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1.
Frontiers in immunology ; 13, 2022.
Article in English | EuropePMC | ID: covidwho-1990170

ABSTRACT

Joining a function-enhanced Fc-portion of human IgG to the SARS-CoV-2 entry receptor ACE2 produces an antiviral decoy with strain transcending virus neutralizing activity. SARS-CoV-2 neutralization and Fc-effector functions of ACE2-Fc decoy proteins, formatted with or without the ACE2 collectrin domain, were optimized by Fc-modification. The different Fc-modifications resulted in distinct effects on neutralization and effector functions. H429Y, a point mutation outside the binding sites for FcγRs or complement caused non-covalent oligomerization of the ACE2-Fc decoy proteins, abrogated FcγR interaction and enhanced SARS-CoV-2 neutralization. Another Fc mutation, H429F did not improve virus neutralization but resulted in increased C5b-C9 fixation and transformed ACE2-Fc to a potent mediator of complement-dependent cytotoxicity (CDC) against SARS-CoV-2 spike (S) expressing cells. Furthermore, modification of the Fc-glycan enhanced cell activation via FcγRIIIa. These different immune profiles demonstrate the capacity of Fc-based agents to be engineered to optimize different mechanisms of protection for SARS-CoV-2 and potentially other viral pathogens.

2.
ACS Nano ; 2022 Jun 27.
Article in English | MEDLINE | ID: covidwho-1908087

ABSTRACT

Humans commonly have low level antibodies to poly(ethylene) glycol (PEG) due to environmental exposure. Lipid nanoparticle (LNP) mRNA vaccines for SARS-CoV-2 contain small amounts of PEG, but it is not known whether PEG antibodies are enhanced by vaccination and what their impact is on particle-immune cell interactions in human blood. We studied plasma from 130 adults receiving either the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) mRNA vaccines or no SARS-CoV-2 vaccine for PEG-specific antibodies. Anti-PEG IgG was commonly detected prior to vaccination and was significantly boosted a mean of 13.1-fold (range 1.0-70.9) following mRNA-1273 vaccination and a mean of 1.78-fold (range 0.68-16.6) following BNT162b2 vaccination. Anti-PEG IgM increased 68.5-fold (range 0.9-377.1) and 2.64-fold (0.76-12.84) following mRNA-1273 and BNT162b2 vaccination, respectively. The rise in PEG-specific antibodies following mRNA-1273 vaccination was associated with a significant increase in the association of clinically relevant PEGylated LNPs with blood phagocytes ex vivo. PEG antibodies did not impact the SARS-CoV-2 specific neutralizing antibody response to vaccination. However, the elevated levels of vaccine-induced anti-PEG antibodies correlated with increased systemic reactogenicity following two doses of vaccination. We conclude that PEG-specific antibodies can be boosted by LNP mRNA vaccination and that the rise in PEG-specific antibodies is associated with systemic reactogenicity and an increase of PEG particle-leukocyte association in human blood. The longer-term clinical impact of the increase in PEG-specific antibodies induced by lipid nanoparticle mRNA vaccines should be monitored. It may be useful to identify suitable alternatives to PEG for developing next-generation LNP vaccines to overcome PEG immunogenicity in the future.

3.
Immunity ; 55(7): 1316-1326.e4, 2022 07 12.
Article in English | MEDLINE | ID: covidwho-1867266

ABSTRACT

Vaccination against SARS-CoV-2 protects from infection and improves clinical outcomes in breakthrough infections, likely reflecting residual vaccine-elicited immunity and recall of immunological memory. Here, we define the early kinetics of spike-specific humoral and cellular immunity after vaccination of seropositive individuals and after Delta or Omicron breakthrough infection in vaccinated individuals. Early longitudinal sampling revealed the timing and magnitude of recall, with the phenotypic activation of B cells preceding an increase in neutralizing antibody titers. While vaccination of seropositive individuals resulted in robust recall of humoral and T cell immunity, recall of vaccine-elicited responses was delayed and variable in magnitude during breakthrough infections and depended on the infecting variant of concern. While the delayed kinetics of immune recall provides a potential mechanism for the lack of early control of viral replication, the recall of antibodies coincided with viral clearance and likely underpins the protective effects of vaccination against severe COVID-19.


