scholarly journals Engineering an Antibody V Gene-Selective Vaccine

2021 ◽  
Vol 12 ◽  
Author(s):  
Larance Ronsard ◽  
Ashraf S. Yousif ◽  
Julianne Peabody ◽  
Vintus Okonkwo ◽  
Pascal Devant ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Antibody Repertoire ◽  
Proof Of Concept ◽  
Broadly Neutralizing Antibodies ◽  
Antigen Binding Site ◽  
Virus Like Particle ◽  
Binding Surface ◽  
Complementarity Determining Regions

The ligand-binding surface of the B cell receptor (BCR) is formed by encoded and non-encoded antigen complementarity determining regions (CDRs). Genetically reproducible or ‘public’ antibodies can arise when the encoded CDRs play deterministic roles in antigen recognition, notably within human broadly neutralizing antibodies against HIV and influenza virus. We sought to exploit this by engineering virus-like-particle (VLP) vaccines that harbor multivalent affinity against gene-encoded moieties of the BCR antigen binding site. As proof of concept, we deployed a library of RNA bacteriophage VLPs displaying random peptides to identify a multivalent antigen that selectively triggered germline BCRs using the human VH gene IGVH1-2*02. This VLP selectively primed IGHV1-2*02 BCRs that were present within a highly diversified germline antibody repertoire within humanized mice. Our approach thus provides methodology to generate antigens that engage specific BCR configurations of interest, in the absence of structure-based information.

scholarly journals Broadly Neutralizing Bovine Antibodies: Highly Effective New Tools against Evasive Pathogens?

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 473
Author(s):  
Matthew J. Burke ◽  
Peter G. Stockley ◽  
Joan Boyes
Keyword(s):  
Neutralizing Antibodies ◽  
Current Knowledge ◽  
Antibody Repertoire ◽  
Antigen Binding ◽  
Broadly Neutralizing Antibodies ◽  
Antigen Binding Site ◽  
Vdj Recombination ◽  
Vast Array ◽  
Hiv 1 ◽  
Potent Neutralization

Potent antibody-mediated neutralization is critical for an organism to combat the vast array of pathogens it will face during its lifetime. Due to the potential genetic diversity of some viruses, such as HIV-1 and influenza, standard neutralizing antibodies are often ineffective or easily evaded as their targets are masked or rapidly mutated. This has thwarted efforts to both prevent and treat HIV-1 infections and means that entirely new formulations are required to vaccinate against influenza each year. However, some rare antibodies isolated from infected individuals confer broad and potent neutralization. A subset of these broadly neutralizing antibodies possesses a long complementarity-determining 3 region of the immunoglobulin heavy chain (CDR H3). This feature generates unique antigen binding site configurations that can engage conserved but otherwise inaccessible epitope targets thus neutralizing many viral variants. Remarkably, ultralong CDR H3s are a common feature of the cow antibody repertoire and are encoded by a single variable, diversity, joining (VDJ) recombination that is extensively diversified prior to antigen exposure. Recently, it was shown that cows rapidly generate a broadly neutralizing response upon exposure to HIV-1 and this is primarily mediated by these novel ultralong antibody types. This review summarises the current knowledge of these unusual CDR H3 structures and discusses their known and potential future uses.

scholarly journals HIV-1 Envelope Conformation, Allostery, and Dynamics

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 852
Author(s):  
Ashley Lauren Bennett ◽  
Rory Henderson
Keyword(s):  
Host Cell ◽  
Conformational Changes ◽  
Neutralizing Antibodies ◽  
Critical Role ◽  
Cell Receptor ◽  
Broadly Neutralizing Antibodies ◽  
Structural Mapping ◽  
Host Cell Receptor ◽  
Immunogen Design ◽  
Hiv 1

The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing antibodies, our understanding of these transitions plays a critical role in vaccine immunogen design. Here, we review available experimental data interrogating the HIV-1 Env conformation and detail computational efforts aimed at delineating the series of conformational changes connecting these rearrangements. These studies have provided a structural mapping of prefusion closed, open, and transition intermediate structures, the allosteric elements controlling rearrangements, and state-to-state transition dynamics. The combination of these investigations and innovations in molecular modeling set the stage for advanced studies examining rearrangements at greater spatial and temporal resolution.

