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Authors: Sandra C. A. Nielsen et al. 2020

Link to paper: https://www.researchsquare.com/article/rs-27220/v1

Journal/ Pre-Print: Research Square

Tags: Immunology/Immunity, Cell Biology, Bioinformatics, Molecular Biology

Research Highlights 

1. IgG-expressing clonally expanded lineages in patients correlates with serum anti-SARS-CoV-2 receptor binding domain (RBD) IgG levels.

2. SARS-CoV-2 primary infection fosters polyclonal B cell responses (IgG 1,2,3 and IgA 1,2 subclasses), with preferential use of IgHV3-30 and IgHV3-9 (which is enriched in IgG B cells).

3. SARS-CoV-2 patients IGHV repertoires show convergent antibody rearrangements (124 clusters) with IgG and IgA class-switching and low levels of somatic mutation, in all 6 patients.

Summary

The study provides a detailed clonal analysis of the IgHV repertoire in peripheral blood samples from 6 SARS-CoV-2 patients. Firstly, the authors observed a general polyclonal B cell response to the covid19 infection. They identify a burst of expanded clones with low SHM, conserved shifts in the utilization of IgHV genes and subclasses, and longer, hydrophobic CDR-H3 regions to dominate the molecular changes observed in IGHV rearrangement. The SARS-CoV-2 response featured a predominance of IgG1-expression among IgG subclasses, and IgA1 relative to IgA2, suggesting an influx of recently recruited naïve B cells in the response. There was a preferential use of IgHV 3-30 and 3-9. They also observe potentially convergent antibody responses (124 clusters) shared (variably) among patients infected with SARS-CoV-2.

Impact for SARS-CoV2/COVID19 research efforts

Understand the immune response to SARS-CoV2/COVID19: Insight into B cell expansion and IGH rearrangement after Sars-CoV-2 infection.

Develop diagnostic tools for SARS-CoV2/COVID19: Convergent SARS-CoV-2-specific antibody sequences in the memory B cell pools of recovered individuals could offer evidence of prior exposure. 

Study Type

· In silico study / bioinformatics study

· Patient Case study

Strengths and limitations of the paper

Novelty: The paper offers novel insight into the antibody response, IGHV. rearrangement and isotype class-switching of B cell clones in response to SARS-CoV-1 infection.

Standing in the field: The methodology for clonal analysis is of good standing, however some results do contrast with select recent literature which has not found convergence between Covid-19 patients.

Appropriate statistics: Yes, appropriate statistics are described, although in certain figures appropriate visualisation of controls is missing (ie. serology analyses).

Viral model used: N/A

Translatability: Potential for translation if sample number is increased and longitudinal studies are performed. Functional analysis explained.

Main limitations:

· Analysis is restricted to 6 patients and only 1 patient has two sample dates (ie. only one longitudinal data point). The analysis is very good but needs to be expanded.

· No correlation to clinical outcomes

· The authors do not look at the neutralising potential of the convergent clones they have identified

· The authors only look at plasma antibody testing for IgG and IgM specific for SARS-CoV-2 spike protein receptor binding domain (RBD), however other epitopes have been shown to lay outside of this region

· The authors do not provide any clinical information for the 6 patients they performed High-throughput DNA analysis of, including the exact days post-infection that the samples are acquired.

· Why was no serological testing done of sample 7453-D2 and 7455 is not explained.

· Poor figure quality, too pixelated to see details, thus impossible to gage precisely the authors assertions.