Boards, Advisory Committees, Professional Organizations
Investigator, Chan Zuckerberg Biohub (2017 - Present)
Young Physician-Scientist Award, The American Society for Clinical Investigation (2017 - Present)
Member, American Society for Microbiology (2016 - Present)
Associate Scientific Advisor, Science Translational Medicine (2015 - 2016)
Member, The American Association of Immunologists (2012 - Present)
Member, New York Academy of Sciences (2007 - Present)
MSCI, Rockefeller University, Masters of Science in Clinical Investigation (2015)
Postdoctoral training, Rockefeller University, Fc receptor biology and human immunology
MD, Mount Sinai School of Medicine, Medicine (2012)
PhD, Mount Sinai School of Medicine, Virology (2010)
Current Research and Scholarly Interests
Studies in our lab are driven by the hypothesis that IgG repertoire diversity is a central driver of heterogeneity in human immune functioning and susceptibility to diseases. We are specifically interested in diversity that exists in the Fc domain repertoire among people, which we define by serum IgG subclass and Fc glycoform distributions. We have found that the Fc domain repertoire of an individual impacts key immune processes such as vaccine responses and susceptibility to antibody-dependent enhancement of dengue disease (Wang TT, Cell. 2015 and Wang TT, Science. 2017). This is because IgG subclasses and Fc glycoforms dictate the structure of Fc domains within immune complexes that form during vaccination or infection. This, in turn, determines the affinity of immune complexes for various Fc receptors on effector cells. Thus, our research seeks to define how the Fc domain repertoire of an individual determines the quality of effector cell responses that can be recruited during immune activation.
We are particularly interested in training students and postdocs who will go on to be independent investigators in mechanistic studies relevant to human disease.
Current clinical studies:
An Open Label Study of IgG Fc Glycan Composition in Human Immunity
Principal Investigator: Taia T. Wang, MD, PhD
IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity.
Science (New York, N.Y.)
2017; 355 (6323): 395–98
Dengue virus (DENV) infection in the presence of reactive, non-neutralizing immunoglobulin G (IgG) (RNNIg) is the greatest risk factor for dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Progression to DHF/DSS is attributed to antibody-dependent enhancement (ADE); however, because only a fraction of infections occurring in the presence of RNNIg advance to DHF/DSS, the presence of RNNIg alone cannot account for disease severity. We discovered that DHF/DSS patients respond to infection by producing IgGs with enhanced affinity for the activating Fc receptor FcγRIIIA due to afucosylated Fc glycans and IgG1 subclass. RNNIg enriched for afucosylated IgG1 triggered platelet reduction in vivo and was a significant risk factor for thrombocytopenia. Thus, therapeutics and vaccines restricting production of afucosylated, IgG1 RNNIg during infection may prevent ADE of DENV disease.
View details for DOI 10.1126/science.aai8128
View details for PubMedID 28126818
Increasing the breadth and potency of response to the seasonal influenza virus vaccine by immune complex immunization.
Proceedings of the National Academy of Sciences of the United States of America
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.
View details for DOI 10.1073/pnas.1707950114
View details for PubMedID 28874545
Signaling by Antibodies: Recent Progress
Annual Review of Immunology
2017; 35 (April 26): 285-311
View details for DOI 10.1146/annurev-immunol-051116-052433
The Role and Function of Fcγ Receptors on Myeloid Cells.
2016; 4 (6)
A key determinant for the survival of organisms is their capacity to recognize and respond efficiently to foreign antigens. This is largely accomplished by the orchestrated activity of the innate and adaptive branches of the immune system. Antibodies are specifically generated in response to foreign antigens, facilitating thereby the specific recognition of antigens of almost infinite diversity. Receptors specific for the Fc domain of antibodies, Fc receptors, are expressed on the surface of the various myeloid leukocyte populations and mediate the binding and recognition of antibodies by innate leukocytes. By directly linking the innate and the adaptive components of immunity, Fc receptors play a central role in host defense and the maintenance of tissue homeostasis through the induction of diverse proinflammatory, anti-inflammatory, and immunomodulatory processes that are initiated upon engagement by the Fc domain. In this chapter, we discuss the mechanisms that regulate Fc domain binding to the various types of Fc receptors and provide an overview of the astonishing diversity of effector functions that are mediated through Fc-FcR interactions on myeloid cells. Lastly, we discuss the impact of FcR-mediated interactions in the context of IgG-mediated inflammation, autoimmunity, susceptibility to infection, and responsiveness to antibody-based therapeutics.
