Convergence of a common solution for broad ebolavirus neutralization by glycan cap-directed human antibodies

Murin, Charles D.; Gilchuk, Pavlo; Ilinykh, Philipp A.; Huang, Kai; Kuzmina, Natalia; Shen, Xiaoli; Bruhn, Jessica F.; Bryan, Aubrey L.; Davidson, Edgar; Doranz, Benjamin J.; Williamson, Lauren E.; Copps, Jeffrey; Alkutkar, Tanwee; Flyak, Andrew I.; Bukreyev, Alexander; Crowe, James E.; Ward, Andrew B.

doi:10.1016/j.celrep.2021.108984

Cited by 24 publications

(42 citation statements)

References 85 publications

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“…In summary, our data support and expand existing data sets about the importance of antibodies directed to the EBOV GP GC for protection from EVD [31,32,38]. Our findings also demonstrate that both the GC and MLD are dispensable for VSV-EBOV-based vaccine vector replication in vitro .…”

Section: Discussionsupporting

confidence: 88%

“…In addition, the monoclonal antibody cocktail ZMapp contains the GC-binding antibody 13c6 [37]. Recently, inhibition of cathepsin cleavage by these GC-binding antibodies was proposed as a mechanism [38]. Therefore, while a deletion of the GC and MLD might not interfere with the GP’s ability to drive VSV replication, it could result in reduced protective immunity against EBOV infection.…”

Section: Discussionmentioning

confidence: 99%

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Ebola virus glycoprotein domains associated with protective efficacy

Bhatia

Furuyama

Hoenen

et al. 2021

Preprint

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Ebola virus (EBOV) is the cause of sporadic outbreaks of human hemorrhagic disease in Africa, and the best-characterized virus in the filovirus family. The West Africa epidemic accelerated the clinical development of vaccines and therapeutics leading to licensure of vaccines and antibody-based therapeutics for human use in recent years. The most widely used vaccine is based on vesicular stomatitis virus (VSV) expressing the EBOV glycoprotein (GP)(VSV-EBOV). Due to its favorable immune cell targeting, this vaccine has also been used as base-vector for the development of second generation VSV-based vaccines against Influenza, Nipah, and Zika viruses. However, in these situations it may be beneficial if the immunogenicity against EBOV GP is minimized to induce a better protective immune response against the other foreign immunogen. Here, we analyzed if EBOV GP can be truncated to be less immunogenic yet still able to drive replication of the vaccine vector. We found that the EBOV GP glycan cap and the mucin-like domain are both dispensable for VSV-EBOV replication. The glycan cap domain, however, appears critical for mediating a protective immune response against lethal EBOV challenge in mice.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Ebola virus glycoprotein domains associated with protective efficacy

Bhatia

Furuyama

Hoenen

et al. 2021

Preprint

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“…Several recent studies showed that memory B cells in several individuals used genetically similar B cell receptor genes to encode neutralizing mAbs (20,56,57). Another study described common structural and genetic features of the glycan cap recognition by several broadly-reactive human mAbs isolated from memory B cells (41). In our study of serological response in one donor we characterized three major epitope classes of mAbs using a relatively small panel of 52 mAbs.…”

Section: Discussionmentioning

confidence: 96%

“…For individual mAbs, alanine scanning mutagenesis studies identified key binding site residues that mostly were located on the top part of the glycan cap (Figures 4, 5B). Many of these residues were defined previously by us and others as key contact residues for potent neutralizing glycan cap-specific human mAbs BDBV-289 (W275), EBOV-237 (N278), EBOV-337 (W275), EBOV-442 (W275, P273), and EBOV-548 (T240, T270, I274, W275), weakly neutralizing protective murine mAb 1H3 (K276), or the non-neutralizing protective mAb 13C6 (T270, K272) (6,33,40,41). We also assessed mAbs from this study in a competition-binding assay and demonstrated competition with mAb 13C6 for GP binding, which confirmed the glycan cap specificity of these mAbs (Figure 4).…”

