scholarly journals Novel neutralization mechanism of a human antibody with pan-coronavirus reactivity

2021 ◽  
Author(s):  
Xiaoyu Sun ◽  
Chunyan Yi ◽  
Yuanfei Zhu ◽  
Longfei Ding ◽  
Shuai Xia ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Broad Spectrum ◽  
Neutralizing Antibodies ◽  
Fusion Peptide ◽  
Spike Protein ◽  
Human Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Neutralization Activity ◽  
Treatment Models ◽  
Trimeric Structure

Abstract The recurrent outbreak of coronaviruses and variants underscores the need for broadly reactive antivirals and vaccines. Here, a novel broad-spectrum human antibody named 76E1 was isolated from a COVID-19 convalescent patient and showed broad neutralization activity against multiple α- and β-coronaviruses, including the SARS-CoV-2 variants and also exhibited the binding breath to peptides containing the epitope from γ- and δ- coronaviruses. 76E1 cross-protects mice from SARS-CoV-2 and HCoV-OC43 infection in both prophylactic and treatment models. The epitope including the fusion peptide and S2’ cleavage site recognized by 76E1 was significantly conserved among α-, β-, γ- and δ- coronaviruses. We uncovered a novel mechanism of antibody neutralization that the epitope of 76E1 was proportionally less exposed in the prefusion trimeric structure of spike protein but could be unmasked by binding to the receptor ACE2. Once the epitope exposed, 76E1 inhibited S2’ cleavage, thus blocked the membrane fusion process. Our data demonstrate a key epitope targeted by broadly-neutralizing antibodies and will guide next-generation epitope-based pan-coronavirus vaccine design.

scholarly journals A recurring YYDRxG pattern in broadly neutralizing antibodies to a conserved site on SARS-CoV-2, variants of concern, and related viruses

2021 ◽  
Author(s):  
Hejun Liu ◽  
Chengzi I. Kaku ◽  
Ge Song ◽  
Meng Yuan ◽  
Raiees Andrabi ◽  
...  
Keyword(s):  
Immune System ◽  
Neutralizing Antibodies ◽  
Human Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Human Immune System ◽  
Neutralization Activity ◽  
Humoral Immune ◽  
Humoral Immune System ◽  
Targeting Strategy ◽  
Conserved Epitope

Studying the antibody response to SARS-CoV-2 informs on how the human immune system can respond to antigenic variants as well as other SARS-related viruses. Here, we structurally and functionally characterized a potent human antibody ADI-62113 that also neutralizes SARS-CoV- 2 variants of concern and cross-reacts with many other sarbecoviruses. A YYDRxG motif encoded by IGHD3-22 in CDR H3 facilitates targeting to a highly conserved epitope on the SARS-CoV-2 receptor binding domain. A computational search for a YYDRxG pattern in publicly available sequences identified many antibodies with broad neutralization activity against SARS-CoV-2 variants and SARS-CoV. Thus, the YYDRxG motif represents a common convergent solution for the human humoral immune system to counteract sarbecoviruses. These findings also suggest an epitope targeting strategy to identify potent and broadly neutralizing antibodies that can aid in the design of pan-sarbecovirus vaccines and antibody therapeutics.

scholarly journals Hybrid immunity improves B cell frequency, antibody potency and breadth against SARS-CoV-2 and variants of concern

2021 ◽  
Author(s):  
Emanuele Andreano ◽  
Ida Paciello ◽  
Giulia Piccini ◽  
Noemi Manganaro ◽  
Piero Pileri ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
B Cells ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Primary Vaccination ◽  
Spike Protein ◽  
Broadly Neutralizing Antibodies ◽  
Neutralization Activity ◽  
Cell Responses ◽  
Specific Memory

To understand the nature of the antibody response to SARS-CoV-2 vaccination, we analyzed at single cell level the B cell responses of five naïve and five convalescent people immunized with the BNT162b2 mRNA vaccine. Convalescents had higher frequency of spike protein specific memory B cells and by cell sorting delivered 3,532 B cells, compared with 2,352 from naïve people. Of these, 944 from naïve and 2,299 from convalescents produced monoclonal antibodies against the spike protein and 411 of them neutralized the original Wuhan SARS-CoV-2 virus. More than 75% of the monoclonal antibodies from naïve people lost their neutralization activity against the B.1.351 (beta) and B.1.1.248 (gamma) variants while this happened only for 61% of those from convalescents. The overall loss of neutralization was lower for the B.1.1.7 (alpha) and B.1.617.2 (delta) variants, however it was always significantly higher in those of naïve people. In part this was due to the IGHV2-5;IGHJ4-1 germline, which was found only in convalescents and generated potent and broadly neutralizing antibodies. Overall, vaccination of seropositive people increases the frequency of B cells encoding antibodies with high potency and that are not susceptible to escape by any of the four variants of concern. Our data suggest that people that are seropositive following infection or primary vaccination will produce antibodies with increased potency and breadth and will be able to better control SARS-CoV-2 emerging variants.

