scholarly journals Mapping the Antibody Repertoires in Ferrets with Repeated Influenza A/H3 Infections: Is Original Antigenic Sin Really “Sinful”?

2020 ◽  
Author(s):  
Tal Einav ◽  
Martina Kosikova ◽  
Peter Radvak ◽  
Yuan-Chia Kuo ◽  
Hyung Joon Kwon ◽  
...  
Keyword(s):  
Immune Response ◽  
Specific Antibody ◽  
Influenza A ◽  
Neutralizing Antibody ◽  
Antibody Repertoire ◽  
Computational Tool ◽  
Broadly Neutralizing Antibody ◽  
Antibody Repertoires ◽  
Repeated Infections ◽  
Original Antigenic Sin

AbstractThe influenza-specific antibody repertoire is continuously reshaped by infection and vaccination. The host immune response to contemporary viruses can be redirected to preferentially boost antibodies specific for viruses encountered early in life, a phenomenon called original antigenic sin (OAS) that is suggested to be responsible for diminished vaccine effectiveness after repeated vaccination. In this study, we used a new computational tool called Neutralization Map to determine the hemagglutination inhibition profiles of individual antibodies within ferret antisera elicited by repeated influenza A/H3 infections. Our results suggest that repeated infections continuously reshape the ferret antibody repertoire, but that a broadly neutralizing antibody signature can nevertheless be induced irrespective of OAS. Overall, our study offers a new way to visualize how immune history shapes individual antibodies within a repertoire, which may help inform future vaccine design.

scholarly journals A broadly neutralizing antibody protects against SARS-CoV, pre-emergent bat CoVs, and SARS-CoV-2 variants in mice

2021 ◽  
Author(s):  
David R. Martinez ◽  
Alexandra Schaefer ◽  
Sophie Gobeil ◽  
Dapeng Li ◽  
Gabriela De la Cruz ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Receptor Binding ◽  
Specific Antibody ◽  
Neutralizing Antibody ◽  
Affinity Binding ◽  
Receptor Binding Domain ◽  
High Affinity Binding ◽  
High Affinity ◽  
Broadly Neutralizing Antibody ◽  
Conserved Epitope

AbstractSARS-CoV in 2003, SARS-CoV-2 in 2019, and SARS-CoV-2 variants of concern (VOC) can cause deadly infections, underlining the importance of developing broadly effective countermeasures against Group 2B Sarbecoviruses, which could be key in the rapid prevention and mitigation of future zoonotic events. Here, we demonstrate the neutralization of SARS-CoV, bat CoVs WIV-1 and RsSHC014, and SARS-CoV-2 variants D614G, B.1.1.7, B.1.429, B1.351 by a receptor-binding domain (RBD)-specific antibody DH1047. Prophylactic and therapeutic treatment with DH1047 demonstrated protection against SARS-CoV, WIV-1, RsSHC014, and SARS-CoV-2 B1.351infection in mice. Binding and structural analysis showed high affinity binding of DH1047 to an epitope that is highly conserved among Sarbecoviruses. We conclude that DH1047 is a broadly neutralizing and protective antibody that can prevent infection and mitigate outbreaks caused by SARS-like strains and SARS-CoV-2 variants. Our results argue that the RBD conserved epitope bound by DH1047 is a rational target for pan Group 2B coronavirus vaccines.

scholarly journals Differences in the Binding Affinity of an HIV-1 V2 Apex-Specific Antibody for the SIVsmm/macEnvelope Glycoprotein Uncouple Antibody-Dependent Cellular Cytotoxicity from Neutralization

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Benjamin von Bredow ◽  
Raiees Andrabi ◽  
Michael Grunst ◽  
Andres G. Grandea ◽  
Khoa Le ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Specific Antibody ◽  
Neutralizing Antibody ◽  
Glycosylation Site ◽  
Antibody Binding ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Broadly Neutralizing Antibody ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTAs a consequence of their independent evolutionary origins in apes and Old World monkeys, human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency viruses of the SIVsmm/maclineage express phylogenetically and antigenically distinct envelope glycoproteins. Thus, HIV-1 Env-specific antibodies do not typically cross-react with the Env proteins of SIVsmm/macisolates. Here we show that PGT145, a broadly neutralizing antibody to a quaternary epitope at the V2 apex of HIV-1 Env, directs the lysis of SIVsmm/mac-infected cells by antibody-dependent cellular cytotoxicity (ADCC) but does not neutralize SIVsmm/macinfectivity. Amino acid substitutions in the V2 loop of SIVmac239 corresponding to the epitope for PGT145 in HIV-1 Env modulate sensitivity to this antibody. Whereas a substitution in a conserved N-linked glycosylation site (N171Q) eliminates sensitivity to ADCC, a lysine-to-serine substitution in this region (K180S) increases ADCC and renders the virus susceptible to neutralization. These differences in function correlate with an increase in the affinity of PGT145 binding to Env on the surface of virus-infected cells and to soluble Env trimers. To our knowledge, this represents the first instance of an HIV-1 Env-specific antibody that cross-reacts with SIVsmm/macEnv and illustrates how differences in antibody binding affinity for Env can differentiate sensitivity to ADCC from neutralization.IMPORTANCEHere we show that PGT145, a potent broadly neutralizing antibody to HIV-1, directs the lysis of SIV-infected cells by antibody-dependent cellular cytotoxicity but does not neutralize SIV infectivity. This represents the first instance of cross-reactivity of an HIV-1 Env-specific antibody with SIVsmm/macEnv and reveals that antibody binding affinity can differentiate sensitivity to ADCC from neutralization.

