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Review 3: "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 25, 2024
Review 3: "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

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:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.


Review: This manuscript addresses the longevity of SARS-CoV-2 antibody responses by describing the phenotype of human bone marrow plasma cell specific to spike protein. The authors conclude that mRNA vaccine-induced immunity fails to produce CD19- long-lived plasma cells (LLPC) specific to SARS-CoV-2 spike protein.

The authors set out to determine the heterogeneity of the SARS-CoV-2 spike protein specific plasma cells in the bone marrow of human donors. They applied their previously described flow cytometry protocol for identification of immature and mature plasma cells based on CD19 expression (PMID 26187412). Using this system for defining plasma cell subsets, the authors sorted out plasma cells from human bone marrow aspirates. They focused on 3 populations that consist of 2 CD19+ subsets that are considered short-lived and 1 CD19- subset that they define as LLPC. Spike-specific plasma cells were compared to influenza-HA- and Tetanus toxoid-specific plasma cells. Their main conclusion is that IgG-secreting plasma cells specific to spike protein are largely absent from the putative LLPC population, which contrasts with both HA and tetanus toxoid. Notably, they observe a robust population of CD19+plasma cells specific to spike. The authors conclude that SARS-CoV-2 fails to induce LLPC by either infection or vaccination with mRNA vaccines.

This study presents interesting findings that have implications for our understanding of how LLPCs are defined and how they are generated. However, the authors conclusions are entirely supported by their data. The authors themselves acknowledge some of the caveats in their discussion. For example, they note that they observe heterogeneity in the CD19+ bone marrow plasma cell population that could include LLPCs. Another issue is the small sample size and variability of timing throughout the study. It is difficult to design an ideal human study with a large sample size of volunteers willing to provide a bone marrow aspirate, but the low number of study participants makes some of the concluding statements too strong. The choice of influenza and tetanus toxoid as controls for LLPC is interesting considering that both are known to be relatively short-lived responses compared to other common vaccines. Additionally, these control antigens have to potential for repeated exposure throughout life, with Tetanus vaccination recommended every 10 years throughout adulthood and influenza vaccination recommended yearly with potential environmental exposure as well. A perhaps more compelling control would be vaccination against Yellow Fever due to the fact that it is not commonly provided in the United States, and it offers robust life-long immunity. This would provide a true primary immune response to compare to the novel coronavirus.

Overall, the data are very interesting and provide a valuable view into the phenotype of bone marrow plasma cells in response to SARS-CoV-2 immunization and infection. However, the variability of the sample collection and immunization/infection history make the sample size too small to support the strong conclusion that mRNA vaccines fail to generate LLPC.

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