scholarly journals Unique structural solution from a VH3-30 antibody targeting the hemagglutinin stem of influenza A viruses

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wayne D. Harshbarger ◽  
Derrick Deming ◽  
Gordon J. Lockbaum ◽  
Nattapol Attatippaholkun ◽  
Maliwan Kamkaew ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Influenza A ◽  
Critical Role ◽  
Binding Activity ◽  
Human Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Influenza A Viruses ◽  
Universal Vaccine ◽  
Structural Details ◽  
Structural Solution

AbstractBroadly neutralizing antibodies (bnAbs) targeting conserved influenza A virus (IAV) hemagglutinin (HA) epitopes can provide valuable information for accelerating universal vaccine designs. Here, we report structural details for heterosubtypic recognition of HA from circulating and emerging IAVs by the human antibody 3I14. Somatic hypermutations play a critical role in shaping the HCDR3, which alone and uniquely among VH3-30 derived antibodies, forms contacts with five sub-pockets within the HA-stem hydrophobic groove. 3I14 light-chain interactions are also key for binding HA and contribute a large buried surface area spanning two HA protomers. Comparison of 3I14 to bnAbs from several defined classes provide insights to the bias selection of VH3-30 antibodies and reveals that 3I14 represents a novel structural solution within the VH3-30 repertoire. The structures reported here improve our understanding of cross-group heterosubtypic binding activity, providing the basis for advancing immunogen designs aimed at eliciting a broadly protective response to IAV.

scholarly journals A glycoside analog of mammalian oligomannose formulated with a TLR4-stimulating adjuvant elicits HIV-1 cross-reactive antibodies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jean-François Bruxelle ◽  
Tess Kirilenko ◽  
Nino Trattnig ◽  
Yiqiu Yang ◽  
Matteo Cattin ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Envelope Protein ◽  
Protein Sequence ◽  
Neutralizing Antibodies ◽  
Human Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Specific Antibodies ◽  
Strong Binding ◽  
Hiv Envelope ◽  
Hiv 1

AbstractThe occurrence of oligomannose-specific broadly neutralizing antibodies (bnAbs) has spurred efforts to develop immunogens that can elicit similar antibodies. Here, we report on the antigenicity and immunogenicity of a CRM197-conjugate of a previously reported oligomannose mimetic. Oligomannose-specific bnAbs that are less dependent on interactions with the HIV envelope protein sequence showed strong binding to the glycoconjugates, with affinities approximating those reported for their cognate epitope. The glycoconjugate is also recognized by inferred germline precursors of oligomannose-specific bnAbs, albeit with the expected low avidity, supporting its potential as an immunogen. Immunization of human-antibody transgenic mice revealed that only a TLR4-stimulating adjuvant formulation resulted in antibodies able to bind a panel of recombinant HIV trimers. These antibodies bound at relatively modest levels, possibly explaining their inability to neutralize HIV infectivity. Nevertheless, these findings contribute further to understanding conditions for eliciting HIV-cross-reactive oligomannose-specific antibodies and inform on next steps for improving on the elicited response.

scholarly journals Virus-Like Particle Based Vaccines Elicit Neutralizing Antibodies against the HIV-1 Fusion Peptide

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 765
Author(s):  
Alemu Tekewe Mogus ◽  
Lihong Liu ◽  
Manxue Jia ◽  
Diane T. Ajayi ◽  
Kai Xu ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccination Strategy ◽  
Fusion Peptide ◽  
Linear Epitope ◽  
Broadly Neutralizing Antibodies ◽  
Virus Like Particle ◽  
Boost Immunization ◽  
Potential Vaccine ◽  
Hiv Envelope ◽  
Hiv 1

Broadly neutralizing antibodies (bnAbs) isolated from HIV-infected individuals delineate vulnerable sites on the HIV envelope glycoprotein that are potential vaccine targets. A linear epitope within the N-terminal region of the HIV-1 fusion peptide (FP8) is the primary target of VRC34.01, a bnAb that neutralizes ~50% of primary HIV isolates. FP8 has attracted attention as a potential HIV vaccine target because it is a simple linear epitope. Here, platform technologies based on RNA bacteriophage virus-like particles (VLPs) were used to develop multivalent vaccines targeting the FP8 epitope. Both recombinant MS2 VLPs displaying the FP8 peptide and Qβ VLPs displaying chemically conjugated FP8 peptide induced high titers of FP8-specific antibodies in mice. Moreover, a heterologous prime-boost-boost regimen employing the two FP8-VLP vaccines and native envelope trimer was the most effective approach for eliciting HIV-1 neutralizing antibodies. Given the potent immunogenicity of VLP-based vaccines, this vaccination strategy—inspired by bnAb-guided epitope mapping, VLP bioengineering, and prime-boost immunization approaches—may be a useful strategy for eliciting bnAb responses against HIV.

