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Review 1: "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 onApr 13, 2024
Review 1: "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

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:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: In this manuscript, authors analyzed ASCs from BM aspirates from patients and found that while tetanus- and influenza-specific ASCs were mostly CD19neg, SARS-Cov-2-specific ASCs were mostly CD19+, even past 2 years from initial exposure.

Understanding the longevity of vaccine responses to SARS-Cov-2 in patients is important and poorly understood. Initial reports such as Turner et al (PMID 34030176) indicate LLPCs in the BM based on their presence, while this work provides more context by characterizing the ASCs as being CD19+, suggesting they are not bona fide LLPC. Thus, these studies are an important dataset, particularly as it is challenging to get BM aspirates from donors. The analyses performed are sound. A main conclusion from this study is that the SARS-specific ASCs are different than those from Tetanus or Influenza is clear. The conclusion that they are not long-lived compartment is based solely on CD19 expression may be an over-interpretation of the data. For one thing, if you have ASCs that have been present for 2 years or longer, by definition, they are long-lived. However, it is not clear when the ASCs were generated as many patients had recent exposures to vaccines within 3-6 months, and thus they may be sampling mostly newly generated. With regard to CD19 loss of expression defining human LLPC, as the authors acknowledge, this has limitations. Indeed Tet+ ASCs have a considerable PopB population, and are likely long-lived. The author’s own prior scRNAseq data (Ref 11) also shows considerable overlap between PopB/D populations. The authors address all of these limitations in the nicely discussion. But fundamentally, the major conclusion one can draw here is that these SARS-Cov2 ASCs are different and mostly express CD19, but are likely still long-lived. It remains unclear why in some cases long-lived ASCs are CD19+ and some are CD19- or both, and what role CD19 play functionally or physiologically for these LLPCs. This is an important question to resolve in the future.

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