients of convergent B cell clonotypes previously reported in SARS-CoV infection predicts the presence of SARS-CoV/SARS-CoV-2 cross-reactive antibody titers specific for the receptor-binding domain. These findings offer molecular insights into shared features of human B cell responses to SARS-CoV-2 and SARS-CoV.
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http://dx.doi.org/10.1016/j.chom.2020.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470783PMC
October 2020

Competitive SARS-CoV-2 Serology Reveals Most Antibodies Targeting the Spike Receptor-Binding Domain Compete for ACE2 Binding.

mSphere 2020 09 16;5(5). Epub 2020 Sep 16.

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread around the world, there is an urgent need for new assay formats to characterize the humoral response to infection. Here, we present an efficient, competitive serological assay that can simultaneously determine an individual's seroreactivity against the SARS-CoV-2 Spike protein and determine the proportion of anti-Spike antibodies that block interaction with the human angiotensin-converting enzyme 2 (ACE2) required for viral entry. In this approach based on the use of enzyme-linked immunosorbent assays (ELISA), we present natively folded viral Spike protein receptor-binding domain (RBD)-containing antigens via avidin-biotin interactions. Sera are then competed with soluble ACE2-Fc, or with a higher-affinity variant thereof, to determine the proportion of ACE2 blocking anti-RBD antibodies. Assessment of sera from 144 SARS-CoV-2 patients ultimately revealed that a remarkably consistent and high proportion of antibodies in the anti-RBD pool targeted the epitope responsible for ACE2 engagement (83% ± 11%; 50% to 107% signal inhibition in our largest cohort), further underscoring the importance of tailoring vaccines to promote the development of such antibodies. With the emergence and continued spread of the SARS-CoV-2 virus, and of the associated disease, coronavirus disease 2019 (COVID-19), there is an urgent need for improved understanding of how the body mounts an immune response to the virus. Here, we developed a competitive SARS-CoV-2 serological assay that can simultaneously determine whether an individual has developed antibodies against the SARS-CoV-2 Spike protein receptor-binding domain (RBD) and measure the proportion of these antibodies that block interaction with the human angiotensin-converting enzyme 2 (ACE2) required for viral entry. Using this assay and 144 SARS-CoV-2 patient serum samples, we found that a majority of anti-RBD antibodies compete for ACE2 binding. These results not only highlight the need to design vaccines to generate such blocking antibodies but also demonstrate the utility of this assay to rapidly screen patient sera for potentially neutralizing antibodies.
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http://dx.doi.org/10.1128/mSphere.00802-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494835PMC
September 2020

Engineering luminescent biosensors for point-of-care SARS-CoV-2 antibody detection.

medRxiv 2020 Aug 21. Epub 2020 Aug 21.

Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, 94158, USA.

Current serology tests for SARS-CoV-2 antibodies mainly take the form of enzyme-linked immunosorbent assays or lateral flow assays, with the former being laborious and the latter being expensive and often lacking sufficient sensitivity and scalability. Here we present the development and validation of a rapid, low-cost solution-based assay to detect antibodies in serum, plasma, whole blood, and saliva, using rationally designed split luciferase antibody biosensors (spLUC). This new assay, which generates quantitative results in as short as 5 minutes, substantially reduces the complexity and improves the scalability of COVID-19 antibody tests for point-of-care and broad population testing.
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http://dx.doi.org/10.1101/2020.08.17.20176925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444307PMC
August 2020

SARS-CoV-2 Antibody Responses Correlate with Resolution of RNAemia But Are Short-Lived in Patients with Mild Illness.

medRxiv 2020 Aug 17. Epub 2020 Aug 17.

SARS-CoV-2-specific antibodies, particularly those preventing viral spike receptor binding domain (RBD) interaction with host angiotensin-converting enzyme 2 (ACE2) receptor, could offer protective immunity, and may affect clinical outcomes of COVID-19 patients. We analyzed 625 serial plasma samples from 40 hospitalized COVID-19 patients and 170 SARS-CoV-2-infected outpatients and asymptomatic individuals. Severely ill patients developed significantly higher SARS-CoV-2-specific antibody responses than outpatients and asymptomatic individuals. The development of plasma antibodies was correlated with decreases in viral RNAemia, consistent with potential humoral immune clearance of virus. Using a novel competition ELISA, we detected antibodies blocking RBD-ACE2 interactions in 68% of inpatients and 40% of outpatients tested. Cross-reactive antibodies recognizing SARS-CoV RBD were found almost exclusively in hospitalized patients. Outpatient and asymptomatic individuals' serological responses to SARS-CoV-2 decreased within 2 months, suggesting that humoral protection may be short-lived.
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http://dx.doi.org/10.1101/2020.08.15.20175794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444305PMC
August 2020

B cell clonal expansion and convergent antibody responses to SARS-CoV-2.

