Abstract
Background: Ebola virus disease (EVD) is an often-fatal infection where the effectiveness of medical countermeasures is uncertain. During the West African outbreak (2013–2016), several patients were treated with different types of anti-viral therapies including monoclonal antibody-based cocktails that had the potential to neutralise Ebola virus (EBOV). However, at the time, the efficacy of these therapies was uncertain. Given the scale of the outbreak, several clinical phenotypes came to the forefront including the ability of the same virus to cause recrudescence in the same patient—perhaps through persisting in immune privileged sites. Several key questions remained including establishing if monoclonal antibody therapy was effective in humans with severe EVD, whether virus escape mutants were selected during treatment, and what is the potential mechanism(s) of persistence. This was made possible through longitudinal samples taken from a UK patient with EVD. Methods: Several different sample types, plasma and cerebrospinal fluid, were collected and sequenced using Illumina-based RNAseq. Sequence reads were mapped both to EBOV and the human genome and differential gene expression analysis used to identify changes in the abundance of gene transcripts as infection progressed. Digital Cell Quantitation analysis was used to predict the immune phenotype in samples derived from blood. Results: The findings were compared to equivalent data from West African patients. The study found that both virus and host markers were predictive of a fatal outcome. This suggested that the extensive supportive care, and most likely the application of the medical countermeasure ZMab (a monoclonal antibody cocktail), contributed to survival of the UK patient. The switch from progression to a ‘fatal’ outcome to a ‘survival’ outcome could be seen in both the viral and host markers. The UK patient also suffered a recrudescence infection 10 months after the initial infection. Analysis of the sequencing data indicated that the virus entered a period of reduced or minimal replication, rather than other potential mechanisms of persistence—such as defective interfering genomes. Conclusions: The data showed that comprehensive supportive care and the application of medical countermeasures are worth pursuing despite an initial unfavourable prognosis.
| Original language | English |
|---|---|
| Article number | 5 |
| Number of pages | 18 |
| Journal | Genome Medicine |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 11 Jan 2021 |
Bibliographical note
Funding Information:We would like to thank Richard Randall and Elizabeth Wignall-Fleming at the University of St. Andrews for discussions on DIs. We would like to thank UK2 for permission to analyse their blood samples.?We thank Professor Gary Kobinger (University of Laval, Quebec; formerly Public Health Laboratory of Canada) for supply of ZMAb.
Funding Information:
The research was funded by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections at the University of Liverpool in partnership with Public Health England (PHE) and Liverpool School of Tropical Medicine (LSTM), which directly supported the PhD studentships of A.B. and N.Y.R. and a fellowship for N.Y.R. The work was also funded by the Food and Drug Administration (USA) to J.A.H and M.W.C. number HHSF223201510104C and assessing animal models for MCM development, number HHSF223201710194C, and directly supported X.D and I.G.-D. E.T. is funded by a Wellcome Trust clinical intermediate fellowship (102789/Z/13/A) and core funding from the Medical Research Council (MC_UU_12014/1).
Keywords
- NONHUMAN-PRIMATES
- QUANTIFICATION
- INFECTION
- SEQUENCE
- INFERENCE
- GENOMES