Subject(s)
COVID-19 , Viral Vaccines , Antibodies, Neutralizing , Antibodies, Viral , Humans , SARS-CoV-2 , Vaccination
4.
Nat Immunol ; 23(5): 768-780, 2022 05.
Article in English | MEDLINE | ID: covidwho-1751739

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination elicit CD4+ T cell responses to the spike protein, including circulating follicular helper T (cTFH) cells that correlate with neutralizing antibodies. Using a novel HLA-DRB1*15:01/S751 tetramer to track spike-specific CD4+ T cells, we show that primary infection or vaccination induces robust S751-specific CXCR5- and cTFH cell memory responses. Secondary exposure induced recall of CD4+ T cells with a transitory CXCR3+ phenotype, and drove expansion of cTFH cells transiently expressing ICOS, CD38 and PD-1. In both contexts, cells exhibited a restricted T cell antigen receptor repertoire, including a highly public clonotype and considerable clonotypic overlap between CXCR5- and cTFH populations. Following a third vaccine dose, the rapid re-expansion of spike-specific CD4+ T cells contrasted with the comparatively delayed increase in antibody titers. Overall, we demonstrate that stable pools of cTFH and memory CD4+ T cells established by infection and/or vaccination are efficiently recalled upon antigen reexposure and may contribute to long-term protection against SARS-CoV-2.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , Epitopes/metabolism , Humans , Receptors, CXCR5/metabolism , T-Lymphocytes, Helper-Inducer
5.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327469

ABSTRACT

Following infection with SARS-CoV-2, virus-specific antibodies are generated which can both neutralise virions and clear infection via Fc effector functions. The importance of IgG antibodies for protection and control of SARS-CoV-2 has been extensively reported. In comparison, other antibody isotypes including IgA have been poorly characterized. Here we characterized plasma IgA from 41 early convalescent COVID-19 subjects for neutralisation and Fc effector functions. We find that convalescent plasma IgA from >60% of the cohort have the capacity to inhibit the interaction between wild-type RBD and ACE2. Furthermore, a third of the cohort induced stronger IgA-mediated inhibition of RBD binding to ACE2 than IgG, when tested at equivalent concentrations. Plasma IgA and IgG from the cohort, broadly recognize similar RBD epitopes and showed similar ability to inhibit ACE2 from binding 22 of 23 different prevalent RBD proteins with single amino acid mutations. Plasma IgA was largely incapable of mediating antibody-dependent phagocytosis in comparison to plasma IgG. Overall, convalescent plasma IgA contributes to neutralisation towards wild-type RBD and various RBD single mutants in most subjects, although this response is heterogeneous and less potent than IgG.

6.
J Leukoc Biol ; 111(2): 355-365, 2022 02.
Article in English | MEDLINE | ID: covidwho-1499281

ABSTRACT

Vaccination remains the most effective mechanism to reduce the impact of COVID-19. Induction of neutralizing antibodies is a strong correlate of protection from infection and severe disease. An understanding of the cellular events that underpin the generation of effective neutralizing antibodies is therefore key to the development of efficacious vaccines that target emerging variants of concern. Analysis of the immune response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and vaccination has identified circulating T follicular helper cells (cTFH ) as a robust correlate of the neutralizing antibody response. Here, we discuss the analysis of cTFH cells and their lymphoid counterparts in human humoral immune responses during COVID-19, and in response to vaccination with SARS-CoV-2 spike. We discuss the phenotypic heterogeneity of cTFH cells and the utility of cTFH subsets as informative biomarkers for development of humoral immunity. We posit that the analysis of the most effective cTFH will be critical to inducing durable immunity to new variants of SARS-CoV-2.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/immunology , Immunity, Cellular , Immunity, Humoral , SARS-CoV-2/immunology , T Follicular Helper Cells/immunology , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/prevention & control , COVID-19/virology , Humans
7.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-291856

