+
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Ebola virus antibody decay–stimulation in a high proportion of survivors

Nature volume 590, pages 468–472 (2021)Cite this article

Subjects

Abstract

Neutralizing antibody function provides a foundation for the efficacy of vaccines and therapies1,2,3. Here, using a robust in vitro Ebola virus (EBOV) pseudo-particle infection assay and a well-defined set of solid-phase assays, we describe a wide spectrum of antibody responses in a cohort of healthy survivors of the Sierra Leone EBOV outbreak of 2013–2016. Pseudo-particle virus-neutralizing antibodies correlated with total anti-EBOV reactivity and neutralizing antibodies against live EBOV. Variant EBOV glycoproteins (1995 and 2014 strains) were similarly neutralized. During longitudinal follow-up, antibody responses fluctuated in a ‘decay–stimulation–decay’ pattern that suggests de novo restimulation by EBOV antigens after recovery. A pharmacodynamic model of antibody reactivity identified a decay half-life of 77–100 days and a doubling time of 46–86 days in a high proportion of survivors. The highest antibody reactivity was observed around 200 days after an individual had recovered. The model suggests that EBOV antibody reactivity declines over 0.5–2 years after recovery. In a high proportion of healthy survivors, antibody responses undergo rapid restimulation. Vigilant follow-up of survivors and possible elective de novo antigenic stimulation by vaccine immunization should be considered in order to prevent EBOV viral recrudescence in recovering individuals and thereby to mitigate the potential risk of reseeding an outbreak.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: EBOV-GP HIV-1 pseudo-typed virus neutralization assay.
Fig. 2: Convalescent plasma neutralizing antibody titres.
Fig. 3: Rates of EBOV antibody decay and recovery following the 2013–2016 West Africa outbreak.

Similar content being viewed by others

Data availability

All datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Source data are provided with this paper.

References

  1. Kasangye, K. A. et al. in Advances in Ebola Control (ed. Okware, S. I.) (IntechOpen, 2017).

  2. Heeney, J. L. Ebola: hidden reservoirs. Nature 527, 453–455 (2015).

    Article  CAS  ADS  PubMed  Google Scholar 

  3. Sullivan, N. J., Martin, J. E., Graham, B. S. & Nabel, G. J. Correlates of protective immunity for Ebola vaccines: implications for regulatory approval by the animal rule. Nat. Rev. Microbiol. 7, 393–400 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Saphire, E. O. et al. Systematic analysis of monoclonal antibodies against Ebola virus GP defines features that contribute to protection. Cell 174, 938–952.e13 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Henao-Restrepo, A. M. et al. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Lancet 386, 857–866 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Henao-Restrepo, A. M. et al. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!). Lancet 389, 505–518 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhu, F. C. et al. Safety and immunogenicity of a recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in Sierra Leone: a single-centre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 389, 621–628 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. Ringe, R. & Bhattacharya, J. Preventive and therapeutic applications of neutralizing antibodies to human immunodeficiency virus type 1 (HIV-1). Ther. Adv. Vaccines 1, 67–80 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. VanBlargan, L. A., Goo, L. & Pierson, T. C. Deconstructing the antiviral neutralizing-antibody response: implications for vaccine development and immunity. Microbiol. Mol. Biol. Rev. 80, 989–1010 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Crowe, J. E. Jr. Principles of broad and potent antiviral human antibodies: insights for vaccine design. Cell Host Microbe 22, 193–206 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Garraud, O. Use of convalescent plasma in Ebola virus infection. Transfus. Apher. Sci. 56, 31–34 (2017).

