Early generation of a precursor CD8 T cell that can adapt to acute or chronic viral infection.

Virus specific PD-1+ TCF-1+ TOX+ stem-like CD8+ T cells are essential for maintaining T cell responses during chronic infection and are also critical for PD-1 directed immunotherapy. In this study we have used the mouse model of chronic LCMV infection to examine when these virus specific stem-like CD8+ T cells are generated during the course of chronic infection and what is the role of antigen in maintaining the stem-like program. We found that these stem-like CD8+ T cells are generated early (day 5) during chronic infection and that antigen is essential for maintaining their stem-like program. This early generation of stem-like CD8+ T cells suggested that the fate commitment to this cell population was agnostic to the eventual outcome of infection and the immune system prepares a priori for a potential chronic infection. Indeed, we found that an identical virus specific stem-cell like CD8+ T cell population was also generated during acute LCMV infection but these cells were lost once the virus was cleared. To determine the fate of these early PD-1+TCF-1+TOX+ stem-like CD8+ T cells that are generated during both acute and chronic LCMV infection we set up two reciprocal adoptive transfer experiments. In the first experiment we transferred day 5 stem-like CD8+ T cells from chronically infected into acutely infected mice and examined their differentiation after viral clearance. We found that these early stem-like CD8+ T cells downregulated canonical markers of the chronic stem-like CD8+ T cells and expressed markers (CD127 and CD62L) associated with central memory CD8+ T cells. In the second experiment, we transferred day 5 stem-like cells from acutely infected mice into chronically infected mice and found that these CD8+ T cells could function like resource cells after transfer into a chronic environment by generating effector CD8+ T cells in both lymphoid and non-lymphoid tissues while also maintaining the number of stem-like CD8+ T cells. These findings provide insight into the generation and maintenance of virus specific stem-like CD8+ T cells that play a critical role in chronic viral infection. In particular, our study highlights the early generation of stem-like CD8+ T cells and their ability to adapt to either an acute or chronic infection. These findings are of broad significance since these novel stem-like CD8+ T cells play an important role in not only viral infections but also in cancer and autoimmunity.

Circular Business Model for Digital Health Solutions: Protocol for a Scoping Review.

BACKGROUND: The circular economy reshapes the linear "take, make, and dispose" approach and evolves around minimizing waste and recapturing resources in a closed-loop system. The health sector accounts for 4.6% of global greenhouse gas emissions and has, over the decades, been built to rely on single-use devices and deal with high volumes of medical waste. With the increase in the adoption of digital health solutions in the health care industry, leading the industry into a new paradigm of how we provide health care, a focus must be put on the amount of waste that will follow. Digital health solutions will shape health care through the use of technology and lead to improved patient care, but they will also make medical waste more complex to deal with due to the e-waste component. Therefore, a transformation of the health care industry to a circular economy is a crucial cornerstone in decreasing the impact on the environment. OBJECTIVE: This study aims to address the lack of direction in the current literature on circular business models. It will consider micro, meso, and macro factors that would impact the operational validity of circular models using the digital health solutions ePaper label (medical packaging), smart wearable sensor (health monitoring devices), smart pill box (medication management), and endo-cutter (surgical equipment) as examples. METHODS: The study will systematically perform a scoping review through a database and snowball search. We will analyze and classify the studies from a predetermined set of categories and then summarize them into an evidence map. Based on the review, the study will develop a 2D framework for businesses to follow or for future research to take a standpoint from. RESULTS: Preliminarily, the review has analyzed 26 studies in total. The results are close to equally distributed among the micro (8/26, 31%), meso (10/26, 38%), and macro (8/26, 31%) levels. Circular economy studies emphasize several circular practices such as recycling (17/26, 65%), reusing (18/26, 69%), reducing (15/26, 58%), and remanufacturing (8/26, 31%). The value proposition in the examined business model is mostly dominated by stand-alone products (18/26, 69%) compared to product as a service (7/26, 27%), involving stakeholders such as health care professionals or hospitals (20/26, 77%), manufacturers (11/26, 42%), and consumers (9/26, 35%). All studies encompass societal (12/26, 46%), economic (23/26, 88%), and environmental (24/26, 92%) viewpoints. CONCLUSIONS: The study argues that each digital health solution would have to be accessed individually to find the optimal business model to follow. This is due to their differing life cycles and complexity. The manufacturer will need a layered value proposition, implementing several business models dependent on their respective product portfolios. The need to incorporate several business models implies an ecosystem perspective that is relevant to consider. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47874.