View details for DOI 10.1128/microbiolspec.MCHD-0045-2016
View details for PubMedID 28087938
- Sex Differences in Autoimmune Disease Hormones, Brain and Behavior Academic Press. 2016; 3: 445–465
Anti-HA Glycoforms Drive B Cell Affinity Selection and Determine Influenza Vaccine Efficacy
2015; 162 (1): 160-169
Protective vaccines elicit high-affinity, neutralizing antibodies by selection of somatically hypermutated B cell antigen receptors (BCR) on immune complexes (ICs). This implicates Fc-Fc receptor (FcR) interactions in affinity maturation, which, in turn, are determined by IgG subclass and Fc glycan composition within ICs. Trivalent influenza virus vaccination elicited regulation of anti-hemagglutinin (HA) IgG subclass and Fc glycans, with abundance of sialylated Fc glycans (sFc) predicting quality of vaccine response. We show that sFcs drive BCR affinity selection by binding the Type-II FcR CD23, thus upregulating the inhibitory FcγRIIB on activated B cells. This elevates the threshold requirement for BCR signaling, resulting in B cell selection for higher affinity BCR. Immunization with sFc HA ICs elicited protective, high-affinity IgGs against the conserved stalk of the HA. These results reveal a novel, endogenous pathway for affinity maturation that can be exploited for eliciting high-affinity, broadly neutralizing antibodies through immunization with sialylated immune complexes.
View details for DOI 10.1016/j.cell.2015.06.026
View details for Web of Science ID 000357542300017
View details for PubMedID 26140596
Immune Complexes: Not Just an Innocent Bystander in Chronic Viral Infection
2015; 42 (2): 213-215
Understanding of how persistent viral infection impacts humoral immunity is incomplete. In this issue of Immunity, Wieland et al. (2015) and Yamada et al. (2015) find that high amounts of IgG-antigen complexes formed during chronic lymphocytic choriomeningitis infection can interfere with Fcγ-receptor-mediated effector activities, potentially contributing to immune dysfunction.
View details for DOI 10.1016/j.immuni.2015.01.022
View details for Web of Science ID 000349916400006
View details for PubMedID 25692698
Type I and type II Fc receptors regulate innate and adaptive immunity
2014; 15 (8): 707-716
Antibodies produced in response to a foreign antigen are characterized by polyclonality, not only in the diverse epitopes to which their variable domains bind but also in the various effector molecules to which their constant regions (Fc domains) engage. Thus, the antibody's Fc domain mediates diverse effector activities by engaging two distinct classes of Fc receptors (type I and type II) on the basis of the two dominant conformational states that the Fc domain may adopt. These conformational states are regulated by the differences among antibody subclasses in their amino acid sequence and by the complex, biantennary Fc-associated N-linked glycan. Here we discuss the diverse downstream proinflammatory, anti-inflammatory and immunomodulatory consequences of the engagement of type I and type II Fc receptors in the context of infectious, autoimmune, and neoplastic disorders.
View details for DOI 10.1038/ni.2939
View details for Web of Science ID 000339323000006
View details for PubMedID 25045879
Emergence and evolution of the 1918, 1957, 1968, and 2009 pandemic virus strains
Textbook of Influenza
John Wiley & Sons. 2013; 2
View details for DOI DOI: 10.1002/9781118636817.ch14
Seroevidence for H5N1 Influenza Infections in Humans: Meta-Analysis
2012; 335 (6075): 1463-1463
The prevalence of avian H5N1 influenza A infections in humans has not been definitively determined. Cases of H5N1 infection in humans confirmed by the World Health Organization (WHO) are fewer than 600 in number, with an overall case fatality rate of >50%. We hypothesize that the stringent criteria for confirmation of a human case of H5N1 by WHO do not account for a majority of infections but rather the select few hospitalized cases that are more likely to be severe and result in poor clinical outcome. Meta-analysis shows that 1 to 2% of more than 12,500 study participants from 20 studies had seroevidence for prior H5N1 infection.
View details for DOI 10.1126/science.1218888
View details for Web of Science ID 000301837000037
View details for PubMedID 22362880
H5N1 influenza viruses: Facts, not fear
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2012; 109 (7): 2211-2213
The ongoing controversy over publication of two studies involving the transmission in ferrets of H5N1 (H5) subtype influenza viruses and the recommendations of the National Science Advisory Board for Biosecurity to redact key details in the manuscripts call for an examination of relevant scientific facts. In addition, there are calls in the media to destroy the viruses, curtail future research in this area, and protect the public from such "frightening" research efforts. Fear needs to be put to rest with solid science and not speculation.
