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Review 5: "The Majority of SARS-CoV-2 Plasma Cells are Excluded from the Bone Marrow Long-Lived Compartment 33 Months after mRNA Vaccination"

Reviewers suggest caution in interpreting the data, particularly regarding the classification of long-lived plasma cells as well as the researchers' definitive conclusions due to methodological limitations and sample heterogeneity.

Published onMay 02, 2024
Review 5: "The Majority of SARS-CoV-2 Plasma Cells are Excluded from the Bone Marrow Long-Lived Compartment 33 Months after mRNA Vaccination"
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The Majority of SARS-CoV-2 Plasma Cells are Excluded from the Bone Marrow Long-Lived Compartment 33 Months after mRNA Vaccination
The Majority of SARS-CoV-2 Plasma Cells are Excluded from the Bone Marrow Long-Lived Compartment 33 Months after mRNA Vaccination
Description

Abstract The goal of any vaccine is to induce long-lived plasma cells (LLPC) to provide life-long protection. Natural infection by influenza, measles, or mumps viruses generates bone marrow (BM) LLPC similar to tetanus vaccination which affords safeguards for decades. Although the SARS-CoV-2 mRNA vaccines protect from severe disease, the serologic half-life is short-lived even though SARS-CoV-2-specific plasma cells can be found in the BM. To better understand this paradox, we enrolled 19 healthy adults at 1.5-33 months after SARS-CoV-2 mRNA vaccine and measured influenza-, tetanus-, or SARS-CoV-2-specific antibody secreting cells (ASC) in LLPC (CD19−) and non-LLPC (CD19+) subsets within the BM. All individuals had IgG ASC specific for influenza, tetanus, and SARS-CoV-2 in at least one BM ASC compartment. However, only influenza- and tetanus-specific ASC were readily detected in the LLPC whereas SARS-CoV-2 specificities were mostly excluded. The ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.61, 0.44, and 29.07, respectively. Even in five patients with known PCR-proven history of infection and vaccination, SARS-CoV-2-specific ASC were mostly excluded from the LLPC. These specificities were further validated by using multiplex bead binding assays of secreted antibodies in the supernatants of cultured ASC. Similarly, the IgG ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.66, 0.44, and 23.26, respectively. In all, our studies demonstrate that rapid waning of serum antibodies is accounted for by the inability of mRNA vaccines to induce BM LLPC.

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 paper is in principle quite interesting, conducted and presented in a concise manner, the introduction and discussion chapters are well balanced and informative. There are though few points that the authors need to consider before the manuscript can be accepted for publications, as detailed below:

  • One of the key conclusions that the authors state in the abstract, line 17-18: “In all, our studies demonstrate that rapid waning of serum antibodies is accounted for by the inability of mRNA vaccines to induce BM LLPC”. However, this reviewer would like to point out that even in the five individuals with known PCR-proven history of infection along with vaccination, these SARS-CoV-2-specfic plasma cells were not found within the CD19-CD38+CD138+ longlived plasma cell pool and that needs to be addressed by the authors. Thus, this conclusion is argumentative as it is not only after mRNA vaccine itself but also after combination of infection and vaccination (hyprid immunity) that SARS-CoV-2-specfic plasma cells were not found within CD19-CD38+CD138+ longlived plasma cell pool.

  • Therefore one of the discussion point made by the authors also needs to considered; page 3 of the discussion chapter line 4-14 about asymptomatic infections (unconfirmed).

  • Line 13 in abstract: “Even in five patients …” the understanding of the reviewer was that these were 19 healthy adult donors as stated in Methods chapter of Healthy human subjects. The same in the discussion chapter page 3 line 1: “In patient with sequential BM aspirates nearly two years after initial vaccine…”. Furthermore, in page 4 of the discussion chapter it is stated: “In this study, BM samples were collected during hip joint replacement surgery from patients of up to 17 months post vaccination”. Please synchronize the description of the study group throughout the manuscript.

  • Figure legend for Figure 1: the last description of PopD is misspelled as it is written (LLPC; CD19-CD38hiCD138-).

In all, this study indicates that both mRNA vaccines and possibly natural infection by SARS-CoV2 prevent the differentiation of plasmablasts/-cells into long lived plasma cells in the bone marrow thus partially explaining the short duration of humoral response induced.

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