    Article  PubMed  Google Scholar 

  12. Zhang, Q. et al. Potent neutralizing monoclonal antibodies against Ebola virus infection. Sci. Rep. 6, 25856 (2016).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  13. King, L. B., West, B. R., Schendel, S. L. & Saphire, E. O. The structural basis for filovirus neutralization by monoclonal antibodies. Curr. Opin. Immunol. 53, 196–202 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gaudinski, M. R. et al. Safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody mAb114 targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study. Lancet 393, 889–898 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. van Griensven, J., Edwards, T. & Baize, S. Efficacy of convalescent plasma in relation to dose of Ebola virus antibodies. N. Engl. J. Med. 375, 2307–2309 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  16. van Griensven, J. et al. The use of Ebola convalescent plasma to treat Ebola virus disease in resource-constrained settings: a perspective from the field. Clin. Infect. Dis. 62, 69–74 (2016).

    Article  PubMed  Google Scholar 

  17. Chippaux, J. P., Boyer, L. V. & Alagón, A. Post-exposure treatment of Ebola virus using passive immunotherapy: proposal for a new strategy. J. Venom. Anim. Toxins Incl. Trop. Dis. 21, 3 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wec, A. Z. et al. Development of a human antibody cocktail that deploys multiple functions to confer pan-Ebolavirus protection. Cell Host Microbe 25, 39–48.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Flyak, A. I. et al. Cross-reactive and potent neutralizing antibody responses in human survivors of natural Ebolavirus infection. Cell 164, 392–405 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bramble, M. S. et al. Pan-filovirus serum neutralizing antibodies in a subset of Congolese Ebolavirus infection survivors. J. Infect. Dis. 218, 1929–1936 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tedder, R. S. et al. Detection, characterization, and enrollment of donors of Ebola convalescent plasma in Sierra Leone. Transfusion 58, 1289–1298 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Baize, S. et al. Emergence of Zaire Ebola virus disease in Guinea. N. Engl. J. Med. 371, 1418–1425 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Carroll, S. A. et al. Molecular evolution of viruses of the family Filoviridae based on 97 whole-genome sequences. J. Virol. 87, 2608–2616 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hoffmann, M. et al. A polymorphism within the internal fusion loop of the Ebola virus glycoprotein modulates host cell entry. J. Virol. 91, e00177-17 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Urbanowicz, R. A. et al. Human adaptation of Ebola virus during the West African outbreak. Cell 167, 1079–1087.e5 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Marzi, A. et al. Recently identified mutations in the Ebola virus-Makona genome do not alter pathogenicity in animal models. Cell Rep. 23, 1806–1816 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wilkinson, D. E. et al. Comparison of platform technologies for assaying antibody to Ebola virus. Vaccine 35, 1347–1352 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Williamson, L. E. et al. Early human B cell response to Ebola virus in four U.S. survivors of infection. J. Virol. 93, e01439-18 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rimoin, A. W. et al. Ebola virus neutralizing antibodies detectable in survivors of the Yambuku, Zaire outbreak 40 years after infection. J. Infect. Dis. 217, 223–231 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Brown, J. F. et al. Anti-Ebola virus antibody levels in convalescent plasma and viral load after plasma infusion in patients with Ebola virus disease. J. Infect. Dis. 218, 555–562 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dokubo, E. K. et al. Persistence of Ebola virus after the end of widespread transmission in Liberia: an outbreak report. Lancet Infect. Dis. 18, 1015–1024 (2018).

    Article  PubMed  Google Scholar 

  32. Subissi, L. et al. Ebola virus transmission caused by persistently infected survivors of the 2014-2016 outbreak in West Africa. J. Infect. Dis. 218 (Suppl. 5), S287–S291 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Shantha, J. G. et al. Ebola virus persistence in ocular tissues and fluids (EVICT) Study: reverse transcription-polymerase chain reaction and cataract surgery outcomes of Ebola survivors in Sierra Leone. EBioMedicine 30, 217–224 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Whitmer, S. L. M. et al. Active Ebola virus replication and heterogeneous evolutionary rates in EVD survivors. Cell Rep. 22, 1159–1168 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Den Boon, S. et al. Ebola virus infection associated with transmission from survivors. Emerg. Infect. Dis. 25, 249–255 (2019).