scholarly journals Design of nanoparticulate group 2 influenza hemagglutinin stem antigens that activate unmutated ancestor B cell receptors of broadly neutralizing antibody lineages

2018 ◽  
Author(s):  
Kizzmekia S Corbett ◽  
Syed M Moin ◽  
Hadi M Yassine ◽  
Alberto Cagigi ◽  
Masaru Kanekiyo ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Influenza A ◽  
Neutralizing Antibody ◽  
Influenza Viruses ◽  
Surface Glycoprotein ◽  
Loop Optimization ◽  
Influenza Hemagglutinin ◽  
Self Assembling ◽  
Broadly Neutralizing Antibody ◽  
Group 2

Influenza vaccines targeting the highly-conserved stem of the hemagglutinin (HA) surface glycoprotein have the potential to protect against pandemic and drifted seasonal influenza viruses not covered by current vaccines. While HA stem-based immunogens derived from group 1 influenza A have been shown to induce intra-group heterosubtypic protection, HA stem-specific antibody lineages originating from group 2 may be more likely to possess broad cross-group reactivity. We report the structure-guided development of mammalian cell-expressed candidate vaccine immunogens based on influenza A group 2 H3 and H7 HA stem trimers displayed on self-assembling ferritin nanoparticles using an iterative, multipronged approach involving helix stabilization, loop optimization, disulfide bond addition, and side chain repacking. These immunogens were thermostable, formed uniform and symmetric nanoparticles, were recognized by cross-group-reactive broadly neutralizing antibodies (bNAbs) with nanomolar affinity, and elicited protective, homosubtypic antibodies in mice. Importantly, several immunogens were able to activate B cells expressing inferred unmutated common ancestor (UCA) versions of cross-group-reactive human bNAbs from two multi-donor classes, suggesting they could initiate elicitation of these bNAbs in humans.

scholarly journals THE PRODUCTION OF FEVER BY INFLUENZAL VIRUSES

1949 ◽  
Vol 90 (4) ◽  
pp. 335-347 ◽  
Author(s):  
Ivan L. Bennett ◽  
Robert R. Wagner ◽  
Virgil S. LeQuire
Keyword(s):  
Immune Response ◽  
Protective Effect ◽  
Virus Particle ◽  
Specific Antibody ◽  
Antibody Formation ◽  
Influenza A ◽  
Influenza B ◽  
Cross Tolerance ◽  
Initial Injection ◽  
Homologous Virus

The mechanism of the fever caused by the intravenous injection of viruses of the influenza group in rabbits has been studied by observing the effect of repeated injections of the same or heterologous viruses. An initial injection of the PR8 strain of influenza A, the Lee strain of influenza B, or the "B" strain of NDV conferred tolerance to the pyrogenic effect of homologous virus administered on the following day. The period of tolerance lasted approximately 11 days. Prior injection of virus appeared also to protect against the lymphopenic action of homologous strains. These viruses were found to confer tolerance to the fever-producing effect of heterologous strains in an order corresponding to their positions in the receptor gradient of Burnet. Heated virus preparations appeared to confer tolerance in proportion to survival of hemagglutinin. Tolerance is probably unrelated to specific antibody formation since it is lost during a period of rapid immune response and heterologous strains exert a protective effect. No cross-tolerance was demonstrable between viruses and bacterial pyrogens and reticulo-endothelial blockade with thorotrast failed to modify the unresponsiveness of animals to 2nd day injections of homologous virus. Prevention of fever with antipyrine did not interfere with the protective effect of initial injections of virus. Arguments for and against a hypothesis that union of the virus particle with a receptor substance may play a part in the production of fever by these viruses are discussed.

