scholarly journals Influenza Virus Resistance to Human Neutralizing Antibodies

mBio ◽  
2012 ◽  
Vol 3 (4) ◽  
Author(s):  
James E. Crowe
Keyword(s):  
Influenza Virus ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Influenza Viruses ◽  
Surface Proteins ◽  
Progeny Virus ◽  
Human Antibody ◽  
Functional Surface

ABSTRACT The human antibody repertoire has an exceptionally large capacity to recognize new or changing antigens through combinatorial and junctional diversity established at the time of V(D)J recombination and through somatic hypermutation. Influenza viruses exhibit a relentless capacity to escape the human antibody response by altering the amino acids of their surface proteins in hypervariable domains that exhibit a high level of structural plasticity. Both parties in this high-stakes game of shape shifting drive structural evolution of their functional proteins (the B cell receptor/antibody on one side and the viral hemagglutinin and neuraminidase proteins on the other) using error-prone polymerase systems. It is likely that most of the genetic mutations that occur in these systems are deleterious, resulting in the failure of the B cell or virus with mutations to propagate in the immune repertoire or viral quasispecies. A subset of mutations is tolerated in functional surface proteins that enter the B cell or virus progeny pool. In both cases, selection occurs in the population of mutated and unmutated species. In cases where the functional avidity of the B cell receptor is increased significantly, that clone may be selected for preferential expansion. In contrast, an influenza virus that “escapes” the inhibitory effect of secreted antibodies may represent a high proportion of the progeny virus in that host. The recent paper by O’Donnell et al. [C. D. O’Donnell et al., mBio 3(3):e00120-12, 2012] identifies a mechanism for antibody resistance that does not require escape from binding but rather achieves a greater efficiency in replication.

scholarly journals Mapping of a Novel H3-Specific Broadly Neutralizing Monoclonal Antibody Targeting the Hemagglutinin Globular Head Isolated from an Elite Influenza Virus-Immunized Donor Exhibiting Serological Breadth

2019 ◽  
Vol 94 (6) ◽  
Author(s):  
Yu Qiu ◽  
Svetlana Stegalkina ◽  
Jianxin Zhang ◽  
Ekaterina Boudanova ◽  
Anna Park ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Sialic Acid ◽  
Neutralizing Antibodies ◽  
Vaccine Design ◽  
Binding Pocket ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Human Antibody ◽  
Sialic Acid Binding ◽  
Globular Head

ABSTRACT The discovery of potent and broadly protective influenza virus epitopes could lead to improved vaccines that are resistant to antigenic drift. Here, we describe human antibody C585, isolated from a vaccinee with remarkable serological breadth as measured by hemagglutinin inhibition (HAI). C585 binds and neutralizes multiple H3N2 strains isolated between 1968 and 2016, including strains that emerged up to 4 years after B cells were isolated from the vaccinated donor. The crystal structure of C585 Fab in complex with the HA from A/Switzerland/9715293/2013 (H3N2) shows that the antibody binds to a novel and well-conserved epitope on the globular head of H3 HA and that it differs from other antibodies not only in its epitope but in its binding geometry and hypermutated framework 3 region, thereby explaining its breadth and ability to mediate hemagglutination inhibition across decades of H3N2 strains. The existence of epitopes such as the one elucidated by C585 has implications for rational vaccine design. IMPORTANCE Influenza viruses escape immunity through continuous antigenic changes that occur predominantly on the viral hemagglutinin (HA). Induction of broadly neutralizing antibodies (bnAbs) targeting conserved epitopes following vaccination is a goal of universal influenza vaccines and advantageous in protecting hosts against virus evolution and antigenic drift. To date, most of the discovered bnAbs bind either to conserved sites in the stem region or to the sialic acid-binding pocket. Generally, antibodies targeting the stem region offer broader breadth with low potency, while antibodies targeting the sialic acid-binding pocket cover narrower breadth but usually have higher potency. In this study, we identified a novel neutralizing epitope in the head region recognized by a broadly neutralizing human antibody against a broad range of H3N2 with high potency. This epitope may provide insights for future universal vaccine design.