View details for DOI 10.1073/pnas.1121297109
View details for Web of Science ID 000300489200018
View details for PubMedID 22308474
Hemagglutinin stalk antibodies elicited by the 2009 pandemic influenza virus as a mechanism for the extinction of seasonal H1N1 viruses
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2012; 109 (7): 2573-2578
After the emergence of pandemic influenza viruses in 1957, 1968, and 2009, existing seasonal viruses were observed to be replaced in the human population by the novel pandemic strains. We have previously hypothesized that the replacement of seasonal strains was mediated, in part, by a population-scale boost in antibodies specific for conserved regions of the hemagglutinin stalk and the viral neuraminidase. Numerous recent studies have shown the role of stalk-specific antibodies in neutralization of influenza viruses; the finding that stalk antibodies can effectively neutralize virus alters the existing dogma that influenza virus neutralization is mediated solely by antibodies that react with the globular head of the viral hemagglutinin. The present study explores the possibility that stalk-specific antibodies were boosted by infection with the 2009 H1N1 pandemic virus and that those antibodies could have contributed to the disappearance of existing seasonal H1N1 influenza virus strains. To study stalk-specific antibodies, we have developed chimeric hemagglutinin constructs that enable the measurement of antibodies that bind the hemagglutinin protein and neutralize virus but do not have hemagglutination inhibition activity. Using these chimeric hemagglutinin reagents, we show that infection with the 2009 pandemic H1N1 virus elicited a boost in titer of virus-neutralizing antibodies directed against the hemagglutinin stalk. In addition, we describe assays that can be used to measure influenza virus-neutralizing antibodies that are not detected in the traditional hemagglutination inhibition assay.
View details for DOI 10.1073/pnas.1200039109
View details for Web of Science ID 000300489200081
View details for PubMedID 22308500
Why Do Influenza Virus Subtypes Die Out? A Hypothesis
2011; 2 (5)
Novel pandemic influenza viruses enter the human population with some regularity and can cause disease that is severe and widespread. The emergence of novel viruses, historically, has often been coupled with the disappearance of existing seasonal virus strains. Here, we propose that the elimination of seasonal strains during virus pandemics is a process mediated, at the population level, by humoral immunity. Specifically, we suggest that infection with a novel virus strain, in people previously exposed to influenza viruses, can elicit a memory B cell response against conserved hemagglutinin stalk epitopes and/or neuraminidase epitopes. The anti-stalk and/or anti-neuraminidase antibodies then act to diminish the clinical severity of disease caused by novel influenza viruses and to eliminate seasonal virus strains.
View details for DOI 10.1128/mBio.00150-11
View details for Web of Science ID 000296844300005
View details for PubMedID 21878571
- Biochemistry. Catching a moving target. Science 2011; 333 (6044): 834-835
Vaccination with a synthetic peptide from the influenza virus hemagglutinin provides protection against distinct viral subtypes
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2010; 107 (44): 18979-18984
Current influenza virus vaccines protect mostly against homologous virus strains; thus, regular immunization with updated vaccine formulations is necessary to guard against the virus' hallmark remodeling of regions that mediate neutralization. Development of a broadly protective influenza vaccine would mark a significant advance in human infectious diseases research. Antibodies with broad neutralizing activity (nAbs) against multiple influenza virus strains or subtypes have been reported to bind the stalk of the viral hemagglutinin, suggesting that a vaccine based on this region could elicit a broadly protective immune response. Here we describe a hemagglutinin subunit 2 protein (HA2)-based synthetic peptide vaccine that provides protection in mice against influenza viruses of the structurally divergent subtypes H3N2, H1N1, and H5N1. The immunogen is based on the binding site of the recently described nAb 12D1, which neutralizes H3 subtype viruses, demonstrates protective activity in vivo, and, in contrast to a majority of described nAbs, appears to bind to residues within a single α-helical portion of the HA2 protein. Our data further demonstrate that the specific design of our immunogen is integral in the induction of broadly active anti-hemagglutinin antibodies. These results provide proof of concept for an HA2-based influenza vaccine that could diminish the threat of pandemic influenza disease and generally reduce the significance of influenza viruses as human pathogens.