scholarly journals Neuraminidase inhibition contributes to influenza A virus neutralization by anti-hemagglutinin stem antibodies

2019 ◽  
Vol 216 (2) ◽  
pp. 304-316 ◽  
Author(s):  
Ivan Kosik ◽  
Davide Angeletti ◽  
James S. Gibbs ◽  
Matthew Angel ◽  
Kazuyo Takeda ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Influenza A ◽  
Cell Activation ◽  
Immune Cell ◽  
Broadly Neutralizing Antibodies ◽  
Neutralization Activity ◽  
Immune Cell Activation ◽  
Influenza Virus Hemagglutinin ◽  
Infected Cells

Broadly neutralizing antibodies (Abs) that bind the influenza virus hemagglutinin (HA) stem may enable universal influenza vaccination. Here, we show that anti-stem Abs sterically inhibit viral neuraminidase (NA) activity against large substrates, with activity inversely proportional to the length of the fibrous NA stalk that supports the enzymatic domain. By modulating NA stalk length in recombinant IAVs, we show that anti-stem Abs inhibit virus release from infected cells by blocking NA, accounting for their in vitro neutralization activity. NA inhibition contributes to anti-stem Ab protection in influenza-infected mice, likely due at least in part to NA-mediated inhibition of FcγR-dependent activation of innate immune cells by Ab bound to virions. Food and Drug Administration–approved NA inhibitors enhance anti-stem–based Fc-dependent immune cell activation, raising the possibility of therapeutic synergy between NA inhibitors and anti-stem mAb treatment in humans.

scholarly journals A glycoside analog of mammalian oligomannose formulated with a TLR4-stimulating adjuvant elicits HIV-1 cross-reactive antibodies

2021 ◽  
Author(s):  
Jean-Francois Bruxelle ◽  
Tess Kirilenko ◽  
Nino Trattnig ◽  
Yiqiu Yang ◽  
Matteo Cattin ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Envelope Protein ◽  
Protein Sequence ◽  
Neutralizing Antibodies ◽  
Human Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Specific Antibodies ◽  
Strong Binding ◽  
Hiv Envelope ◽  
Hiv 1

Abstract The occurrence of oligomannose-specific broadly neutralizing antibodies (bnAbs) has spurred efforts to develop immunogens that can elicit similar antibodies. Here, we report on the antigenicity and immunogenicity of a CRM197-conjugate of a previously reported oligomannose mimetic. Oligomannose-specific bnAbs that are less dependent on interactions with the HIV envelope protein sequence showed strong binding to the glycoconjugates, with affinities approximating those reported for their cognate epitope. The glycoconjugate is also recognized by germline precursors of oligomannose-specific bnAbs, albeit with the expected low avidity, supporting its potential as an immunogen. Immunization of human-antibody transgenic mice revealed that only a TLR4-stimulating adjuvant formulation evoked antibodies able to bind a panel of recombinant HIV trimers. These antibodies bound at relatively modest levels, likely explaining their inability to neutralize HIV infectivity. Nevertheless, these findings contribute further to understanding conditions for eliciting HIV-cross-reactive oligomannose-specific antibodies and inform on next steps for improving on the elicited response.

scholarly journals An Epitope of the Semliki Forest Virus Fusion Protein Exposed during Virus-Membrane Fusion

1999 ◽  
Vol 73 (12) ◽  
pp. 10029-10039 ◽  
Author(s):  
Anna Ahn ◽  
Matthew R. Klimjack ◽  
Prodyot K. Chatterjee ◽  
Margaret Kielian
Keyword(s):  
Membrane Fusion ◽  
Binding Site ◽  
Semliki Forest Virus ◽  
Fusion Reaction ◽  
Ph Dependence ◽  
Fusion Peptide ◽  
Endocytic Pathway ◽  
Spike Protein ◽  
Viral Fusion ◽  
Wide Range