    Article  Google Scholar 

  36. Purpura, L. J. et al. Ebola virus RNA in semen from an HIV-positive survivor of Ebola. Emerg. Infect. Dis. 23, 714–715 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kendrick, F. et al. Analysis of a compartmental model of endogenous immunoglobulin G metabolism with application to multiple myeloma. Front. Physiol. 8, 149 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Davis, C. W. et al. Longitudinal analysis of the human B cell response to Ebola virus infection. Cell 177, 1566–1582.e17 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Carroll, M. W. et al. Temporal and spatial analysis of the 2014–2015 Ebola virus outbreak in West Africa. Nature 524, 97–101 (2015).

    Article  CAS  ADS  PubMed  Google Scholar 

  40. Dudas, G. et al. Virus genomes reveal factors that spread and sustained the Ebola epidemic. Nature 544, 309–315 (2017).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  41. Scott, J. T. et al. Post-Ebola syndrome, Sierra Leone. Emerg. Infect. Dis. 22, 641–646 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jagadesh, S. et al. Disability among Ebola survivors and their close contacts in Sierra Leone: a retrospective case-controlled cohort study. Clin. Infect. Dis. 66, 131–133 (2018).

    Article  PubMed  Google Scholar 

  43. Jacobs, M. et al. Late Ebola virus relapse causing meningoencephalitis: a case report. Lancet 388, 498–503 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Scott, J. T. & Semple, M. G. Ebola virus disease sequelae: a challenge that is not going away. Lancet Infect. Dis. 17, 470–471 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Platt, E. J., Bilska, M., Kozak, S. L., Kabat, D. & Montefiori, D. C. Evidence that ecotropic murine leukemia virus contamination in TZM-bl cells does not affect the outcome of neutralizing antibody assays with human immunodeficiency virus type 1. J. Virol. 83, 8289–8292 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Takeuchi, Y., McClure, M. O. & Pizzato, M. Identification of gammaretroviruses constitutively released from cell lines used for human immunodeficiency virus research. J. Virol. 82, 12585–12588 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wei, X. et al. Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob. Agents Chemother. 46, 1896–1905 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Derdeyn, C. A. et al. Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120. J. Virol. 74, 8358–8367 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Platt, E. J., Wehrly, K., Kuhmann, S. E., Chesebro, B. & Kabat, D. Effects of CCR5 and CD4 cell surface concentrations on infections by macrophagetropic isolates of human immunodeficiency virus type 1. J. Virol. 72, 2855–2864 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Biek, R., Walsh, P. D., Leroy, E. M. & Real, L. A. Recent common ancestry of Ebola Zaire virus found in a bat reservoir. PLoS Pathog. 2, e90 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Connor, R. I., Chen, B. K., Choe, S. & Landau, N. R. Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes. Virology 206, 935–944 (1995).

    Article  CAS  PubMed  Google Scholar 

  52. Wei, X. et al. Antibody neutralization and escape by HIV-1. Nature 422, 307–312 (2003).

    Article  CAS  ADS  PubMed  Google Scholar 

  53. Neely, M. N., van Guilder, M. G., Yamada, W. M., Schumitzky, A. & Jelliffe, R. W. Accurate detection of outliers and subpopulations with Pmetrics, a nonparametric and parametric pharmacometric modeling and simulation package for R. Ther. Drug Monit. 34, 467–476 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  54. R Core Team. R: A Language and Environment for Statistical Computing v. 3.1.0 (R Foundation for Statistical Computing, 2014).

  55. De Cock, R. F. W. et al. Role of modelling and simulation in paediatric clinical research. Eur. J. Clin. Pharmacol. 67, S5–S16 (2011).

    Article  Google Scholar 

  56. Aarons, L. et al. Role of modelling and simulation in phase I drug development. Eur. J. Pharm. Sci. 13, 115–122 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Roberts, J. A. et al. Plasma and target-site subcutaneous tissue population pharmacokinetics and dosing simulations of cefazolin in post-trauma critically ill patients. J. Antimicrob. Chemother. 70, 1495–1502 (2015).