View details for DOI 10.1073/pnas.1013387107
View details for Web of Science ID 000283749000045
View details for PubMedID 20956293
A Nine-Segment Influenza A Virus Carrying Subtype H1 and H3 Hemagglutinins
JOURNAL OF VIROLOGY
2010; 84 (16): 8062-8071
Influenza virus genomic RNAs possess segment-specific packaging signals that include both noncoding regions (NCRs) and adjacent terminal coding region sequences. Using reverse genetics, an A/Puerto Rico/8/34 (A/PR/8/34) virus was rescued that contained a modified PB1 gene such that the PB1 packaging sequences were exchanged for those of the neuraminidase (NA) gene segment. To accomplish this, the PB1 open reading frame, in which the terminal packaging signals were inactivated by serial synonymous mutations, was flanked by the NA segment-specific packaging sequences including the NCRs and the coding region packaging signals. Next, the ATGs located on the 3' end of the NA packaging sequences of the resulting PB1 chimeric segment were mutated to allow for correct translation of the full-length PB1 protein. The virus containing this chimeric PB1 segment was viable and able to stably carry a ninth, green fluorescent protein (GFP), segment flanked by PB1 packaging signals. Utilizing this method, we successfully generated an influenza virus that contained the genes coding for both the H1 hemagglutinin (HA) from A/PR/8/34 and the H3 HA from A/Hong Kong/1/68 (A/HK/1/68); both subtypes of HA protein were also incorporated into the viral envelope. Immunization of mice with this recombinant virus conferred complete protection from lethal challenge with recombinant A/PR/8/34 virus and with X31 virus that expresses the A/HK/1/68 HA and NA. Using the described methodology, we show that a ninth segment can also be incorporated by manipulation of the PB2 or PA segment-specific packaging signals. This approach offers a means of generating a bivalent influenza virus vaccine.
View details for DOI 10.1128/JVI.00722-10
View details for Web of Science ID 000279983200014
View details for PubMedID 20519387
PB1-F2 Expression by the 2009 Pandemic H1N1 Influenza Virus Has Minimal Impact on Virulence in Animal Models
JOURNAL OF VIROLOGY
2010; 84 (9): 4442-4450
Unlike previous pandemic viruses, the 2009 H1N1 pandemic influenza virus does not code for the virulence factor PB1-F2. The genome of the 2009 H1N1 virus contains three stop codons preventing PB1-F2 expression; however, PB1-F2 production could occur following genetic mutation or reassortment. Thus, it is of great interest to understand the impact that expression of the PB1-F2 protein might have in the context of the 2009 pandemic influenza virus, A/California/04/2009 (Cal/09). We have addressed this question by generating two Cal/09 viruses with productive PB1-F2 open reading frames containing either an asparagine at position 66 of PB1-F2 (66N) or a serine at position 66 (66S): this N66S change has previously been shown to be associated with increased virulence in mice. We used these viruses to investigate the effect on virulence conferred by expression of the 66N or the 66S PB1-F2 protein in both in vitro and in vivo systems. Our results show enhanced replication of the 66S virus in A549 cells, while studies of BALB/c and DBA/2 mice and ferrets revealed no significant differences in symptoms of infection with wild-type Cal/09 versus the 66N or 66S virus variant. Also, coinfection of mice with Streptococcus pneumoniae and the different viruses (recombinant wild-type [rWT] Cal/09 and the 66N and 66S viruses) did not result in significant differences in mortality. Mice infected with either PB1-F2-expressing virus did demonstrate altered protein levels of proinflammatory cytokines; differences were observed to be greater in infection caused by the 66S virus. In summary, our study demonstrates that PB1-F2 expression by the Cal/09 virus modulates the immune response to infection while having a minimal effect on virus virulence in two mammalian models.
View details for DOI 10.1128/JVI.02717-09
View details for Web of Science ID 000276358000030
View details for PubMedID 20181699
Influenza Virus Vaccine Based on the Conserved Hemagglutinin Stalk Domain
2010; 1 (1)
Although highly effective in the general population when well matched to circulating influenza virus strains, current influenza vaccines are limited in their utility due to the narrow breadth of protection they provide. The strain specificity of vaccines presently in use mirrors the exquisite specificity of the neutralizing antibodies that they induce, that is, antibodies which bind to the highly variable globular head domain of hemagglutinin (HA). Herein, we describe the construction of a novel immunogen comprising the conserved influenza HA stalk domain and lacking the globular head. Vaccination of mice with this headless HA construct elicited immune sera with broader reactivity than those obtained from mice immunized with a full-length HA. Furthermore, the headless HA vaccine provided full protection against death and partial protection against disease following lethal viral challenge. Our results suggest that the response induced by headless HA vaccines is sufficiently potent to warrant their further development toward a universal influenza virus vaccine.