Influenza A HA's conserved epitopes and broadly neutralizing antibodies: A prediction method

2014 ◽  
Vol 12 (05) ◽  
pp. 1450023 ◽  
Author(s):  
Jing Ren ◽  
John Ellis ◽  
Jinyan Li
Keyword(s):  
Amino Acid ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Conservation Score ◽  
Prediction Method ◽  
Neutralizing Antibody ◽  
Amino Acid Position ◽  
Classification Performance ◽  
Broadly Neutralizing Antibodies ◽  
Broadly Neutralizing Antibody

A conserved epitope is an epitope retained by multiple strains of influenza as the key target of a broadly neutralizing antibody. Identification of conserved epitopes is of strong interest to help design broad-spectrum vaccines against influenza. Conservation score measures the evolutionary conservation of an amino acid position in a protein based on the phylogenetic relationships observed amongst homologous sequences. Here, Average Amino Acid Conservation Score (AAACS) is proposed as a method to identify HA's conserved epitopes. Our analysis shows that there is a clear distinction between conserved epitopes and nonconserved epitopes in terms of AAACS. This method also provides an excellent classification performance on an independent dataset. In contrast, alignment-based comparison methods do not work well for this problem, because conserved epitopes to the same broadly neutralizing antibody are usually not identical or similar. Location-based methods are not successful either, because conserved epitopes are located at both the less-conserved globular head (HA1) and the more-conserved stem (HA2). As a case study, two conserved epitopes on HA are predicted for the influenza A virus H7N9: One should match the broadly neutralizing antibodies CR9114 or FI6v3, while the other is new and requires validation by wet-lab experiments.

scholarly journals Development and properties of recombinant proteins based on the broadly neutralizing antibody to influenza A virus

2016 ◽  
Vol 71 (2) ◽  
pp. 87-92 ◽  
Author(s):  
T. K. Aliev ◽  
I. G. Dement’yeva ◽  
V. A. Toporova ◽  
M. N. Bokov ◽  
L. P. Pozdnyakova ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Recombinant Proteins ◽  
Influenza A ◽  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibody

scholarly journals Structural Basis for the Broad, Antibody-Mediated Neutralization of H5N1 Influenza Virus

2018 ◽  
Vol 92 (17) ◽  
Author(s):  
Qingshan Lin ◽  
Tingting Li ◽  
Yixin Chen ◽  
Siu-Ying Lau ◽  
Minxi Wei ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Influenza A ◽  
Highly Pathogenic Avian Influenza ◽  
Neutralizing Antibody ◽  
Receptor Binding Site ◽  
Highly Pathogenic ◽  
Conformational Rearrangement ◽  
Pathogenic Avian Influenza ◽  
Broadly Neutralizing Antibody ◽  
Complementarity Determining Region

ABSTRACT Human infection with highly pathogenic avian influenza A viruses causes severe disease and fatalities. We previously identified a potent and broadly neutralizing antibody (bnAb), 13D4, against the H5N1 virus. Here, we report the co-crystal structure of 13D4 in complex with the hemagglutinin (HA) of A/Vietnam/1194/2004 (H5N1). We show that heavy-chain complementarity-determining region 3 (HCDR3) of 13D4 confers broad yet specific neutralization against H5N1, undergoing conformational rearrangement to bind to the receptor binding site (RBS). Further, we show that mutating four critical residues within the RBS—Trp153, Lys156, Lys193, and Leu194—disrupts the binding between 13D4 and HA. Viruses bearing Asn193 instead of Lys/Arg can evade 13D4 neutralization, indicating that Lys193 polymorphism might be, at least in part, involved in the antigenicity of recent H5 genotypes (such as H5N6 and H5N8) as distinguished from H5N1. BnAb 13D4 may offers a template for therapeutic RBS inhibitor design and serve as an indicator of antigenic change for current H5 viruses. IMPORTANCE Infection by highly pathogenic avian influenza A virus remains a threat to public health. Our broadly neutralizing antibody, 13D4, is capable of neutralizing all representative H5N1 viruses and protecting mice against lethal challenge. Structural analysis revealed that 13D4 uses heavy-chain complementarity-determining region 3 (HCDR3) to fit the receptor binding site (RBS) via conformational rearrangement. Four conserved residues within the RBS are critical for the broad potency of 13D4. Importantly, polymorphism of Lys193 on the RBS may be associated with the antigenicity shift from H5N1 to other newly emerging viruses, such as H5N6 and H5N8. Our findings may pave the way for highly pathogenic avian influenza virus vaccine development and therapeutic RBS inhibitor design.

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