Review 4: "The Majority of SARS-CoV-2 Plasma Cells are Excluded from the Bone Marrow Long-Lived Compartment 33 Months after mRNA Vaccination"

Mohammad Sajadi; Parham Habibzadeh; George Lewis

doi:doi:10.1162/2e3983f5.43e9aa8f

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.

by Mohammad Sajadi, Parham Habibzadeh, and George Lewis

Published onApr 25, 2024

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

by Doan C. Nguyen, Ian T. Hentenaar, Andrea Morrison-Porter, David Solano, Natalie S. Haddad, Carlos Castrillon, Pedro A. Lamothe, Joel Andrews, Danielle Roberts, Sagar Lonial, Ignacio Sanz, and F. Eun-Hyung Lee

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Published on Mar 05, 2024
www.medrxiv.org

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: This study shows that after Covid mRNA vaccination, there is a lack of specialized antibody producing cells (long lived plasma cells) in the bone marrow, which provides an explanation for why antibody levels after this vaccine do not last.

The authors report that 35% of the subjects had evidence of spike-specific CD19-CD38hiCD138+ (subset D) antibody-secreting cells following mRNA vaccination or hybrid immunity. This is consistent with previous published research (Tehrani et al., Journal of Infectious Diseases, 2024) showing the presence of SARS-CoV-2 specific subset D cells in 25% of patients recovering from COVID-19 infection.

This study expands these findings into those who have received SARS-CoV-2 mRNA vaccines. The study spans a period of almost three years for recruiting 19 healthy adults who underwent bone marrow aspiration within 1.5-33 months after receiving the first dose of the vaccine and 0.5-21 months after the last vaccine dose (total vaccine doses ranging from 2 to 5). Multiple individuals in this cohort had COVID-19 both before and after vaccination. This indeed makes the patient population very heterogeneous in terms of the immune response and requires attention to this matter in the analysis of the results.

The strengths of the study include studying fresh samples, analyzing a variety of antigens, including tetanus and Influenza. The limitations for this study are mostly minor but include the following: 1) heterogeneity of the volunteer samples in terms of timepoints studied (ex: 1 month vs 33 months and after first or second dose of vaccine) makes generalization difficult. 2) It appears that 50% of the secreted antibody in PopD (Figure 3) is one of 2 specificities (Influenza or tetanus), which the authors don’t put into context of their past studies or its contribution to the circulating antibody titers.

Despite these limitations, the study provides important insight into the lack of formation of long-lived plasma cells (i.e., lack of durable humoral immune response) following SARS-CoV-2 mRNA vaccination and calls for further investigation in this important and understudied area.

Review 4: "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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