BA.5 bivalent booster vaccination enhances neutralization of XBB.1.5, XBB.1.16 and XBB.1.9 variants in patients with lung cancer.

This study reports that most patients with NSCLC had a significant increase in the nAb response to the currently circulating Omicron variants after bivalent booster vaccination and had Ab titers comparable to healthy participants. Interestingly, though the durability of the nAb response persisted in most of the healthy participants, patients with NSCLC had significantly reduced nAb titers after 4-6 months of vaccination. Our data highlight the importance of COVID-19 bivalent booster vaccination as the standard of care for patients with NSCLC given the evolution of new variants of concern.

Lessons for the Next Generation of Scientists from the Second Annual Arthur and Sandra Irving Cancer Immunology Symposium.

The Arthur and Sandra Irving Cancer Immunology Symposium has been created as a platform for established cancer immunologists to mentor trainees and young investigators as they launch their research career in the field. By sharing their different paths to success, the senior faculty mentors provide an invaluable resource to support the development of the next generation of leaders in the cancer immunology community. This Commentary describes some of the key topics that were discussed during the 2022 symposium: scientific and career trajectory, leadership, mentoring, collaborations, and publishing. For each of these topics, established investigators discussed the elements that facilitate success in these areas as well as mistakes that can hinder progress. Herein, we outline the critical points raised in these discussions for establishing a successful independent research career. These points are highly relevant for the broader scientific community.

Mechanisms of tertiary lymphoid structure formation: cooperation between inflammation and antigenicity.

To mount an effective anti-tumor immune response capable of controlling or eliminating disease, sufficient numbers of lymphocytes must be recruited to malignant tissue and allowed to sustain their effector functions. Indeed, higher infiltration of T and B cells in tumor tissue, often referred to as "hot tumors", is prognostic for patient survival and predictive of response to immunotherapy in almost all cancer types. The organization of tertiary lymphoid structures (TLS) in solid tumors is a unique example of a hot tumor whereby T and B lymphocytes aggregate with antigen presenting cells and high endothelial venules reflecting the cellular organization observed in lymphoid tissue. Many groups have reported that the presence of preexisting TLS in tumors is associated with a superior adaptive immune response, response to immunotherapy, and improved survivorship over those without TLS. Accordingly, there is significant interest into understanding the mechanisms of how and why TLS organize so that they can be elicited therapeutically in patients with few or no TLS. Unfortunately, the most commonly used mouse models of cancer do not spontaneously form TLS, thus significantly restricting our understanding of TLS biology. This brief review will summarize our current state of knowledge of TLS neogenesis and address the current gaps in the field.

PD-1 blockade increases the self-renewal of stem-like CD8 T cells to compensate for their accelerated differentiation into effectors.