ABSTRACT

CD4+ T cells play a critical role in the immune response to viral infection. SARS-CoV-2 infection and vaccination elicit strong CD4+ T cell responses to the viral spike protein, including circulating T follicular helper (cTFH) cells that correlate with the development of neutralising antibodies. Here we use a novel HLA-DRB1*15:01/S751 tetramer to precisely track spike-specific CD4+ T cells following recovery from mild/moderate COVID-19, or after vaccination with spike-encoding vaccines. SARS-CoV-2 infection induces robust S751-specific responses with both CXCR5- and cTFH phenotypes that are maintained for at least 12 months in a stable, CXCR3-biased, central memory pool. Vaccination of immunologically naïve subjects similarly drives expansion of S751-specific T cells with a highly restricted TCR repertoire comprised of both public and private clonotypes. Vaccination of convalescent individuals drives recall of CD4+ T cell clones established during infection, which are shared between the CXCR5- and cTFH compartments. This recall response is evident 5 days after antigen exposure and includes a population of spike-specific cTFH that persist in the periphery after losing expression of PD-1. Overall this study demonstrates the generation of a stable pool of cTFH and memory CD4+ T cells that can be recalled upon spike antigen re-exposure, which may play an important role in long-term protection against SARS-CoV-2 infection.

8.
Clin Transl Immunology ; 10(11): e1354, 2021.
Article in English | MEDLINE | ID: covidwho-1487459

ABSTRACT

OBJECTIVES: SARS-CoV-2 can be transmitted by aerosols, and the ocular surface may be an important route of transmission. Little is known about protective antibody responses to SARS-CoV-2 in tears after infection or vaccination. We analysed the SARS-CoV-2-specific IgG and IgA responses in human tears after either COVID-19 infection or vaccination. METHODS: We measured the antibody responses in 16 subjects with COVID-19 infection for an average of 7 months before, and 15 subjects before and 2 weeks post-Comirnaty (Pfizer-BioNtech) vaccination. Plasma, saliva and basal tears were collected. Eleven pre-pandemic individuals were included as healthy controls. RESULTS: IgG antibodies to spike and nucleoprotein were detected in tears, saliva and plasma from subjects with prior SARS-CoV-2 infection in comparison with uninfected controls. While receptor-binding domain (RBD)-specific antibodies were detected in plasma, minimal RBD-specific antibodies were detected in tears and saliva. By contrast, high levels of IgG antibodies to spike and RBD, but not nucleoprotein, were induced in tears, saliva and plasma of subjects receiving 2 doses of the Comirnaty vaccine. Increased levels of IgA1 and IgA2 antibodies to SARS-CoV-2 antigens were detected in plasma following infection or vaccination but were unchanged in tears and saliva. Comirnaty vaccination induced high neutralising Abs in the plasma, but limited neutralising antibodies were detected in saliva or tears. CONCLUSION: Both infection and vaccination induce SARS-CoV-2-specific IgG antibodies in tears. RBD-specific IgG antibodies in tears were induced by vaccination but were not present 7 months post-infection. This suggests the neutralising antibodies may be low in the tears late following infection.