    Article  CAS  PubMed  Google Scholar 

  58. Grau, S. et al. Plasma and peritoneal fluid population pharmacokinetics of micafungin in post-surgical patients with severe peritonitis. J. Antimicrob. Chemother. 70, 2854–2861 (2015).

    Article  CAS  PubMed  Google Scholar 

  59. Mould, D. R. & Upton, R. N. Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods. CPT Pharmacometrics Syst. Pharmacol. 2, e38 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank colleagues variously for their support and encouragement: the Sierra Leone Association of Ebola Survivors (Freetown, Sierra Leone); the members of the Convalescent Products and Allied Therapy Intervention Technical Committee; the Research Ethics Committee and the Pharmacy Board Committee (all Ministry of Health and Sanitation, Republic of Sierra Leone); staff in Virus Reference Department Public Health England for handling and clearing samples from quarantine; G. McCann and L. Matthews for project management; I. Bates for expertise in strengthening transfusion services; W. A. Brooks; M. P. Kieny; C. Burm and D. Arango; N. F. Walker; A. Jones; colleagues from the World Health Organization (WHO); and the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). Proofreading support provided by M. de Baar and graphical support provided by S. Yee. The study “Convalescent plasma for early Ebola virus disease in Sierra Leone (Ebola CP)” (ISRCTN13990511 and PACTR201602001355272) was supported by the Wellcome Trust (Award 106491) and Bill and Melinda Gates Foundation; Public Health England Ebola Emergency Response; and the Blood Safety Programme, National Health Service Blood and Transplant. J.T.S. was supported by the Wellcome Trust. M.G.S. and J.T.S. were supported by the UK National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections at the University of Liverpool. The funders had no role in the collection and analysis of the samples, in the interpretation of data, in writing the report, or in the decision to submit the paper for publication.

Author information

Author notes

  1. Catherine C. Smith & C. C. Smith

    Present address: Oxford Vaccine Group, University of Oxford, Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UK

  2. Christine P. Cole & C. P. Cole

    Present address: Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK

  3. R. S. Tedder & Richard S. Tedder

    Present address: Division of Infectious Diseases, Imperial College London, London, UK

  4. These authors contributed equally: Charlene Adaken, Janet T. Scott, Raman Sharma

  5. These authors jointly supervised this work: Richard S. Tedder, Malcolm G. Semple, William A. Paxton, Georgios Pollakis

  6. Deceased: S. Baker

Authors and Affiliations

  1. Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary & Ecological Sciences, University of Liverpool, Liverpool, UK

    Charlene Adaken, William A. Paxton & Georgios Pollakis

  2. NIHR Health Protection Research Unit in Emerging and Zoonotic Infections (HPRU EZI), University of Liverpool, Liverpool, UK

    Charlene Adaken, Janet T. Scott, M. G. Semple, J. T. Scott, R. S. Tedder, Richard S. Tedder, Malcolm G. Semple, William A. Paxton & Georgios Pollakis

  3. Faculty of Health and Life Science, University of Liverpool, Liverpool, UK

    Janet T. Scott, Catherine C. Smith, M. G. Semple, J. T. Scott, C. C. Smith & Malcolm G. Semple

  4. MRC–University of Glasgow Centre for Virus Research, Glasgow, UK

    Janet T. Scott & J. T. Scott

  5. Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, UK

    Raman Sharma

  6. High Containment Microbiology, National Infections Service, Public Health England, London, UK

    Robin Gopal, R. Gopal & T. J. G. Brooks

  7. Blood Borne Virus Unit, National Infection Service, Public Health England, London, UK

    Steven Dicks, Saidia Niazi, Samreen Ijaz, R. S. Tedder & Richard S. Tedder

  8. Transfusion Microbiology, National Health Service Blood and Transplant, London, UK

    Steven Dicks, Saidia Niazi, Samreen Ijaz, R. S. Tedder & Richard S. Tedder

  9. MRC Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, London, UK

    Tansy Edwards, P. G. Smith & T. Edwards

  10. Travel Medicine and International Health Team, Health Protection Scotland, Glasgow, UK

    Catherine C. Smith & C. C. Smith

  11. College of Medicine and Allied Health Sciences, Freetown, Sierra Leone

    Christine P. Cole & C. P. Cole

  12. National Safe Blood Service, Ministry of Health and Sanitation, Freetown, Sierra Leone

    Philip Kamara, Osman Kargbo, Sahr M. Gevao, S. M. Gevao, S. Baker, O. Kargbo & P. Kamara