Res Sq 2020 May 6. Epub 2020 May 6.

Department of Pathology, Stanford University.

During virus infection B cells are critical for the production of antibodies and protective immunity. Establishment of a diverse antibody repertoire occurs by rearrangement of germline DNA at the immunoglobulin heavy and light chain loci to encode the membrane-bound form of antibodies, the B cell antigen receptor. Little is known about the B cells and antigen receptors stimulated by the novel human coronavirus SARS-CoV-2. Here we show that the human B cell compartment in patients with diagnostically confirmed SARS-CoV-2 and clinical COVID-19 is rapidly altered with the early recruitment of B cells expressing a limited subset of V genes, and extensive activation of IgG and IgA subclasses without significant somatic mutation. We detect expansion of B cell clones as well as convergent antibodies with highly similar sequences across SARS-CoV-2 patients, highlighting stereotyped naïve responses to this virus. A shared convergent B cell clonotype in SARS-CoV-2 infected patients was previously seen in patients with SARS. These findings offer molecular insights into shared features of human B cell responses to SARS-CoV-2 and other zoonotic spillover coronaviruses.
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http://dx.doi.org/10.21203/rs.3.rs-27220/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336706PMC
May 2020

Human B cell clonal expansion and convergent antibody responses to SARS-CoV-2.

bioRxiv 2020 Jul 9. Epub 2020 Jul 9.

Department of Pathology, Stanford University, Stanford, CA 94305, USA.

During virus infection B cells are critical for the production of antibodies and protective immunity. Here we show that the human B cell compartment in patients with diagnostically confirmed SARS-CoV-2 and clinical COVID-19 is rapidly altered with the early recruitment of B cells expressing a limited subset of IGHV genes, progressing to a highly polyclonal response of B cells with broader IGHV gene usage and extensive class switching to IgG and IgA subclasses with limited somatic hypermutation in the initial weeks of infection. We identify extensive convergence of antibody sequences across SARS-CoV-2 patients, highlighting stereotyped naïve responses to this virus. Notably, sequence-based detection in COVID-19 patients of convergent B cell clonotypes previously reported in SARS-CoV infection predicts the presence of SARS-CoV/SARS-CoV-2 cross-reactive antibody titers specific for the receptor-binding domain. These findings offer molecular insights into shared features of human B cell responses to SARS-CoV-2 and other zoonotic spillover coronaviruses.
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http://dx.doi.org/10.1101/2020.07.08.194456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359515PMC
July 2020

Immunoglobulin E sialylation regulates allergic responses.

Immunol Cell Biol 2020 09 7;98(8):617-619. Epub 2020 Jul 7.

Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA, USA.

Shade et al. demonstrate that people with peanut allergies produce IgE antibodies that are enriched for sialic acid-containing glycoforms. The sialylated IgE triggered significantly more degranulation by basophils and mast cells, suggesting intrinsic functional differences between IgEs from allergic and nonallergic subjects.
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http://dx.doi.org/10.1111/imcb.12368DOI Listing
September 2020

Proinflammatory IgG Fc structures in patients with severe COVID-19.

medRxiv 2020 Nov 10. Epub 2020 Nov 10.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-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 severe COVID-19 patients produced a unique serologic signature, including increased IgG1 with afucosylated Fc glycans. This Fc modification on SARS-CoV-2 IgGs enhanced interactions with the activating FcγR, FcγRIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including IL-6 and TNF. These results show that disease severity in COVID-19 correlates with the presence of afucosylated IgG1, a pro-inflammatory IgG Fc modification.
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http://dx.doi.org/10.1101/2020.05.15.20103341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252581PMC
November 2020

FcRn, but not FcγRs, drives maternal-fetal transplacental transport of human IgG antibodies.

Proc Natl Acad Sci U S A 2020 06 27;117(23):12943-12951. Epub 2020 May 27.

Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305;

The IgG Fc domain has the capacity to interact with diverse types of receptors, including the neonatal Fc receptor (FcRn) and Fcγ receptors (FcγRs), which confer pleiotropic biological activities. Whereas FcRn regulates IgG epithelial transport and recycling, Fc effector activities, such as antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis, are mediated by FcγRs, which upon cross-linking transduce signals that modulate the function of effector leukocytes. Despite the well-defined and nonoverlapping functional properties of FcRn and FcγRs, recent studies have suggested that FcγRs mediate transplacental IgG transport, as certain Fc glycoforms were reported to be enriched in fetal circulation. To determine the contribution of FcγRs and FcRn to the maternal-fetal transport of IgG, we characterized the IgG Fc glycosylation in paired maternal-fetal samples from patient cohorts from Uganda and Nicaragua. No differences in IgG1 Fc glycan profiles and minimal differences in IgG2 Fc glycans were noted, whereas the presence or absence of galactose on the Fc glycan of IgG1 did not alter FcγRIIIa or FcRn binding, half-life, or their ability to deplete target cells in FcγR/FcRn humanized mice. Modeling maternal-fetal transport in FcγR/FcRn humanized mice confirmed that only FcRn contributed to transplacental transport of IgG; IgG selectively enhanced for FcRn binding resulted in enhanced accumulation of maternal antibody in the fetus. In contrast, enhancing FcγRIIIa binding did not result in enhanced maternal-fetal transport. These results argue against a role for FcγRs in IgG transplacental transport, suggesting Fc engineering of maternally administered antibody to enhance only FcRn binding as a means to improve maternal-fetal transport of IgG.
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http://dx.doi.org/10.1073/pnas.2004325117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293622PMC
June 2020

Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19.

Cell 2020 05 15;181(5):1036-1045.e9. Epub 2020 May 15.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Virus Engineering Center for Therapeutics and Research, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
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http://dx.doi.org/10.1016/j.cell.2020.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227586PMC
May 2020

Maternal Anti-Dengue IgG Fucosylation Predicts Susceptibility to Dengue Disease in Infants.

Cell Rep 2020 05;31(6):107642

Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94518, USA. Electronic address:

Infant mortality from dengue disease is a devastating global health burden that could be minimized with the ability to identify susceptibility for severe disease prior to infection. Although most primary infant dengue infections are asymptomatic, maternally derived anti-dengue immunoglobulin G (IgGs) present during infection can trigger progression to severe disease through antibody-dependent enhancement mechanisms. Importantly, specific characteristics of maternal IgGs that herald progression to severe infant dengue are unknown. Here, we define ≥10% afucosylation of maternal anti-dengue IgGs as a risk factor for susceptibility of infants to symptomatic dengue infections. Mechanistic experiments show that afucosylation of anti-dengue IgGs promotes FcγRIIIa signaling during infection, in turn enhancing dengue virus replication in FcγRIIIa monocytes. These studies identify a post-translational modification of anti-dengue IgGs that correlates with risk for symptomatic infant dengue infections and define a mechanism by which afucosylated antibodies and FcγRIIIa enhance dengue infections.
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http://dx.doi.org/10.1016/j.celrep.2020.107642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344335PMC
May 2020

Functional diversification of IgGs through Fc glycosylation.

J Clin Invest 2019 09;129(9):3492-3498

Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.

IgG antibodies are secreted from B cells and bind to a variety of pathogens to control infections as well as contribute to inflammatory diseases. Many of the functions of IgGs are mediated through Fcγ receptors (FcγRs), which transduce interactions with immune complexes, leading to a variety of cellular outcomes depending on the FcγRs and cell types engaged. Which FcγRs and cell types will be engaged during an immune response depends on the structure of Fc domains within immune complexes that are formed when IgGs bind to cognate antigen(s). Recent studies have revealed an unexpected degree of structural variability in IgG Fc domains among people, driven primarily by differences in IgG subclasses and N-linked glycosylation of the CH2 domain. This translates, in turn, to functional immune diversification through type I and type II FcγR-mediated cellular functions. For example, Fc domain sialylation triggers conformational changes of IgG1 that enable interactions with type II FcγRs; these receptors mediate cellular functions including antiinflammatory activity or definition of thresholds for B cell selection based on B cell receptor affinity. Similarly, presence or absence of a core fucose alters type I FcγR binding of IgG1 by modulating the Fc's affinity for FcγRIIIa, thereby altering its proinflammatory activity. How heterogeneity in IgG Fc domains contributes to human immune diversity is now being elucidated, including impacts on vaccine responses and susceptibility to disease and its sequelae during infections. Here, we discuss how Fc structures arising from sialylation and fucosylation impact immunity, focusing on responses to vaccination and infection. We also review work defining individual differences in Fc glycosylation, regulation of Fc glycosylation, and clinical implications of these pathways.
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http://dx.doi.org/10.1172/JCI130029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715372PMC
September 2019

IgG Fc Glycosylation in Human Immunity.