scholarly journals Cross-Reactive SARS-CoV-2 Neutralizing Antibodies From Deep Mining of Early Patient Responses

2021 ◽  
Vol 12 ◽  
Author(s):  
Georgia Bullen ◽  
Jacob D. Galson ◽  
Gareth Hall ◽  
Pedro Villar ◽  
Lien Moreels ◽  
...  
Keyword(s):  
Antibody Response ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Passive Immunization ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Deep Mining ◽  
Recent Emergence ◽  
Repertoire Sequencing ◽  
Patient Responses

Passive immunization using monoclonal antibodies will play a vital role in the fight against COVID-19. The recent emergence of viral variants with reduced sensitivity to some current antibodies and vaccines highlights the importance of broad cross-reactivity. This study describes deep-mining of the antibody repertoires of hospitalized COVID-19 patients using phage display technology and B cell receptor (BCR) repertoire sequencing to isolate neutralizing antibodies and gain insights into the early antibody response. This comprehensive discovery approach has yielded a panel of potent neutralizing antibodies which bind distinct viral epitopes including epitopes conserved in SARS-CoV-1. Structural determination of a non-ACE2 receptor blocking antibody reveals a previously undescribed binding epitope, which is unlikely to be affected by the mutations in any of the recently reported major viral variants including B.1.1.7 (from the UK), B.1.351 (from South Africa) and B.1.1.28 (from Brazil). Finally, by combining sequences of the RBD binding and neutralizing antibodies with the B cell receptor repertoire sequencing, we also describe a highly convergent early antibody response. Similar IgM-derived sequences occur within this study group and also within patient responses described by multiple independent studies published previously.

scholarly journals Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 13 ◽  
Author(s):  
Christoph Kreer ◽  
Henning Gruell ◽  
Thierry Mora ◽  
Aleksandra M. Walczak ◽  
Florian Klein
Keyword(s):  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Antibody Repertoire ◽  
Human Antibody ◽  
Malignant Cells ◽  
Vaccination Strategies ◽  
Receptor Repertoire ◽  
Hiv 1 ◽  
Cell Receptor Repertoire

The human antibody repertoire is generated by the recombination of different gene segments as well as by processes of somatic mutation. Together these mechanisms result in a tremendous diversity of antibodies that are able to combat various pathogens including viruses and bacteria, or malignant cells. In this review, we summarize the opportunities and challenges that are associated with the analyses of the B cell receptor repertoire and the antigen-specific B cell response. We will discuss how recent advances have increased our understanding of the antibody response and how repertoire analyses can be exploited to inform on vaccine strategies, particularly against HIV-1.

scholarly journals Anti–HIV-1 B cell responses are dependent on B cell precursor frequency and antigen-binding affinity

2018 ◽  
Vol 115 (18) ◽  
pp. 4743-4748 ◽  
Author(s):  
Pia Dosenovic ◽  
Ervin E. Kara ◽  
Anna-Klara Pettersson ◽  
Andrew T. McGuire ◽  
Matthew Gray ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Single Cells ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Precursor Frequency ◽  
Anti Hiv ◽  
Hiv 1

The discovery that humans can produce potent broadly neutralizing antibodies (bNAbs) to several different epitopes on the HIV-1 spike has reinvigorated efforts to develop an antibody-based HIV-1 vaccine. Antibody cloning from single cells revealed that nearly all bNAbs show unusual features that could help explain why it has not been possible to elicit them by traditional vaccination and instead would require a sequence of different immunogens. This idea is supported by experiments with genetically modified immunoglobulin (Ig) knock-in mice. Sequential immunization with a series of specifically designed immunogens was required to shepherd the development of bNAbs. However, knock-in mice contain superphysiologic numbers of bNAb precursor-expressing B cells, and therefore how these results can be translated to a more physiologic setting remains to be determined. Here we make use of adoptive transfer experiments using knock-in B cells that carry a synthetic intermediate in the pathway to anti–HIV-1 bNAb development to examine how the relationship between B cell receptor affinity and precursor frequency affects germinal center (GC) B cell recruitment and clonal expansion. Immunization with soluble HIV-1 antigens can recruit bNAb precursor B cells to the GC when there are as few as 10 such cells per mouse. However, at low precursor frequencies, the extent of clonal expansion is directly proportional to the affinity of the antigen for the B cell receptor, and recruitment to GCs is variable and dependent on recirculation.