  13. National Health Service Blood and Transplant, Birmingham, UK

    Heidi A. Doughty & H. A. Doughty

  14. College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

    Heidi A. Doughty & H. A. Doughty

  15. Institute of Tropical Medicine, Antwerp, Belgium

    Johan van Griensven, J. van Griensven, R. Ravinetto & Y. Claeys

  16. Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK

    Peter W. Horby, P. W. Horby & L. Merson

  17. College of Medicine and Allied Health Sciences, University of Sierra Leone, Freetown, Sierra Leone

    Sahr M. Gevao, Foday Sahr, S. M. Gevao, F. Sahr & J. Russell

  18. 34 Military Hospital, Republic of Sierra Leone Armed Forces, Freetown, Sierra Leone

    Foday Sahr & F. Sahr

  19. GlaxoSmithKline, Stevenage, UK

    Richard J. Dimelow

  20. King’s Sierra Leone Health Partnership, King’s Health Partners and King’s College London, London, UK

    M. Lado & C. S. Brown

  21. Physio Fitness Rehabilitation Centre, Freetown, Sierra Leone

    B. Conton

  22. Institute for Tropical Medicine and International Health, Charité, Berlin, Germany

    A. Mari Saez

  23. Department of Sociology, Philosophy and Anthropology, University of Exeter, Exeter, UK

    A. H. Kelly

  24. The Roslin Institute, University of Edinburgh, Edinburgh, UK

    J. K. Baillie

  25. Department of Pandemic and Epidemic Diseases, World Health Organization, Geneva, Switzerland

    N. Shindo & D. Pfeifer

  26. ClinicalRM Inc, Hinckley, OH, USA

    D. L. Hoover

  27. Department of Medicine, University of North Carolina, Chapel Hill, NC, USA

    W. A. Fischer II & D. A. Wohl

  28. Duke University School of Medicine, Durham, NC, USA

    N. M. Thielman

Authors
  1. Charlene Adaken
    View author publications

    Search author on:PubMed Google Scholar

  2. Janet T. Scott
    View author publications

    Search author on:PubMed Google Scholar

  3. Raman Sharma
    View author publications

    Search author on:PubMed Google Scholar

  4. Robin Gopal
    View author publications

    Search author on:PubMed Google Scholar

  5. Steven Dicks
    View author publications

    Search author on:PubMed Google Scholar

  6. Saidia Niazi
    View author publications

    Search author on:PubMed Google Scholar

  7. Samreen Ijaz
    View author publications

    Search author on:PubMed Google Scholar

  8. Tansy Edwards
    View author publications

    Search author on:PubMed Google Scholar

  9. Catherine C. Smith
    View author publications

    Search author on:PubMed Google Scholar

  10. Christine P. Cole
    View author publications

    Search author on:PubMed Google Scholar

  11. Philip Kamara
    View author publications

    Search author on:PubMed Google Scholar

  12. Osman Kargbo
    View author publications

    Search author on:PubMed Google Scholar

  13. Heidi A. Doughty
    View author publications

    Search author on:PubMed Google Scholar

  14. Johan van Griensven
    View author publications

    Search author on:PubMed Google Scholar

  15. Peter W. Horby
    View author publications

    Search author on:PubMed Google Scholar

  16. Sahr M. Gevao
    View author publications

    Search author on:PubMed Google Scholar

  17. Foday Sahr
    View author publications

    Search author on:PubMed Google Scholar

  18. Richard J. Dimelow
    View author publications

    Search author on:PubMed Google Scholar

  19. Richard S. Tedder
    View author publications

    Search author on:PubMed Google Scholar

  20. Malcolm G. Semple
    View author publications

