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An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors' CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design

Authors: Herst et al. Link to paper: https://www.biorxiv.org/content/10.1101/2020.02.25.963546v3

Journal/ Pre-Print: BioRxiv

Key Words: Ebola, CTL vaccine, COVID-19, controller

Research Highlights 

1. A single vaccine comprising adjuvant (CpG) and peptide (NP44-52 (YQVNNLEEI)) in a microsphere protected mice from Ebola virus challenge

2. Conserved nucleocapsid proteins in SARS-CoV2 could be targeted by a cytotoxic CD8 lymphocyte (CTL)-based vaccine

Summary 

This study probes the in vivo efficacy of a CTL-based vaccine incorporating the previously identified and conserved Ebola virus nucleocapsid protein sequence NP43-53 in a mouse model. NP43-53 however had no effect on induction of IFNg by splenocytes in vitro. Since this may be due to inefficient MHC binding and presentation, three shorter 9-mer sub-sequences were tested, with NP44-52 triggering the biggest IFNg response. A single vaccine containing 11µM microspheres with NP44-52, CpG adjuvant and a class II epitope from Ebola virus Zaire predicted to be important for efficient vaccination was administered I.P and protected mice from Ebola challenge. The authors hypothesise that a similar approach could be used for SARS-CoV2 and identify candidate 9-mers using in silico approaches.

Impact for SARS-CoV2/COVID19 research efforts

· Utilise methods and knowledge from developing an Ebola vaccine to develop a CTL-based vaccine for SARS-CoV2/COVID19 targeting conserved nucleocapsid protein sequences

Study Type

· Ex vivo splenocyte stimulation

· Pre-clinical in vivo vaccine study (C57BL/6 mice)

· In silico study probing predicted HLA binding affinities for SARS-CoV2 sequences

Strengths and limitations of the paper

Novelty: Ebola nucleocapsid peptide sequences previously identified and tested in vitro are shown here to form a protective vaccine in vivo. Similarly, conserved nucleocapsid sequences in SARS-CoV2 and predicted HLA-binding affinities are discussed.

Standing in the field: Authors have some previous publications in this area of research. Other vaccine approaches (e.g. targeting the spike proteins) are ongoing

Appropriate statistics: Statistical methodology unclear

Viral model used: Mice were challenged with Ebola virus M. musculus/COD/1976/Mayinga-CDC-808012. All SARS-CoV2 work in silico

 

Translatability: Suggested next step is to collect PBMCs from COVID-19 controllers and progressors to assess the presence of a differential response to candidate peptide sequences (e.g. IFNg induction by ELISPOT)

 

Main limitations:

· Early data showing superiority of NP44-52 (Fig 1A) not convincing

· Not consistent with conditions that are shown (e.g. comparing different peptide sequences) and route of vaccine administration

· Little discussion of the class II epitope from Ebola virus Zaire that was incorporated in the vaccine and the effects of this alone was not shown

· Difficult to follow in pre-print form e.g. acronyms not expanded, new data referred to only in discussion, no distinction between main and supplementary figures

· Extrapolation from mouse to man not clear