9.
Cell Rep ; 37(2): 109822, 2021 10 12.
Article in English | MEDLINE | ID: covidwho-1433046

ABSTRACT

Potent neutralizing monoclonal antibodies are one of the few agents currently available to treat COVID-19. SARS-CoV-2 variants of concern (VOCs) that carry multiple mutations in the viral spike protein can exhibit neutralization resistance, potentially affecting the effectiveness of some antibody-based therapeutics. Here, the generation of a diverse panel of 91 human, neutralizing monoclonal antibodies provides an in-depth structural and phenotypic definition of receptor binding domain (RBD) antigenic sites on the viral spike. These RBD antibodies ameliorate SARS-CoV-2 infection in mice and hamster models in a dose-dependent manner and in proportion to in vitro, neutralizing potency. Assessing the effect of mutations in the spike protein on antibody recognition and neutralization highlights both potent single antibodies and stereotypic classes of antibodies that are unaffected by currently circulating VOCs, such as B.1.351 and P.1. These neutralizing monoclonal antibodies and others that bind analogous epitopes represent potentially useful future anti-SARS-CoV-2 therapeutics.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , Antibodies, Neutralizing/immunology , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/ultrastructure , Animals , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/therapeutic use , Antibodies, Neutralizing/ultrastructure , Antibodies, Viral/immunology , COVID-19/immunology , Cricetinae , Cryoelectron Microscopy/methods , Epitopes/immunology , Female , Humans , Male , Mice , Mice, Inbred C57BL , Middle Aged , Neutralization Tests , Protein Binding/physiology , Receptors, Virus/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
10.
JCI Insight ; 6(16)2021 08 23.
Article in English | MEDLINE | ID: covidwho-1305530

ABSTRACT

The SARS-CoV-2 receptor binding domain (RBD) is both the principal target of neutralizing antibodies and one of the most rapidly evolving domains, which can result in the emergence of immune escape mutations, limiting the effectiveness of vaccines and antibody therapeutics. To facilitate surveillance, we developed a rapid, high-throughput, multiplex assay able to assess the inhibitory response of antibodies to 24 RBD natural variants simultaneously. We demonstrate how this assay can be implemented as a rapid surrogate assay for functional cell-based serological methods to measure the SARS-CoV-2 neutralizing capacity of antibodies at the angiotensin-converting enzyme 2-RBD (ACE2-RBD) interface. We describe the enhanced affinity of RBD variants N439K, S477N, Q493L, S494P, and N501Y to the ACE2 receptor and demonstrate the ability of this assay to bridge a major gap for SARS-CoV-2 research, informing selection of complementary monoclonal antibody candidates and the rapid identification of immune escape to emerging RBD variants following vaccination or natural infection.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/metabolism , High-Throughput Screening Assays , Humans , Immune Evasion , Mutation
11.
Cell Rep Med ; 2(6): 100296, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1225428

ABSTRACT

The capacity of antibodies to engage with immune cells via the Fc region is important in preventing and controlling many infectious diseases. The evolution of such antibodies during convalescence from coronavirus disease 2019 (COVID-19) is largely unknown. We develop assays to measure Fc-dependent antibody functions against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)-expressing cells in serial samples from subjects primarily with mild-moderate COVID-19 up to 149 days post-infection. We find that S-specific antibodies capable of engaging Fcγ receptors decay over time, with S-specific antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent phagocytosis (ADP) activity within plasma declining accordingly. Although there is significant decay in ADCC and ADP activity, they remain readily detectable in almost all subjects at the last time point studied (94%) in contrast with neutralization activity (70%). Although it remains unclear the degree to which Fc effector functions contribute to protection against SARS-CoV-2 re-infection, our results indicate that antibodies with Fc effector functions persist longer than neutralizing antibodies.


Subject(s)
Antibodies, Viral/metabolism , COVID-19/immunology , Immunoglobulin Fc Fragments/metabolism , Antibodies, Viral/blood , Antibody-Dependent Cell Cytotoxicity/immunology , COVID-19/pathology , COVID-19/virology , Cell Line, Tumor , Dimerization , Humans , Immunoglobulin Fc Fragments/genetics , Immunoglobulin Fc Fragments/immunology , Kinetics , Neutralization Tests , Phagocytosis , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Severity of Illness Index , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
12.
Nat Commun ; 12(1): 2037, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1164849

ABSTRACT

The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such divergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children (n = 89), adults (n = 98), elderly (n = 57), and COVID-19 patients (n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy individuals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy individuals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.