Authors:
Taia T Wang

Curr Top Microbiol Immunol 2019 ;423:63-75

Department of Medicine, Division of Infectious Diseases, Department of Microbiology and Immunology, Program in Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA, 94305, USA.

Glycosylation of IgG Fc domains is a central mechanism in the diversification of antibody function. Modifications to the core Fc glycan impact antibody function by shifting the balance of Type I and Type II Fc gamma receptors (FcγR) that will be engaged by immune complexes. This, in turn, modulates the effector cells and functions that can be recruited during immune activation. Critically, humans have evolved to regulate Fc glycan modifications for immune homeostasis. Dysregulation in Fc glycan modifications can lead to loss of immune tolerance, symptomatic autoimmunity, and susceptibility to infectious diseases. Here, we discuss IgG Fc glycosylation and its role in human health and disease.
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http://dx.doi.org/10.1007/82_2019_152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853246PMC
September 2019

The Role of Fc Gamma Receptors in Broad Protection against Influenza Viruses.

Vaccines (Basel) 2018 Jun 29;6(3). Epub 2018 Jun 29.

Department of Medicine, Division of Infectious Diseases, Stanford University School of Medicine, Stanford, CA 94305, USA.

Recent studies have revealed multiple roles for Fc gamma receptors (FcγRs) in broad immunity against influenza viruses. Activating FcγR pathways can be harnessed to confer protection mediated by non-neutralizing anti-HA IgGs and to increase the potency of broadly neutralizing anti-HA IgGs and of anti-NA IgGs. Separate FcγR pathways can be targeted to enhance the breadth of antibody responses elicited by seasonal influenza virus vaccines. Here, we review the current understanding of FcγR pathways in broad influenza immunity and suggest mechanisms to bypass FcγR signaling heterogeneity among people that arises from distinctions in structural repertoires of IgG Fc domains.
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http://dx.doi.org/10.3390/vaccines6030036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160953PMC
June 2018

Immunological responses to influenza vaccination: lessons for improving vaccine efficacy.

Curr Opin Immunol 2018 08 10;53:124-129. Epub 2018 May 10.

The Rockefeller University, 1230 York Avenue, NY 10065, USA. Electronic address:

A critical factor in the maturation of influenza vaccine responses is the nearly inevitable binding of vaccine antigens by exiting anti-influenza IgGs. These antigen-IgG immune complexes direct the response to immunization by modulating cellular processes that determine antibody and T-cell repertoires: maturation of dendritic cells, processing and presentation of antigens to T cells, trafficking of antigens to the germinal center, and selection of B cells for antibody production. By focusing on the recent advances in the study of the immunomodulatory processes mediated by IgG immune complexes upon influenza vaccination, we discuss a pathway that is critical for modulating the breadth and potency of anti-HA antibody responses and has previously led to the development of strategies to improve influenza vaccine efficacy.
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http://dx.doi.org/10.1016/j.coi.2018.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141319PMC
August 2018

Immunity by Design.

Authors:
Taia T Wang

Cell Host Microbe 2018 04;23(4):430-431

Department of Medicine, Division of Infectious Diseases, Stanford Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address:

One outcome of the many advances in basic sciences that have been made over the last decades is the prospect of rational vaccine design. A recent publication by Du et al. (2018) describes a screening method for selection of live-attenuated viral vaccine platforms with enhanced immune-stimulatory properties.
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http://dx.doi.org/10.1016/j.chom.2018.03.017DOI Listing
April 2018

Increasing the breadth and potency of response to the seasonal influenza virus vaccine by immune complex immunization.

Proc Natl Acad Sci U S A 2017 09 5;114(38):10172-10177. Epub 2017 Sep 5.

Leonard Wagner Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065;

The main barrier to reduction of morbidity caused by influenza is the absence of a vaccine that elicits broad protection against different virus strains. Studies in preclinical models of influenza virus infections have shown that antibodies alone are sufficient to provide broad protection against divergent virus strains in vivo. Here, we address the challenge of identifying an immunogen that can elicit potent, broadly protective, antiinfluenza antibodies by demonstrating that immune complexes composed of sialylated antihemagglutinin antibodies and seasonal inactivated flu vaccine (TIV) can elicit broadly protective antihemagglutinin antibodies. Further, we found that an Fc-modified, bispecific monoclonal antibody against conserved epitopes of the hemagglutinin can be combined with TIV to elicit broad protection, thus setting the stage for a universal influenza virus vaccine.
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http://dx.doi.org/10.1073/pnas.1707950114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617290PMC
September 2017
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