    Search author on:PubMed Google Scholar

  21. William A. Paxton
    View author publications

    Search author on:PubMed Google Scholar

  22. Georgios Pollakis
    View author publications

    Search author on:PubMed Google Scholar

Consortia

the Ebola-CP Consortium

  • M. G. Semple
  • , J. T. Scott
  • , S. M. Gevao
  • , F. Sahr
  • , C. P. Cole
  • , J. Russell
  • , S. Baker
  • , O. Kargbo
  • , P. Kamara
  • , M. Lado
  • , C. S. Brown
  • , B. Conton
  • , J. van Griensven
  • , R. Ravinetto
  • , Y. Claeys
  • , R. S. Tedder
  • , R. Gopal
  • , T. J. G. Brooks
  • , C. C. Smith
  • , H. A. Doughty
  • , A. Mari Saez
  • , A. H. Kelly
  • , J. K. Baillie
  • , N. Shindo
  • , D. Pfeifer
  • , D. L. Hoover
  • , W. A. Fischer II
  • , D. A. Wohl
  • , N. M. Thielman
  • , P. W. Horby
  • , L. Merson
  • , P. G. Smith
  •  & T. Edwards

Contributions

G.P., W.A.P., J.T.S. and M.G.S. initiated and designed the study. C.A., R.S.T., J.T.S., R.S., R.J.D. and R.G. collected data and/or performed the analysis. C.A., G.P. and W.A.P. wrote the manuscript. M.G.S., J.T.S., G.P., R.S.T., R.J.D. and W.A.P. edited the manuscript. M.G.S. sourced the funding and is Ebola-CP Consortium Lead Investigator. All authors were critical for study delivery whether through recruitment, coordination, collection of participant data and material, assay development or analysis of samples. All authors read and approved the contents of the manuscript. GSK was not involved in the design, conduct or analysis of the study.

Corresponding author

Correspondence to Georgios Pollakis.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature thanks Jayajit Das and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 Development and characterization of Ebola pseudo-particle virus.

a, Variant pEBOV14-GP plasmid concentrations were transfected alongside 2000 ng of pSG3-HIV-1 backbone. The resulting pseudo-typed virus, quantified by a HIV-1-p24 capsid ELISA (squares), was tested for infectivity in TZM-bl cells as measured by luciferase activity (data are mean ± s.d.). The red marked square identifies the glycoprotein concentrations that can be used in the assay. b, Inhibition profiles with negative plasma donated from six individuals (grey squares), indicating no specific plasma inhibition during the neutralization assay. All negative assays and plasmas were combined to define the range within which negative plasma control were acceptable (red squares) thus defining a valid assay. The blue line shows the lack of reactivity on the HIV-1-enveloped pseudo-typed virus by EBOV neutralizing convalescent plasma (CP) (squares and circles indicate the median and the vertical lines the standard error). c, Neutralization profiles of pEBOV14-GP by the WHO reference panel of anti-EBOV CP. The standard identifiers are shown. d, Reproducibility of the neutralization assay determined by measuring the IC50 of CP on the three EBOV isolates (yellow-pEBOV14-GP, purple- pEBOV95-GP and green- pEBOV14m-GP). The two-tailed parametric paired t-test was used. e, Neutralization potential of CPs against three virus strains (pEBOV14-GP/n = 83, pEBOV95-GP/n = 69 and pEBOV14m-GP/n = 77) expressed in IC70 (data are presented as mean values ± s.d. Kruskal–Wallis test was performed). f, delta-IC70 neutralization titres between virus strain pairs by each post-cure study participant. g, Positive association between PPV IC70 titres the live virus plaque reduction neutralization test (PRNT). h, Positive association between PPV IC70 neutralization titres and the double antigen bridging assay (DABA).

