Exclusion of SARS-CoV-2 Plasma Cells from Bone Marrow Long-Lived Compartment 33 Months Post mRNA Vaccination

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The global pandemic caused by SARS-CoV-2 has presented unprecedented challenges in understanding and managing viral transmission and immunity. With over 772 million people infected worldwide and a death toll reaching seven million, including significant impacts in the United States, the quest for durable immunity against the virus has become a critical area of research. Vaccination efforts have indeed turned the tide against severe disease, hospitalization, and death. However, the vaccines’ inability to provide sterilizing immunity against infection or transmission underscores the complexity of achieving comprehensive protection against the virus.

A focal point of this investigative journey has been the role of long-lived plasma cells (LLPCs) in the context of SARS-CoV-2 immunity. LLPCs, identified by the markers CD19−CD38hiCD138+, reside within the human bone marrow and are pivotal in sustaining long-term humoral immunity. The distinction between antibody-secreting cells (ASCs), encompassing both newly formed plasmablasts and mature plasma cells, highlights the evolutionary stages of the body’s response to pathogens.

Initial observations revealed that SARS2 spike-specific IgG ASCs were detectable in the bone marrow following SARS-CoV-2 infection or vaccination, suggesting a pathway to long-lived humoral protection. This pattern mirrors responses seen in non-human primates vaccinated with the SARS2 spike protein, indicating a conserved mechanism across species. The bone marrow serves as a complex sanctuary for ASCs, where newly minted cells can mature into LLPCs. This maturation is facilitated by a supportive environment in the bone marrow, rich in mesenchymal stromal cells and myeloid cells, providing essential survival and differentiation signals such as IL-6 and APRIL.

Comparative immunology offers insights into the longevity of vaccine-induced immunity. For instance, tetanus vaccination generates Ag-specific BM LLPCs, ensuring protection for decades. Conversely, the protection offered by influenza vaccines wanes within months, yet natural infection can confer immunity lasting decades. This disparity in durability between vaccine-induced and infection-induced immunity highlights the nuanced landscape of human immunological responses.

In the study, the study meticulously analyzed SARS2 spike-specific ASCs across various bone marrow compartments up to 33 months post-vaccination, juxtaposing them against the enduring responses elicited by tetanus and influenza vaccinations. Employing ELISpots and innovative bead-based methodologies, we observed a notable exclusion of SARS2 IgG responses from the LLPC compartment, a trend persisting nearly three years following vaccination. This contrasts sharply with the detection of tetanus- and influenza-specific ASCs within both LLPC and non-LLPC compartments of the bone marrow.

The exclusion of SARS2-specific ASCs from the LLPC niche in healthy subjects, even while mature CD19+CD138+ ASCs are present, sheds light on the transient nature of antibody responses to SARS2 mRNA vaccines. This revelation not only enhances our understanding of vaccine-induced immunity but also sets the stage for future research aimed at deciphering the mechanisms underlying the full differentiation of bone marrow LLPCs. By exploring the intricacies of LLPC maturation, we move closer to unlocking the secrets of long-lasting immunity against SARS-CoV-2 and potentially other formidable pathogens.


Medical concept… explained for everyone…. in a very simple way

Imagine your body has a very special type of soldier cell that’s supposed to remember and fight off viruses like the one that causes COVID-19. When you get a vaccine, it’s like giving these soldiers a training manual to prepare them for the fight. These soldiers are known as ASCs (short for “antibody-secreting cells”). They’re trained to recognize the virus and protect you.

Now, for the best protection, some of these soldiers need to become super soldiers, or what scientists call “long-lived plasma cells” (LLPCs). These super soldiers can remember the virus for a very long time and stay ready to fight it off years after the training (vaccination).

However, becoming a super soldier isn’t easy. It’s a tough process that requires the soldier cells to go through a lot of changes and challenges. They need to learn how to survive for a long time, make lots of weapons (antibodies), and resist dying (apoptosis and autophagy are fancy terms for the processes that help them survive and avoid death).

The study found that not all soldier cells manage to become super soldiers. Especially after getting the COVID-19 mRNA vaccine, it seems that these soldier cells don’t always get the right “imprinting” or training they need to start their journey to become super soldiers. Imprinting is like the initial boost or instruction that sets them on their path. Without it, they can’t find their way to the special places in the body (like the bone marrow) where they can become long-lived.