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 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 Human Follicular Lymphoma Cells Contain Oligomannose Glycans in the Antigen-binding Site of the B-cell Receptor

2006 ◽  
Vol 282 (10) ◽  
pp. 7405-7415 ◽  
Author(s):  
Catherine M. Radcliffe ◽  
James N. Arnold ◽  
David M. Suter ◽  
Mark R. Wormald ◽  
David J. Harvey ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Binding Site ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Antigen Binding ◽  
Antigen Binding Site ◽  
Lymphoma Cells

scholarly journals Multiscale affinity maturation simulations to elicit HIV broadly neutralizing antibodies

2021 ◽  
Author(s):  
Kayla Sprenger ◽  
Simone Conti ◽  
Victor Ovchinnikov ◽  
Arup K Chakraborty ◽  
martin karplus
Keyword(s):  
Neutralizing Antibodies ◽  
Adaptive Immune System ◽  
Multiscale Model ◽  
Cell Receptor ◽  
Affinity Maturation ◽  
Sequencing Data ◽  
Broadly Neutralizing Antibodies ◽  
Adaptive Immune ◽  
Cd4 Binding Site ◽  
Anti Hiv

The design of vaccines against highly mutable pathogens, such as HIV and influenza, requires a detailed understanding of how the adaptive immune system responds to encountering multiple variant antigens (Ags). Here, we describe a multiscale model of B cell receptor (BCR) affinity maturation that employs actual BCR nucleotide sequences and treats BCR/Ag interactions in atomistic detail. We apply the model to simulate the maturation of a broadly neutralizing Ab (bnAb) against HIV. Starting from a germline precursor sequence of the VRC01 anti-HIV Ab, we simulate BCR evolution in response to different vaccination protocols and different Ags, which were previously designed by us. The simulation results provide qualitative guidelines for future vaccine design and reveal unique insights into bnAb evolution against the CD4 binding site of HIV. Our model makes possible direct comparisons of simulated BCR populations with results of deep sequencing data, which will be explored in future applications.

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 Augmenting Neutralization breadth against Diverse HIV-1 by increasing the Ab-Ag interface on V2

2021 ◽  
Author(s):  
Nan Gao ◽  
Yanxin Gai ◽  
Lina Meng ◽  
Chu Wang ◽  
Wei Wang ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Broadly Neutralizing Antibodies ◽  
Binding Surface ◽  
Monomeric Gp120 ◽  
Chinese Rhesus Macaques ◽  
Shiv Infection ◽  
Hiv 1 ◽  
Trimeric Envelope

Understanding maturation pathways of broadly neutralizing antibodies (bnAbs) against HIV-1 in non-human primates can be highly informative for HIV-1 vaccine development. We now obtained a lineage of J038 from Chinese rhesus macaques after 7-years of SHIV infection. J038 has short complementary determining loops and neutralizes 54% of global circulating HIV-1 strains. Its binding induces a unique 'up' conformation for one of the V2 loops in the trimeric envelope glycoprotein (Env) and is heavily dependent on glycan, which provides nearly half of the binding surface. The unmutated common ancestor of the J038 lineage antibodies binds monomeric gp120 and neutralizes the autologous virus. Continuous maturation enhances neutralization potency and breadth of J038 lineage antibodies via expanding antibody-Env contact areas surrounding the core region contacted by germline-encoded residues. Developmental details and recognition features of J038 lineage antibodies revealed here provide a new pathway for maturation elicitation of V2-targeting bnAbs.

scholarly journals Public Immunity: Evolutionary Spandrels for Pathway-Amplifying Protective Antibodies

2021 ◽  
Vol 12 ◽  
Author(s):  
Maya Sangesland ◽  
Daniel Lingwood
Keyword(s):  
B Cell ◽  
Humoral Immunity ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Antibody Responses ◽  
Antibody Repertoire ◽  
Protective Antibodies ◽  
Cognate Antigen ◽  
Rational Vaccine Design ◽  
Antigen Reactivity

Humoral immunity is seeded by affinity between the B cell receptor (BCR) and cognate antigen. While the BCR is a chimeric display of diverse antigen engagement solutions, we discuss its functional activity as an ‘innate-like’ immune receptor, wherein genetically hardwired antigen complementarity can serve as reproducible templates for pathway-amplifying otherwise immunologically recessive antibody responses. We propose that the capacity for germline reactivity to new antigen emerged as a set of evolutionary spandrels or coupled traits, which can now be exploited by rational vaccine design to focus humoral immunity upon conventionally immune-subdominant antibody targets. Accordingly, we suggest that evolutionary spandrels account for the necessary but unanticipated antigen reactivity of the germline antibody repertoire.

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