Achieving cross-reactivity with pan-ebolavirus antibodies

King, Liam B.; Milligan, Jacob C.; West, Brandyn R.; Schendel, Sharon L.; Saphire, Erica Ollmann

doi:10.1016/j.coviro.2019.01.003

Cited by 18 publications

(22 citation statements)

References 62 publications

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“…The footprint of rEBOV-520 is distinct from that of the previously described broad human base-specific mAb ADI-15878 West et al, 2018) but is similar to the footprint of the potent human-base-specific mAb ADI-15946 ( Figure 3D), which fully neutralizes EBOV and BDBV but not SUDV (Wec et al, 2017;West et al, 2019). Both ADI-15946 and rEBOV-520 bound to the 3 10 pocket and IFL stem regions of the fusion loop, unlike human mAb ADI-15878, which binds to the hydrophobic loop end of the structure and bridges to a neighboring GP protomer (King et al, 2019). However, rEBOV-520 likely gained reactivity against SUDV by having a footprint slightly higher on the GP base than the ADI-15946, or a different angle of approach than that of ADI-15946, which was directed downward toward the viral membrane ( Figure 3C), in contrast to ADI-15946, which is directed upward from the membrane .…”

Section: Identification and Functional Properties Of Candidate Cocktasupporting

confidence: 52%

Analysis of a Therapeutic Antibody Cocktail Reveals Determinants for Cooperative and Broad Ebolavirus Neutralization

et al. 2020

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Graphical AbstractHighlights d Human mAbs of two epitope specificities bind cooperatively to the ebolavirus GP d Cooperativity is mediated by a mAb that enhances binding to a vulnerable GP epitope d A two-mAb cocktail exhibits enhanced potency against heterologous ebolaviruses d Two 30 mg/kg doses of the cocktail fully protected nonhuman primates (NHPs) challenged with EBOV SUMMARY Structural principles underlying the composition of protective antiviral monoclonal antibody (mAb) cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic mAb cocktail against Ebola virus. We systematically analyzed the antibody repertoire in human survivors and identified a pair of potently neutralizing mAbs that cooperatively bound to the ebolavirus glycoprotein (GP). High-resolution structures revealed that in a twoantibody cocktail, molecular mimicry was a major feature of mAb-GP interactions. Broadly neutralizing mAb rEBOV-520 targeted a conserved epitope on the GP base region. mAb rEBOV-548 bound to a glycan cap epitope, possessed neutralizing and Fc-mediated effector function activities, and potentiated neutralization by rEBOV-520. Remodeling of the glycan cap structures by the cocktail enabled enhanced GP binding and virus neutralization. The cocktail demonstrated resistance to virus escape and protected non-human primates (NHPs) against Ebola virus disease. These data illuminate structural principles of antibody cooperativity with implications for development of antiviral immunotherapeutics.

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Section: Identification and Functional Properties Of Candidate Cocktasupporting

confidence: 52%

Analysis of a Therapeutic Antibody Cocktail Reveals Determinants for Cooperative and Broad Ebolavirus Neutralization

et al. 2020

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“…This finding was somewhat unexpected, as significant differences were found between soluble E2 core and NP groups at both w2 and w5 in a recent HCV vaccine study (65), suggesting that antibody titers of antigen-presenting NPs may be influenced by antigen size, structure, and epitope distribution. NP display may occlude antibody access to the base and stalk epitopes, which are the targets of many bNAbs (9). This result may also be attributed to other factors such as dosage, as noted in our recent study (65).…”

Section: Immunogenicity Of Ebov Gp Trimers and Nps In Balb/c Mice 380mentioning

confidence: 62%

Single-component multilayered self-assembling nanoparticles presenting rationally designed glycoprotein trimers as Ebola virus vaccines

Chaudhary

Lin

et al. 2020

Preprint

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The Ebola virus (EBOV) glycoprotein (GP) can be recognized by neutralizing antibodies (NAbs) and is the main target for vaccine design. We first investigated the contribution of the stalk and the heptad repeat 1-C (HR1C) region to GP metastability. Specific stalk and HR1C modifications in a mucin-deleted form (GPΔmuc) increased trimer yield, while alteration of HR1C exerted a more complex effect on thermostability. Crystal structures were determined to validate these rationally designed GPΔmuc trimers in their unliganded state. We then displayed a modified GPΔmuc trimer on engineered nanoparticles with encapsulated locking domains (LD) and a cluster of helper T-cell epitopes. In mice and rabbits, GP trimers and nanoparticles elicited cross-ebolavirus NAbs as well as non-NAbs that enhance in-vitro infection. Next-generation sequencing (NGS) revealed B-cell profiles that are specific to vaccine platforms. This study provides insight into GP metastability and paves the way for development of an effective, pan-ebolavirus nanoparticle vaccine.

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“…As several species cause EVD in humans, antibodies that crossreact with additional species are of particular interest. Such crossreactive antibodies have been observed in EVD survivors 14,15,51,52 , and a recent study reported a cocktail of two pan-Ebolavirus antibodies for therapeutic protection of animal models 10 . Although crossreactivity was low in the sera of vaccinees, 30-75% of monoclonal antibodies potently cross-reacted with other Filoviruses.…”

Section: Discussionmentioning

confidence: 90%

Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV

Ehrhardt

Zehner

Krähling

et al. 2019

Nat Med

102

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Recombinant vesicular stomatitis virus-Zaire Ebola virus (rVSV-ZEBOV) is the most advanced Ebola virus vaccine candidate and is currently being used to combat the outbreak of Ebola virus disease (EVD) in the Democratic Republic of the Congo (DRC). Here we examine the humoral immune response in a subset of human volunteers enrolled in a phase 1 rVSV-ZEBOV vaccination trial by performing comprehensive single B cell and electron microscopy structure analyses. Four studied vaccinees show polyclonal, yet reproducible and convergent B cell responses with shared sequence characteristics. EBOV-targeting antibodies cross-react with other Ebolavirus species, and detailed epitope mapping revealed overlapping target epitopes with antibodies isolated from EVD survivors. Moreover, in all vaccinees, we detected highly potent EBOV-neutralizing antibodies with activities comparable or superior to the monoclonal antibodies currently used in clinical trials. These include antibodies combining the IGHV3-15/IGLV1-40 immunoglobulin gene segments that were identified in all investigated individuals. Our findings will help to evaluate and direct current and future vaccination strategies and offer opportunities for novel EVD therapies.

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Achieving cross-reactivity with pan-ebolavirus antibodies

Cited by 18 publications

References 62 publications

Analysis of a Therapeutic Antibody Cocktail Reveals Determinants for Cooperative and Broad Ebolavirus Neutralization

Analysis of a Therapeutic Antibody Cocktail Reveals Determinants for Cooperative and Broad Ebolavirus Neutralization

Single-component multilayered self-assembling nanoparticles presenting rationally designed glycoprotein trimers as Ebola virus vaccines

Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV

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