Complement-Mediated Neutralisation Identified in Ebola Virus Disease Survivor Plasma: Implications for Protection and Pathogenesis

Jack Mellors*, Tom Tipton, Sarah Katharina Fehling, Joseph Akoi Bore, Fara Raymond Koundouno, Yper Hall, Jacob Hudson, Frances Alexander, Stephanie Longet, Stephen Taylor, Andrew Gorringe, N’Faly Magassouba, Mandy Kader Konde, Julian Hiscox, Thomas Strecker, Miles Carroll

*Corresponding author for this work

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Abstract

The 2013–2016 Ebola virus (EBOV) epidemic in West Africa was unprecedented in case numbers and fatalities, and sporadic outbreaks continue to arise. Antibodies to the EBOV glycoprotein (GP) are strongly associated with survival and their use in immunotherapy is often initially based on their performance in neutralisation assays. Other immune effector functions also contribute to EBOV protection but are more complex to measure. Their interactions with the complement system in particular are comparatively under-researched and commonly excluded from cellular immunoassays. Using EBOV convalescent plasma samples from the 2013–2016 epidemic, we investigated antibody and complement-mediated neutralisation and how these interactions can influence immunity in response to EBOV-GP and its secreted form (EBOV-sGP). We defined two cohorts: one with low-neutralising titres in relation to EBOV-GP IgG titres (LN cohort) and the other with a direct linear relationship between neutralisation and EBOV-GP IgG titres (N cohort). Using flow cytometry antibody-dependent complement deposition (ADCD) assays, we found that the LN cohort was equally efficient at mediating ADCD in response to the EBOV-GP but was significantly lower in response to the EBOV-sGP, compared to the N cohort. Using wild-type EBOV neutralisation assays with a cohort of the LN plasma, we observed a significant increase in neutralisation associated with the addition of pooled human plasma as a source of complement. Flow cytometry ADCD was also applied using the GP of the highly virulent Sudan virus (SUDV) of the Sudan ebolavirus species. There are no licensed vaccines or therapeutics against SUDV and it overlaps in endemicity with EBOV. We found that the LN plasma was significantly less efficient at cross-reacting and mediating ADCD. Overall, we found a differential response in ADCD between LN and N plasma in response to various Ebolavirus glycoproteins, and that these interactions could significantly improve EBOV neutralisation for selected LN plasma samples. Preservation of the complement system in immunoassays could augment our understanding of neutralisation and thus protection against infection.

Original languageEnglish
Article number857481
JournalFrontiers in Immunology
Volume13
DOIs
Publication statusPublished - 12 Apr 2022

Bibliographical note

Funding Information: This work was funded via a UK Health Security Agency studentship programme and by the US Food and Drug Administration Medical Countermeasures Initiative contract 75F40120C00085 and contract HHSF223201510104C. Author T.S. received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Projektnummer 197785619 - SFB1021.

Open Access: This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Publisher Copyright: © 2022 Mellors, Tipton, Fehling, Akoi Bore, Koundouno, Hall, Hudson, Alexander, Longet, Taylor, Gorringe, Magassouba, Konde, Hiscox, Strecker and Carroll.

Citation: Mellors J, Tipton T, Fehling SK, Akoi Bore J, Koundouno FR, Hall Y, Hudson J, Alexander F, Longet S, Taylor S, Gorringe A, Magassouba NF, Konde MK, Hiscox J, Strecker T and Carroll M (2022) Complement-Mediated Neutralisation Identified in Ebola Virus Disease Survivor Plasma: Implications for Protection and Pathogenesis. Front. Immunol. 13:857481.

DOI: 10.3389/fimmu.2022.857481

Keywords

  • antibodies
  • complement system
  • ebola virus
  • immunology
  • neutralisation
  • pathogenesis
  • protection
  • virology

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