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Authors: Kevin Ng et al.

Link to paper:

Journal/ Pre-Print: bioRxiv

Tags: Immunology/Immunity, Clinical/ Diagnostics

Research Highlights

1. Some SARS-CoV-2 negative blood donors with recent HCoV infections display IgG cross-reactivity towards the SARS-CoV-2 Spike (S) and nucleocapsid (N) proteins.

2. SARS-CoV-2 patients demonstrate IgM, IgG, and IgA reactivity towards Spike, and uniquely towards the S1 subunit and RBD within the S protein.


The study examines IgM, IgG, and IgA antibodies reactive against the SARS-CoV-2 Spike (S) protein and its subunit S1, in serum or plasma of 31 SARS-CoV-2 positive (by RT-qPCR detection) patients, 34 HCoV positive/SARS-CoV-2 negative donors, 30 HCoV unknown/SARS-Cov-2 negative donors and 31 HCoV negative/SARS-CoV-2 negative control donors. Furthermore, it compares the sensitivity of FACS-based and ELISA-based antibody detection methods. It demonstrates that some patients (approximately 10% in this study) with recent HCoV infections display IgG cross-reactivity towards the Sars-CoV-2 S protein, which also display neutralising potential against SARS-CoV-2 pseudovirus.

Impact for SARS-CoV2/COVID19 research efforts

Understand the immune response to SARS-CoV2/COVID19: the study provides confirmation of IgM, IgG, and IgA responses towards SARS-CoV2; and some evidence that prior exposure to HCoV may have some benefit.

Develop a vaccine for SARS-CoV2/COVID19: the study provides very useful insight regarding what to look for when assessing vaccine efficacy (in terms of Ig response).

Develop diagnostic tools for SARS-CoV2/COVID19: the study demonstrates the diagnostic requirement to distinguish between IgG responses towards S due to prior HCoV infection or due to SARS-CoV2, as well as the applicability and relevance of FACS-based detections methods.

Study Type

· In vitro study

· Patient Case study

Strengths and limitations of the paper

Novelty: The study demonstrates presence of IgG anti-Spike cross-reactive antibodies in some HCoV+ individuals without prior exposure to SARS-CoV-2. This indicates the need to use non-cross-reactive fragments of the SARS-CoV-2 S protein for serologic tests when screening SARS-CoV-specific antibodies (Abs) in human patients and in animal reservoirs to exclude false positives due to the cross-reactivity with human or animal CoVs.

Standing in the field: Cross-reactivity between coronaviruses in humans is well-characterised, but cross-neutralisation of live virus is not well-known.

Appropriate statistics: No, we are missing their full data set and the included figures do not show statistical significance (or it is not represented, rather).

Viral model used: Pseudovirus (lentivirus with either SARS-CoV-2 S or Vesicular Stomatitis Virus glycoprotein (VSVg) as control; SIV backbone & GFP reporter).

Translatability: High – it is very relevant for ongoing SARS-CoV-2 diagnostic testing.

Main limitations

· Unable to access extended data, so cannot comment on many of the study’s findings especially regarding the FACS versus ELISA sensitivity experiments (we are limited to what is shown).

· Generally, the figures we do have are missing essential data points to perform statistical analysis and interpretations (ie. Figure 1 c/d, regarding soluble S1 displacement of HCoV IgGs)

· Link to clinical outcomes for IgA/IgG/IgM responses in SARS-CoV-2 necessary to comment on protection from S-binding IgG responses.

· Cross-neutralisation experiments need to be repeated with live virus to better assess protection.

· In the ACE2 overexpression experiments (in HEK293 cells), the authors do not confirm whether the protein is expressed on the surface of the HEK293 cells (accessible to pseudoparticles) or not (remain cytoplasmic), so we cannot then conclude that it has no effect on the SARS2 Spike pseudoviral particle alternative entry (via CD145).

· Multiple sera samples (longitudinal studies) from SARS-CoV-2 patients would be needed to assess the Ig response.