scholarly journals Multi-clonal SARS-CoV-2 neutralization by antibodies isolated from severe COVID-19 convalescent donors

2021 ◽  
Vol 17 (2) ◽  
pp. e1009165 ◽  
Author(s):  
Michael Mor ◽  
Michal Werbner ◽  
Joel Alter ◽  
Modi Safra ◽  
Elad Chomsky ◽  
...  
Keyword(s):  
B Cell ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Antibody Therapy ◽  
Severe Infection ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Cell Responses ◽  
Syncytia Formation ◽  
Potent Neutralization

The interactions between antibodies, SARS-CoV-2 and immune cells contribute to the pathogenesis of COVID-19 and protective immunity. To understand the differences between antibody responses in mild versus severe cases of COVID-19, we analyzed the B cell responses in patients 1.5 months post SARS-CoV-2 infection. Severe, and not mild, infection correlated with high titers of IgG against Spike receptor binding domain (RBD) that were capable of ACE2:RBD inhibition. B cell receptor (BCR) sequencing revealed that VH3-53 was enriched during severe infection. Of the 22 antibodies cloned from two severe donors, six exhibited potent neutralization against authentic SARS-CoV-2, and inhibited syncytia formation. Using peptide libraries, competition ELISA and mutagenesis of RBD, we mapped the epitopes of the neutralizing antibodies (nAbs) to three different sites on the Spike. Finally, we used combinations of nAbs targeting different immune-sites to efficiently block SARS-CoV-2 infection. Analysis of 49 healthy BCR repertoires revealed that the nAbs germline VHJH precursors comprise up to 2.7% of all VHJHs. We demonstrate that severe COVID-19 is associated with unique BCR signatures and multi-clonal neutralizing responses that are relatively frequent in the population. Moreover, our data support the use of combination antibody therapy to prevent and treat COVID-19.

scholarly journals Antigen-specific B-cell receptor sensitizes B cells to infection by influenza virus

Nature ◽  
2013 ◽  
Vol 503 (7476) ◽  
pp. 406-409 ◽  
Author(s):  
Stephanie K. Dougan ◽  
Joseph Ashour ◽  
Roos A. Karssemeijer ◽  
Maximilian W. Popp ◽  
Ana M. Avalos ◽  
...  
Keyword(s):  
Influenza Virus ◽  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor

scholarly journals Deep Sequencing of B Cell Receptor Repertoires From COVID-19 Patients Reveals Strong Convergent Immune Signatures

2020 ◽  
Vol 11 ◽  
Author(s):  
Jacob D. Galson ◽  
Sebastian Schaetzle ◽  
Rachael J. M. Bashford-Rogers ◽  
Matthew I. J. Raybould ◽  
Aleksandr Kovaltsuk ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cell ◽  
Deep Sequencing ◽  
Neutralizing Antibodies ◽  
Convergent Sequence ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Data Sets ◽  
Patient Responses ◽  
The Uk

Deep sequencing of B cell receptor (BCR) heavy chains from a cohort of 31 COVID-19 patients from the UK reveals a stereotypical naive immune response to SARS-CoV-2 which is consistent across patients. Clonal expansion of the B cell population is also observed and may be the result of memory bystander effects. There was a strong convergent sequence signature across patients, and we identified 1,254 clonotypes convergent between at least four of the COVID-19 patients, but not present in healthy controls or individuals following seasonal influenza vaccination. A subset of the convergent clonotypes were homologous to known SARS and SARS-CoV-2 spike protein neutralizing antibodies. Convergence was also demonstrated across wide geographies by comparison of data sets between patients from UK, USA, and China, further validating the disease association and consistency of the stereotypical immune response even at the sequence level. These convergent clonotypes provide a resource to identify potential therapeutic and prophylactic antibodies and demonstrate the potential of BCR profiling as a tool to help understand patient responses.

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