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Review 2: "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 2: "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

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 aims to address the heterogeneity in the induction of long-lived bone marrow plasma cells (LLPCs) and consequently of stable, long-term protective antibody titers between different antigen exposures in humans. The data presented are almost exclusively derived from ELISpot experiments, which to this day represent the functional gold-standard readout for the capacity of putative ASCs to actually secrete antibody, and from a novel ASC culture system that is perhaps somewhat more contentious and harder to interpret.

The experiments focus on how ASCs specific to influenza, tetanus and SARS-CoV-2 antigens are distributed among 4 different subsets of bone marrow ASCs – a flow-cytometry-based surface marker classification, which the authors established in a previous publication (PMID 26187412) and which they claim can faithfully discriminate between short-lived and long-lived plasma cells. They focus in particular on the distinction between what they call subsets ‘A’ and ‘B’ (representing shorter-lived ASCs) and population ‘D’, their putative LLPC subset. It should be noted though, that this classification system has been disputed by other groups (PMID 28104812, PMID 36183942).

What they find is that, in contrast to the other two comparator antigens (influenza and tetanus), there is a relative dearth in SARS-CoV-2 S2P-specific ASCs that fall into their ‘subset D’ classification of putative LLPCs. While this observation is clear and direct evidence of a relative de-enrichment of SARS-CoV-2 specific cells for this particular ‘population D’, the authors extrapolate very broadly from these findings to a relative deficit in long-term, protective antibody titers against SARS-CoV2 following mRNA vaccination – a fairly big claim that is not directly supported by the data, but rather inferred exclusively on the basis of their ASC classification system. This classification may simply not hold for SARS-CoV-2-specific plasma cells for reasons other than longevity, and this question can ultimately only be resolved through a more systematic approach with decades worth of antibody titer data and/or unequivocal fate-mapping tools.

Despite some possibly important ramifications, the manuscript has some significant caveats that need to be considered: 

  • For one, their case stands and falls with the veracity and universality of their ASC subset classification as it pertains to the identification of short-lived vs. long-lived plasma cells. This is, in and of itself, a fairly contentious issue that this manuscript ultimately cannot resolve due to a lack of data that would directly corroborate their claims (i.e., longitudinal ELISA or neutralizing titers that directly measure the longevity of the antigen-specific serum antibodies). This exclusive dependence on the flow-based ASC classification system is by far the biggest caveat of the manuscript.

  • Second, there is a large degree of variability in the data that is not sufficiently taken into account in their analysis: differences in the timing of sample collection, the highly variable exposure history of the individuals studied, sampling biases inherent to ELISpot data etc. So, even though the N is admirably large for -a human subjects study that necessitates as invasive a procedure as BM aspiration, the inherent noise in the data makes it difficult to arrive at globally valid conclusions. 

  • Last, the language throughout the manuscript is fairly deterministic and strong. And in some cases, generalizations are made that the data doesn’t directly support.

In summary, this is an interesting and though-provoking study that tackles a central question of humoral immunity. But, unfortunately, it does so through some overly broad inferences from fairly contentious primary data derived from a very heterogeneous human sample collection.

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