Subject(s)
Antibodies, Viral/blood , Antibodies, Viral/immunology , Antibody Formation/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/immunology , COVID-19 Vaccines/immunology , Child , Child, Preschool , Cross Reactions/immunology , Humans , Immunoglobulin A/blood , Immunoglobulin A/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin M/blood , Immunoglobulin M/immunology , Middle Aged , Receptors, IgG/immunology , Spike Glycoprotein, Coronavirus/immunology , Young Adult
13.
Clin Transl Immunology ; 10(3): e1264, 2021.
Article in English | MEDLINE | ID: covidwho-1144232

ABSTRACT

OBJECTIVES: Endemic human coronaviruses (hCoVs) circulate worldwide but cause minimal mortality. Although seroconversion to hCoV is near ubiquitous during childhood, little is known about hCoV-specific T-cell memory in adults. METHODS: We quantified CD4 T-cell and antibody responses to hCoV spike antigens in 42 SARS-CoV-2-uninfected individuals. Antigen-specific memory T cells and circulating T follicular helper (cTFH) cells were identified using an activation-induced marker assay and characterised for memory phenotype and chemokine receptor expression. RESULTS: T-cell responses were widespread within conventional memory and cTFH compartments but did not correlate with IgG titres. SARS-CoV-2 cross-reactive T cells were observed in 48% of participants and correlated with HKU1 memory. hCoV-specific T cells exhibited a CCR6+ central memory phenotype in the blood, but were enriched for frequency and CXCR3 expression in human lung-draining lymph nodes. CONCLUSION: Overall, hCoV-specific humoral and cellular memory are independently maintained, with a shared phenotype existing among coronavirus-specific CD4 T cells. This understanding of endemic coronavirus immunity provides insight into the homeostatic maintenance of immune responses that are likely to be critical components of protection against SARS-CoV-2.

14.
Nat Commun ; 12(1): 1403, 2021 03 03.
Article in English | MEDLINE | ID: covidwho-1117351

ABSTRACT

SARS-CoV-2 vaccines are advancing into human clinical trials, with emphasis on eliciting high titres of neutralising antibodies against the viral spike (S). However, the merits of broadly targeting S versus focusing antibody onto the smaller receptor binding domain (RBD) are unclear. Here we assess prototypic S and RBD subunit vaccines in homologous or heterologous prime-boost regimens in mice and non-human primates. We find S is highly immunogenic in mice, while the comparatively poor immunogenicity of RBD is associated with limiting germinal centre and T follicular helper cell activity. Boosting S-primed mice with either S or RBD significantly augments neutralising titres, with RBD-focussing driving moderate improvement in serum neutralisation. In contrast, both S and RBD vaccines are comparably immunogenic in macaques, eliciting serological neutralising activity that generally exceed levels in convalescent humans. These studies confirm recombinant S proteins as promising vaccine candidates and highlight multiple pathways to achieving potent serological neutralisation.


Subject(s)
COVID-19 Vaccines/therapeutic use , SARS-CoV-2/pathogenicity , Animals , Antibodies, Neutralizing/immunology , Antibody Formation/physiology , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Macaca , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , Viral Vaccines/therapeutic use
15.
Nat Commun ; 12(1): 1162, 2021 02 19.
Article in English | MEDLINE | ID: covidwho-1091489

ABSTRACT

The durability of infection-induced SARS-CoV-2 immunity has major implications for reinfection and vaccine development. Here, we show a comprehensive profile of antibody, B cell and T cell dynamics over time in a cohort of patients who have recovered from mild-moderate COVID-19. Binding and neutralising antibody responses, together with individual serum clonotypes, decay over the first 4 months post-infection. A similar decline in Spike-specific CD4+ and circulating T follicular helper frequencies occurs. By contrast, S-specific IgG+ memory B cells consistently accumulate over time, eventually comprising a substantial fraction of circulating the memory B cell pool. Modelling of the concomitant immune kinetics predicts maintenance of serological neutralising activity above a titre of 1:40 in 50% of convalescent participants to 74 days, although there is probably additive protection from B cell and T cell immunity. This study indicates that SARS-CoV-2 immunity after infection might be transiently protective at a population level. Therefore, SARS-CoV-2 vaccines might require greater immunogenicity and durability than natural infection to drive long-term protection.