View details for DOI 10.1128/mBio.00018-10
View details for Web of Science ID 000284716600002
View details for PubMedID 20689752
Broadly Protective Monoclonal Antibodies against H3 Influenza Viruses following Sequential Immunization with Different Hemagglutinins
2010; 6 (2)
As targets of adaptive immunity, influenza viruses are characterized by the fluidity with which they respond to the selective pressure applied by neutralizing antibodies. This mutability of structural determinants of protective immunity is the obstacle in developing universal influenza vaccines. Towards the development of such vaccines and other immune therapies, our studies are designed to identify regions of influenza viruses that are conserved and that mediate virus neutralization. We have specifically focused on viruses of the H3N2 subtype, which have persisted as a principal source of influenza-related morbidity and mortality in humans since the pandemic of 1968. Three monoclonal antibodies have been identified that are broadly-neutralizing against H3 influenza viruses spanning 40 years. The antibodies react with the hemagglutinin glycoprotein and appear to bind in regions that are refractory to the structural variation required for viral escape from neutralization. The antibodies demonstrate therapeutic efficacy in mice against H3N2 virus infection and have potential for use in the treatment of human influenza disease. By mapping the binding region of one antibody, 12D1, we have identified a continuous region of the hemagglutinin that may act as an immunogen to elicit broadly protective immunity to H3 viruses. The anti-H3 monoclonal antibodies were identified after immunization of mice with the hemagglutinin of four different viruses (A/Hong Kong/1/1968, A/Alabama/1/1981, A/Beijing/47/1992, A/Wyoming/3/2003). This immunization schedule was designed to boost B cells specific for conserved regions of the hemagglutinin from distinct antigenic clusters. Importantly, our antibodies are of naturally occurring specificity rather than selected from cloned libraries, demonstrating that broad-spectrum humoral immunity to influenza viruses can be elicited in vivo.
View details for DOI 10.1371/journal.ppat.1000796
View details for Web of Science ID 000275295900042
View details for PubMedID 20195520
Unraveling the Mystery of Swine Influenza Virus
2009; 137 (6): 983-985
Influenza virus outbreaks occur with regularity, but the severity of outbreaks is not consistent. The recent flu epidemic caused by an H1N1 swine influenza virus presents an opportunity to examine what is known about virulence factors and the spread of infection to better prepare for major influenza outbreaks in the future.
View details for DOI 10.1016/j.cell.2009.05.032
View details for Web of Science ID 000266916400006
View details for PubMedID 19524497
- Universal epitopes of influenza virus hemagglutinins? NATURE STRUCTURAL & MOLECULAR BIOLOGY 2009; 16 (3): 233-234
The capsule of Bacillus anthracis behaves as a thymus-independent type 2 antigen
INFECTION AND IMMUNITY
2004; 72 (9): 5460-5463
Bacillus anthracis elaborates a homopolymeric capsule composed of gamma-D-glutamic acid residues. Mice were immunized with formalin-fixed encapsulated B. anthracis bacilli, and the serum antibody response to a gamma-D-glutamyl capsular epitope was measured. Antiglutamyl antibodies were elicited in athymic BALB/c Nu/Nu, BALB/c Nu/+, and CBA/J mice but not in CBA/N xid mice. These response patterns define the capsule of B. anthracis as a thymus-independent type 2 antigen.
View details for DOI 10.1128/IAI.72.9.5460-5463.2004
View details for Web of Science ID 000223580400062
View details for PubMedID 15322045
Induction of opsonic antibodies to the gamma-D-glutamic acid capsule of Bacillus anthracis by immunization with a synthetic peptide-carrier protein conjugate
FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY
2004; 40 (3): 231-237
The capsule of Bacillus anthracis, a polymer of gamma-D-glutamic acid, functions as a virulence determinant and is a poor immunogen. In this study we show that antibodies reactive with the B. anthracis capsule can be elicited in mice by immunization with a conjugate consisting of a synthetic gamma-D-glutamic acid nonamer peptide (gamma-D-glu9) covalently coupled to keyhole limpet hemocyanin. The serum response to gamma-D-glu9 was comprised primarily of IgG antibodies that recognized an epitope requiring a minimum of four gamma-linked D-glutamic acid residues. Antibodies to (gamma-D-glu9) bound to the surface of encapsulated B. anthracis cells and mediated opsonophagoctosis. These findings suggest that anti-capsular antibodies could mediate the clearance of vegetative B. anthracis cells in vivo. Thus, inclusion of an immunogenic capsular component as well as protective antigen in new anthrax vaccines would generate immune responses targeting both the bacteremic and toxigenic aspects of anthrax infection and thus may increase protective efficacy.
View details for DOI 10.1016/S0928-8244(03)00366-3
View details for Web of Science ID 000220582800008
View details for PubMedID 15039099