Source data

Extended Data Fig. 2 Pseudo-particle virus neutralization profiles by convalescent plasma.

a–c, Anti-EBOV14-GP (a; n = 92), anti-EBOV14m-GP (b; n = 70) and anti-EBOV95-GP (c; n = 76) neutralization curves using serial dilutions of CP inhibiting PPV cell entry, as described in methods. The plasma samples were deciphered as possessing low (blue), intermediate (magenta) or high (orange) neutralization to demonstrate the similar profiles of the three virus glycoproteins studied. The red square curve indicates the range of inhibition by control plasma. d, Comparison of the analyses (n = 30) (i) considering the 0% inhibition value whenever two reciprocal consecutive high plasma dilutions produced equal infection levels, and (ii) considering 0% inhibition as the infection values of virus in the absence of convalescent plasma performed in each individual experiment. The Pearson correlation coefficients were computed.

Source data

Extended Data Fig. 3 Association of IC50 and IC70 neutralizing dilutions of the post-cure plasma samples inhibiting cell entry of pseudotyped virus particles harbouring the variant EBOV GP molecules.

The Pearson correlation coefficients were computed.

Source data

Extended Data Fig. 4 Longitudinal post convalescence nAb variation in the plasma of individuals 18, 19 and 21 demonstrated by pseudotyped virus particle neutralization.

Anti-EBOV14-GP (light blue) and anti-EBOV95-GP (dark blue) nAb titres were overlaid with the blocking EIAs carried out for the detection of antibody against the nucleoprotein [NP] (brown squares), the viral matrix protein 40 [VP40] (purple squares) and the glycoprotein [GP] (green squares).

Source data

Extended Data Fig. 5 Longitudinal G-capture and competitive EIAs performed using plasma from individuals 18, 19, 21, 45 and 49 against the glycoprotein as previously described.

The longitudinal G-capture (pink) and competitive (green) EIAs were performed against the glycoprotein as previously described21. The antibody reactivities were overlaid with pseudotyped virus particle IC50 neutralization values against EBOV14-GP (light blue) and EBOV95-GP (dark blue).

Source data

Extended Data Fig. 6 Total antibody reactivity as measured by double antigen bridging assay (DABA) (average of a duplicate measurement) for the Ebola post-cure cohort participants with longitudinal follow up (≥2 data points, n = 51) demonstrating decline–restimulation–decline (in any order) of antibody reactivity over time.

Decline is indicated by a black line and restimulation by a yellow horizontal line.

Source data

Extended Data Fig. 7 Total antibody reactivity as measured by double antigen bridging assay (DABA).

‘Lowest titre following decline’ is the last point in a participant presenting antibody titre decline, while ‘High titre upon stimulation’ is the subsequent point demonstrating antibody stimulation. Two-tailed parametric paired t-test (P = 0.0014).

Source data

Extended Data Fig. 8 Observed versus predicted plots for the growth and decay models as determined by the DABA assay.

a, b, Plots for selected logistic growth model for antibody stimulation. a, Population predicted values. b, Individual predicted values. c, d, Plots for selected two-compartment decay model with saturable recycling for antibody stimulation. c, Population predicted values. d, Individual predicted values. Solid red circles represent the individual observed or model-predicted Ab values. Solid blue line and dotted red line represent the line of regression and line of unity, respectively.

Source data

Extended Data Fig. 9 Flow diagram describing the observed antibody decrease and increase events as measured by DABA.

These were used to develop the compartmental population pharmacodynamic models.

Supplementary information

Supplementary Tables

This file contains Supplementary Tables 1-4 – see contents page for details.

Reporting Summary

Source data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Adaken, C., Scott, J.T., Sharma, R. et al. Ebola virus antibody decay–stimulation in a high proportion of survivors. Nature 590, 468–472 (2021). https://doi.org/10.1038/s41586-020-03146-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41586-020-03146-y

This article is cited by

Comments

Commenting on this article is now closed.

  1. sb

    I wonder if the reported incidences recrudescence of SARS-CoV-2 could be due to the same "reservoir" effect and whether anybody is already researching this area?

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载