Section: Major Antigenic Binding Sites Targeted By Class-representative Plasma Mabs Revealed Common Featuresmentioning

confidence: 99%

Proteo-Genomic Analysis Identifies Two Major Sites of Vulnerability on Ebolavirus Glycoprotein for Neutralizing Antibodies in Convalescent Human Plasma

et al. 2021

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Three clinically relevant ebolaviruses – Ebola (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) viruses, are responsible for severe disease and occasional deadly outbreaks in Africa. The largest Ebola virus disease (EVD) epidemic to date in 2013-2016 in West Africa highlighted the urgent need for countermeasures, leading to the development and FDA approval of the Ebola virus vaccine rVSV-ZEBOV (Ervebo®) in 2020 and two monoclonal antibody (mAb)-based therapeutics (Inmazeb® [atoltivimab, maftivimab, and odesivimab-ebgn] and Ebanga® (ansuvimab-zykl) in 2020. The humoral response plays an indispensable role in ebolavirus immunity, based on studies of mAbs isolated from the antibody genes in peripheral blood circulating ebolavirus-specific human memory B cells. However, antibodies in the body are not secreted by circulating memory B cells in the blood but rather principally by plasma cells in the bone marrow. Little is known about the protective polyclonal antibody responses in convalescent plasma. Here we exploited both single-cell antibody gene sequencing and proteomic sequencing approaches to assess the composition of the ebolavirus glycoprotein (GP)-reactive antibody repertoire in the plasma of an EVD survivor. We first identified 1,512 GP-specific mAb variable gene sequences from single cells in the memory B cell compartment. Using mass spectrometric analysis of the corresponding GP-specific plasma IgG, we found that only a portion of the large B cell antibody repertoire was represented in the plasma. Molecular and functional analysis of proteomics-identified mAbs revealed recognition of epitopes in three major antigenic sites - the GP head domain, the glycan cap, and the base region, with a high prevalence of neutralizing and protective mAb specificities that targeted the base and glycan cap regions on the GP. Polyclonal plasma antibodies from the survivor reacted broadly to EBOV, BDBV, and SUDV GP, while reactivity of the potently neutralizing mAbs we identified was limited mostly to the homologous EBOV GP. Together these results reveal a restricted diversity of neutralizing humoral response in which mAbs targeting two antigenic sites on GP – glycan cap and base – play a principal role in plasma-antibody-mediated protective immunity against EVD.

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“…It binds to its epitope with 5× greater affinity once EBOV-548 is bound to the GC. Together, EBOV-520 and EBOV-548 can fully protect NHPs from mortality, though EBOV-520 alone has also demonstrated partial protection in animal models [ 82 , 83 , 84 ]. Finally, 13C6 is a non-neutralising antibody from the ZMapp cocktail that binds to the GC but is removed during cathepsin cleavage.…”

Section: Antibody-based Therapeutics and Vaccinesmentioning

confidence: 99%

Filovirus Neutralising Antibodies: Mechanisms of Action and Therapeutic Application

et al. 2021

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Filoviruses, especially Ebola virus, cause sporadic outbreaks of viral haemorrhagic fever with very high case fatality rates in Africa. The 2013–2016 Ebola epidemic in West Africa provided large survivor cohorts spurring a large number of human studies which showed that specific neutralising antibodies played a key role in protection following a natural Ebola virus infection, as part of the overall humoral response and in conjunction with the cellular adaptive response. This review will discuss the studies in survivors and animal models which described protective neutralising antibody response. Their mechanisms of action will be detailed. Furthermore, the importance of neutralising antibodies in antibody-based therapeutics and in vaccine-induced responses will be explained, as well as the strategies to avoid immune escape from neutralising antibodies. Understanding the neutralising antibody response in the context of filoviruses is crucial to furthering our understanding of virus structure and function, in addition to improving current vaccines & antibody-based therapeutics.

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Convergence of a common solution for broad ebolavirus neutralization by glycan cap-directed human antibodies

Cited by 24 publications

References 85 publications

Ebola virus glycoprotein domains associated with protective efficacy

Ebola virus glycoprotein domains associated with protective efficacy

Proteo-Genomic Analysis Identifies Two Major Sites of Vulnerability on Ebolavirus Glycoprotein for Neutralizing Antibodies in Convalescent Human Plasma

Filovirus Neutralising Antibodies: Mechanisms of Action and Therapeutic Application

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