Subject(s)
Antibodies, Viral/immunology , Antibody Formation , COVID-19/immunology , Immunity, Cellular , Immunologic Memory , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Humans , Immunoglobulin G/immunology , Longitudinal Studies , Models, Theoretical , Neutralization Tests , T-Lymphocytes, Helper-Inducer/immunology
17.
Nat Microbiol ; 5(10): 1185-1191, 2020 10.
Article in English | MEDLINE | ID: covidwho-752497

ABSTRACT

Antibody-based drugs and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being expedited through preclinical and clinical development. Data from the study of SARS-CoV and other respiratory viruses suggest that anti-SARS-CoV-2 antibodies could exacerbate COVID-19 through antibody-dependent enhancement (ADE). Previous respiratory syncytial virus and dengue virus vaccine studies revealed human clinical safety risks related to ADE, resulting in failed vaccine trials. Here, we describe key ADE mechanisms and discuss mitigation strategies for SARS-CoV-2 vaccines and therapies in development. We also outline recently published data to evaluate the risks and opportunities for antibody-based protection against SARS-CoV-2.


Subject(s)
Antibody-Dependent Enhancement , Betacoronavirus , Coronavirus Infections/immunology , Coronavirus Infections/therapy , Pneumonia, Viral/immunology , Pneumonia, Viral/therapy , Viral Vaccines/adverse effects , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Neutralizing/administration & dosage , Antibodies, Viral/administration & dosage , Antibodies, Viral/immunology , Antibody-Dependent Enhancement/immunology , Betacoronavirus/immunology , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Humans , Immunization, Passive/adverse effects , In Vitro Techniques , Models, Immunological , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Respiratory Tract Diseases/etiology , Respiratory Tract Diseases/immunology , Risk Factors , SARS-CoV-2 , Safety , Viral Vaccines/immunology
18.
Nat Med ; 26(9): 1428-1434, 2020 09.
Article in English | MEDLINE | ID: covidwho-641392

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has dramatically expedited global vaccine development efforts1-3, most targeting the viral 'spike' glycoprotein (S). S localizes on the virion surface and mediates recognition of cellular receptor angiotensin-converting enzyme 2 (ACE2)4-6. Eliciting neutralizing antibodies that block S-ACE2 interaction7-9, or indirectly prevent membrane fusion10, constitute an attractive modality for vaccine-elicited protection11. However, although prototypic S-based vaccines show promise in animal models12-14, the immunogenic properties of S in humans are poorly resolved. In this study, we characterized humoral and circulating follicular helper T cell (cTFH) immunity against spike in recovered patients with coronavirus disease 2019 (COVID-19). We found that S-specific antibodies, memory B cells and cTFH are consistently elicited after SARS-CoV-2 infection, demarking robust humoral immunity and positively associated with plasma neutralizing activity. Comparatively low frequencies of B cells or cTFH specific for the receptor binding domain of S were elicited. Notably, the phenotype of S-specific cTFH differentiated subjects with potent neutralizing responses, providing a potential biomarker of potency for S-based vaccines entering the clinic. Overall, although patients who recovered from COVID-19 displayed multiple hallmarks of effective immune recognition of S, the wide spectrum of neutralizing activity observed suggests that vaccines might require strategies to selectively target the most potent neutralizing epitopes.


Subject(s)
Antibodies, Neutralizing/pharmacology , Coronavirus Infections/immunology , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/immunology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibodies, Viral/pharmacology , Antigens, Viral/immunology , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/pathology , Coronavirus Infections/virology , Epitopes/immunology , Humans , Immunity, Cellular/immunology , Pandemics , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , T-Lymphocytes, Helper-Inducer/immunology , Vero Cells/immunology
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