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Review 2: "Durable SARS-CoV-2 B cell immunity after mild or severe disease"

This study investigates B cell responses in COVID-19 patients and finds infection elicits S protein RBD-specific memory B cells in most participants. Reviewers deem the study reliable, but find some claims overreaching citing lack of functional data.

Published onJan 20, 2021
Review 2: "Durable SARS-CoV-2 B cell immunity after mild or severe disease"
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Durable SARS-CoV-2 B cell immunity after mild or severe disease
Description

AbstractMultiple studies have shown loss of SARS-CoV-2 specific antibodies over time after infection, raising concern that humoral immunity against the virus is not durable. If immunity wanes quickly, millions of people may be at risk for reinfection after recovery from COVID-19. However, memory B cells (MBC) could provide durable humoral immunity even if serum neutralizing antibody titers decline. We performed multi-dimensional flow cytometric analysis of S protein receptor binding domain (S-RBD)-specific MBC in cohorts of ambulatory COVID-19 patients with mild disease, and hospitalized patients with moderate to severe disease, at a median of 54 (39-104) days after onset of symptoms. We detected S-RBD-specific class-switched MBC in 13 out of 14 participants, including 4 of the 5 participants with lowest plasma levels of anti-S-RBD IgG and neutralizing antibodies. Resting MBC (rMBC) made up the largest proportion of S-RBD-specific class-switched MBC in both cohorts. FCRL5, a marker of functional memory when expressed on rMBC, was dramatically upregulated on S-RBD-specific rMBC. These data indicate that most SARS-CoV-2-infected individuals develop S-RBD-specific, class-switched MBC that phenotypically resemble germinal center-derived B cells induced by effective vaccination against other pathogens, providing evidence for durable B cell-mediated immunity against SARS-CoV-2 after recovery from mild or severe COVID-19 disease.Graphical Abstract

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

The study by Ogega and colleagues relates to the highly important question of the strength and durability of B cell immunity to SARS-CoV-2 generated by COVID-19. Early studies reported that levels of key protective antibodies (Abs) against the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein wane quickly in the months following infection, raising the possibility that B cell immunity to the virus is short-lived. However, relatively brief Ab production should not be surprising when the response is against a novel antigen (the RBD). What is important to recognize is that the B cell response to the RBD generates not only Abs, but also memory B cells (MBCs). It is well-established that classical (also called “resting”) class-switched MBC populations are maintained for many years (perhaps decades) and respond with rapid and vigorous Ab production on re-exposure to their target antigen. MBCs provide strong backup protection when pre-existing antiviral Ab levels fall.

The study by Ogega et al. adds to the growing number of reports that COVID-19 generates strong formation of MBCs reactive to the SARS-CoV-2 S protein, including its RBD (1,2,3,4,5; these cited reports of MBC formation after COVID-19 are just a sampling). Ogega et al. analyzed blood collected from subjects with mild and severe COVID-19 approximately 1-3 months after symptom onset. Healthy subject samples were included for comparison. A flow cytometric approach incorporating an RBD probe was used to enumerate RBD-specific cells in the following B cell subsets: non-class-switched B cells, class-switched MBCs, and class-switched Ab-secreting cells. Class-switched MBCs were further subsetted based on CD21 and CD27 expression and characterized for expression of a small panel of markers that could reflect function. RBD-binding Ab and SARS-CoV-2 neutralizing Ab levels in plasma were measured and related to the cellular analysis. Overall, the key finding is that RBD-specific class-switched MBCs are generated in COVID-19 patients with both mild and severe disease, even when there is little production of anti-RBD Abs and neutralizing Abs. Notably, the phenotyping of class-switched MBC subsets indicates strong formation of RBD-specific resting MBCs that would be expected to provide durable protection on repeat infection. The work is well-performed and claims made by the authors are well-supported by the data.

The findings of the manuscript are consistent with numerous other studies and provide no surprises. However, the focus of the study is highly important, since it deals with an aspect of immunity to SARS-CoV-2 that has taken a surprisingly long time to be appreciated and has not been well-communicated to the public. The authors have not comprehensively considered all related studies in presenting their work, but this is a challenge given that many of these studies are still only to be found as preprints. The clarity of the presentation of the work is strong and there are no concerns related to ethics, diversity, and inclusion.

References

1. Nguyen-Contant P et al. S Protein-Reactive IgG and Memory B Cell Production after Human SARS-CoV-2 Infection Includes Broad Reactivity to the S2 Subunit. mBio. 2020 Sep 25;11(5):e01991-20. doi: 10.1128/mBio.01991-20.

2. Wilson P et al. Distinct B cell subsets give rise to antigen-specific antibody responses against SARS-CoV-2. doi: 10.21203/rs.3.rs-80476/v1.

3. Gaebler C et al. Evolution of Antibody Immunity to SARS-CoV-2. doi: 10.1101/2020.11.03.367391.

4. Dan JM et al. Immunological memory to SARS-CoV-2 assessed for greater than six months after infection. doi: https://doi.org/10.1101/2020.11.15.383323.

5. Hartley GE et al. Rapid and lasting generation of B-cell memory to SARS-CoV-2 spike and nucleocapsid proteins in COVID-19 disease and convalescence. doi: https://doi.org/10.1101/2020.11.17.20233544.

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