PD-1+TCF-1+ stem-like CD8 T cells act as critical resource cells for maintaining T cell immunity in chronic viral infections and cancer. In addition, they provide the proliferative burst of effector CD8 T cells after programmed death protein 1 (PD-1)-directed immunotherapy. However, it is not known whether checkpoint blockade diminishes the number of these stem-like progenitor cells as effector cell differentiation increases. To investigate this, we used the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. Treatment of chronically infected mice with either αPD-1 or αPD-L1 antibody not only increased effector cell differentiation from the virus-specific stem-like CD8 T cells but also increased their proliferation so their numbers were maintained. The increased self-renewal of LCMV-specific stem-like CD8 T cells was mTOR dependent. We used microscopy to understand the division of these progenitor cells and found that after PD-1 blockade, an individual dividing cell could give rise to a differentiated TCF-1- daughter cell alongside a self-renewing TCF-1+ sister cell. This asymmetric division helped to preserve the number of stem-like cells. Moreover, we found that the PD-1+TCF-1+ stem-like CD8 T cells retained their transcriptional program and their in vivo functionality in terms of responding to viral infection and to repeat PD-1 blockade. Together, our results demonstrate that PD-1 blockade does not deplete the stem-like population despite increasing effector differentiation. These findings have implications for PD-1-directed immunotherapy in humans.

Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1+ PD-1+ CD8 T cells.

During persistent antigen stimulation, such as in chronic infections and cancer, CD8 T cells differentiate into a hypofunctional programmed death protein 1-positive (PD-1+) exhausted state. Exhausted CD8 T cell responses are maintained by precursors (Tpex) that express the transcription factor T cell factor 1 (TCF-1) and high levels of the costimulatory molecule CD28. Here, we demonstrate that sustained CD28 costimulation is required for maintenance of antiviral T cells during chronic infection. Low-level CD28 engagement preserved mitochondrial fitness and self-renewal of Tpex, whereas stronger CD28 signaling enhanced glycolysis and promoted Tpex differentiation into TCF-1neg exhausted CD8 T cells (Tex). Furthermore, enhanced differentiation by CD28 engagement did not reduce the Tpex pool. Together, these findings demonstrate that continuous CD28 engagement is needed to sustain PD-1+ CD8 T cells and suggest that increasing CD28 signaling promotes Tpex differentiation into more functional effector-like Tex, possibly without compromising long-term responses.

The Tumor-Specific Immune Landscape in HPV+ Head and Neck Cancer.

Human papillomaviruses (HPVs) are the causative agent of several anogenital cancers as well as head and neck cancers, with HPV+ head and neck squamous cell carcinoma (HNSCC) becoming a rapidly growing public health issue in the Western world. Due its viral etiology and potentially its subanatomical location, HPV+ HNSCC exhibits an immune microenvironment which is more inflamed and thus distinct from HPV-negative HNSCC. Notably, the antigenic landscape in most HPV+ HNSCC tumors extends beyond the classical HPV oncoproteins E6/7 and is extensively targeted by both the humoral and cellular arms of the adaptive immune system. Here, we provide a comprehensive overview of HPV-specific immune responses in patients with HPV+ HNSCC. We highlight the localization, antigen specificity, and differentiation states of humoral and cellular immune responses, and discuss their similarities and differences. Finally, we review currently pursued immunotherapeutic treatment modalities that attempt to harness HPV-specific immune responses for improving clinical outcomes in patients with HPV+ HNSCC.

Novel Immunotherapeutic Approaches to Treating HPV-Related Head and Neck Cancer.

Head and neck cancer (HNC) is the seventh most common malignancy, with oropharyngeal squamous cell carcinoma (OPSCC) accounting for a majority of cases in the western world. While HNC accounts for only 5% of all cancers in the United States, the incidence of a subset of OPSCC caused by human papillomavirus (HPV) is increasing rapidly. The treatment for OPSCC is multifaceted, with a recently emerging focus on immunotherapeutic approaches. With the increased incidence of HPV-related OPSCC and the approval of immunotherapy in the management of recurrent and metastatic HNC, there has been rising interest in exploring the role of immunotherapy in the treatment of HPV-related OPSCC specifically. The immune microenvironment in HPV-related disease is distinct from that in HPV-negative OPSCC, which has prompted further research into various immunotherapeutics. This review focuses on HPV-related OPSCC, its immune characteristics, and current challenges and future opportunities for immunotherapeutic applications in this virus-driven cancer.

Longitudinal Analysis of the Phenotype, Transcriptional Profile, and Anatomic Location of Memory CD8 T Cell Subsets after Acute Viral Infection.