Memory B cells are like the recruits that have the potential to become super soldiers, and they need the right conditions, like the timing between vaccine doses and the right environment (cytokine milieu), to succeed. But the study suggests that the COVID-19 mRNA vaccines might not be setting up these conditions well enough for the soldier cells to become super soldiers and stay in the body for a very long time.

So, in simple terms, this research is saying that after getting the mRNA COVID-19 vaccine, our bodies might not be producing enough of these super soldiers that remember the virus for a very long time, which is important for long-term protection against the virus.


DISCUSSION – Unraveling the Mysteries of SARS-CoV-2 Vaccine Response: A Deeper Dive into the Durability of Humoral Immunity

In an era defined by the urgent global response to the COVID-19 pandemic, the rapid development and deployment of mRNA vaccines marked a significant milestone in our collective fight against the virus. However, despite their effectiveness in curbing the spread and severity of the disease, questions have emerged regarding the durability of the immune response they elicit. A comprehensive study delves into the mechanistic underpinnings of why the immunity conferred by these vaccines may not be as long-lasting as hoped, specifically focusing on the role of antibody-secreting cells (ASC) in the bone marrow (BM) and their progression into long-lived plasma cells (LLPC).

ASCs, pivotal in the body’s defense against pathogens, differentiate into LLPCs that reside in the BM, continuously producing antibodies. This differentiation process is intricate, involving significant morphological, transcriptional, and epigenetic changes. Despite the presence of SARS-CoV-2-specific ASC in the BM’s short-lived plasma cell compartment, they are notably absent in the LLPC compartment, contrasting sharply with the BM LLPC’s usual residents, which include influenza- and tetanus-specific ASCs. This absence offers a mechanistic insight into the fleeting nature of serological responses post-mRNA vaccination and the challenges in inducing LLPC formation.

The study underscores the complex journey of early-minted ASCs to the BM and the arduous maturation process into LLPCs, which involves a plethora of pathways such as increased immunoglobulin (Ig) transcripts, the unfolded protein response, and anti-apoptotic and autophagy programs. The difficulty of this maturation process means that not all ASCs can successfully become LLPCs, highlighting a significant barrier in the vaccine’s ability to induce long-term immunity.

Further exploration into the formation of LLPCs suggests that not all ASCs have the inherent potential to mature into these long-lived cells. The imprinting of ASCs at the time of their initial activation, along with their terminal maturation in specific survival niches, plays a crucial role in determining their longevity. Memory B cells (mBC), influenced by factors like the interval between vaccine doses and the cytokine milieu, are thought to be precursors to LLPCs. However, SARS-CoV-2 mRNA vaccines seemingly fail to instigate the imprinting necessary for ASCs to embark on the path to becoming LLPCs.

A notable observation from the study is the persistent exclusion of SARS-CoV-2-specific ASCs from the LLPC compartment, even 33 months post-vaccination. This suggests that the timeframe for the development of these long-lived cells cannot simply be extended to overcome the lack of LLPC formation. Moreover, the presence of SARS-CoV-2 specificity in ASC populations following asymptomatic infections points to the complex interplay between vaccination, infection, and immune memory.

Comparisons with previous studies further validate the findings, revealing a consistent pattern of SARS-CoV-2-specific ASC exclusion from the LLPC compartment post-vaccination and infection. These observations underscore the need for a deeper understanding of the ASC maturation process and the unique challenges posed by SARS-CoV-2 in inducing durable immunity.

The study also sheds light on the broader implications of the mRNA vaccine’s efficacy, highlighting the role of vaccine platforms and the spike protein’s structural characteristics in the induction of long-lasting antibody responses. Despite the strengths of mRNA and adenovirus (Ad) vector vaccines in generating strong germinal center reactions, their failure to sustain humoral immunity raises critical questions about the vaccine-induced immune response’s longevity.

In conclusion, this in-depth analysis provides critical insights into the challenges of inducing LLPC formation through mRNA vaccination against SARS-CoV-2, highlighting the need for innovative approaches to enhance the durability of vaccine-induced immunity. As the quest for long-lasting protection against COVID-19 continues, this study underscores the importance of advancing our understanding of the immune system’s intricacies and developing more effective vaccination strategies.


REFERENCE LINK : https://www.researchsquare.com/article/rs-3979237/v1

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