ABSTRACT Semliki Forest virus (SFV) is an enveloped alphavirus that infects cells via a membrane fusion reaction triggered by acidic pH in the endocytic pathway. Fusion is mediated by the spike protein E1 subunit, an integral membrane protein that contains the viral fusion peptide and forms a stable homotrimer during fusion. We have characterized four monoclonal antibodies (MAbs) specific for the acid conformation of E1. These MAbs did not inhibit fusion, suggesting that they bind to an E1 region different from the fusion peptide. Competition analyses demonstrated that all four MAbs bound to spatially related sites on acid-treated virions or isolated spike proteins. To map the binding site, we selected for virus mutants resistant to one of the MAbs, E1a-1. One virus isolate, SFV 4-2, showed reduced binding of three acid-specific MAbs including E1a-1, while its binding of one acid-specific MAb as well as non-acid-specific MAbs to E1 and E2 was unchanged. The SFV 4-2 mutant was fully infectious, formed the E1 homotrimer, and had the wild-type pH dependence of infection. Sequence analysis demonstrated that the relevant mutation in SFV 4-2 was a change of E1 glycine 157 to arginine (G157R). Decreased binding of MAb E1a-1 was observed under a wide range of assay conditions, strongly suggesting that the E1 G157R mutation directly affects the MAb binding site. These data thus localize an E1 region that is normally hidden in the neutral pH structure and becomes exposed as part of the reorganization of the spike protein to its fusion-active conformation.

scholarly journals Redundancy and Plasticity of Neutralizing Antibody Responses Are Cornerstone Attributes of the Human Immune Response to the Smallpox Vaccine

2008 ◽  
Vol 82 (7) ◽  
pp. 3751-3768 ◽  
Author(s):  
Mohammed Rafii-El-Idrissi Benhnia ◽  
Megan M. McCausland ◽  
Hua-Poo Su ◽  
Kavita Singh ◽  
Julia Hoffmann ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Safety Net ◽  
Antibody Responses ◽  
Smallpox Vaccine ◽  
Human Antibody ◽  
Neutralization Activity ◽  
Antibody Titers ◽  
Human Immune Response ◽  
Human Immune

ABSTRACT The smallpox vaccine is widely considered the gold standard for human vaccines, yet the key antibody targets in humans remain unclear. We endeavored to identify a stereotypic, dominant, mature virion (MV) neutralizing antibody target in humans which could be used as a diagnostic serological marker of protective humoral immunity induced by the smallpox vaccine (vaccinia virus [VACV]). We have instead found that diversity is a defining characteristic of the human antibody response to the smallpox vaccine. We show that H3 is the most immunodominant VACV neutralizing antibody target, as determined by correlation analysis of immunoglobulin G (IgG) specificities to MV neutralizing antibody titers. It was determined that purified human anti-H3 IgG is sufficient for neutralization of VACV; however, depletion or blockade of anti-H3 antibodies revealed no significant reduction in neutralization activity, showing anti-H3 IgG is not required in vaccinated humans (or mice) for neutralization of MV. Comparable results were obtained for human (and mouse) anti-L1 IgG and even for anti-H3 and anti-L1 IgG in combination. In addition to H3 and L1, human antibody responses to D8, A27, D13, and A14 exhibited statistically significant correlations with virus neutralization. Altogether, these data indicate the smallpox vaccine succeeds in generating strong neutralizing antibody responses not by eliciting a stereotypic response to a single key antigen but instead by driving development of neutralizing antibodies to multiple viral proteins, resulting in a “safety net” of highly redundant neutralizing antibody responses, the specificities of which can vary from individual to individual. We propose that this is a fundamental attribute of the smallpox vaccine.

scholarly journals Mapping the immunogenic landscape of near-native HIV-1 envelope trimers in non-human primates

2020 ◽  
Author(s):  
Christopher A. Cottrell ◽  
Jelle van Schooten ◽  
Charles A. Bowman ◽  
Meng Yuan ◽  
David Oyen ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Fusion Peptide ◽  
Antibody Responses ◽  
Envelope Glycoproteins ◽  
Broadly Neutralizing Antibodies ◽  
Vaccine Candidates ◽  
Hiv 1

AbstractThe induction of broad and potent immunity by vaccines is the key focus of research efforts aimed at protecting against HIV-1 infection. Soluble native-like HIV-1 envelope glycoproteins have shown promise as vaccine candidates as they can induce potent autologous neutralizing responses in rabbits and non-human primates. In this study, monoclonal antibodies were isolated and characterized from rhesus macaques immunized with the BG505 SOSIP.664 trimer to better understand vaccine-induced antibody responses. Our studies reveal a diverse landscape of antibodies recognizing immunodominant strain-specific epitopes and non-neutralizing neo-epitopes. Additionally, we isolated a subset of mAbs against an epitope cluster at the gp120-gp41 interface that recognize the highly conserved fusion peptide and the glycan at position 88 and have characteristics akin to several human-derived broadly neutralizing antibodies.

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