Increased demand for novel, highly effective vaccination strategies necessitates a better understanding of long-lived memory CD8 T cell differentiation. To achieve this understanding, we used the mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection. We reexamined classical memory CD8 T cell subsets and performed in-depth, longitudinal analysis of their phenotype, transcriptional programming, and anatomic location within the spleen. All analyses were performed at multiple time points from 8 days to 1 year postinfection. Memory subsets are conventionally defined by their expression of KLRG1 and IL-7Rα, as follows: KLRG1+IL-7Rα- terminal effectors (TEs) and KLRG1-IL-7Rα+ memory precursors (MPs). But we also characterized a third KLRG1+IL-7Rα+ subset which we refer to as KLRG1+ MPs. In these analyses, we defined a comprehensive memory phenotype that is associated with higher levels of CD28 expression. We also demonstrated that MPs, KLRG1+ MPs, and TEs have distinct localization programs within the spleen. We found that MPs became preferentially enriched in the white pulp as early as 1 to 2 weeks postinfection, and their predominance in the white pulp was maintained throughout the course of a year. On the other hand, KLRG1+ MPs and TEs localized to the red pulp just as early, and they consistently localized to the red pulp thereafter. These findings indicate that location may be crucial for memory formation and that white pulp-derived signals may contribute to long-term memory survival. Achieving robust memory responses following vaccination may require more deliberate consideration of which memory phenotypes are induced, as well as where they traffic, as these factors could impact their longevity. IMPORTANCE CD8 T cells play a critical role in viral immunity and it is important to understand how memory cells are formed and what processes lead to their long-term maintenance. Here, we use a mouse model of acute infection to perform an in-depth, longitudinal analysis of memory CD8 T cell differentiation, examining the phenotype and location of memory cells out to 1 year postinfection.

Therapeutic Cancer Vaccines for the Management of Recurrent and Metastatic Head and Neck Cancer: A Review.

Importance: Squamous cell carcinoma of the head and neck (HNSCC) is prevalent globally and in the US. Management, particularly after disease recurrence, can be challenging, and exploring additional treatment modalities, such as therapeutic cancer vaccines, may offer an opportunity to improve outcomes in this setting. Observations: This review provides an overview of the clinical efficacy of different treatment modalities that are currently available for the treatment of recurrent and metastatic HNSCC, including checkpoint inhibitors and targeted therapies, with a detailed summary of the numerous T-cell vaccines that have been studied in the setting of HNSCC, as well as a detailed summary of B-cell therapeutic vaccines being investigated for various malignant tumors. Conclusions and Relevance: The findings of this review suggest that several therapeutic T-cell and B-cell vaccines, which have been recently developed and evaluated in a clinical setting, offer a promising treatment modality with the potential to improve outcomes for patients with recurrent and metastatic HNSCC.

mTOR regulates T cell exhaustion and PD-1-targeted immunotherapy response during chronic viral infection.

T cell exhaustion is a state of T cell dysfunction associated with expression of programmed death 1 (PD-1). Exhausted CD8+ T cells are maintained by self-renewing stem-like T cells that provide differentiated TIM3+ cells, a part of which possesses effector-like properties. PD-1-targeted therapies enhance T cell response by promoting differentiation of stem-like T cells toward TIM3+ cells, but the role of mTOR during T cell exhaustion remains elusive. Here, we showed that mTOR inhibition has distinct outcomes during the beginning of and after the establishment of chronic viral infection. Blocking mTOR during the T cell expansion phase enhanced the T cell response by causing accumulation of stem-like T cells, leading to improved efficacy of PD-1 immunotherapy; whereas, after exhaustion progressed, mTOR inhibition caused immunosuppression, characterized by decreased TIM3+ cells and increased viral load with minimal changes in stem-like T cells. Mechanistically, a cell-intrinsic mTOR signal was vital for differentiation of stem-like T cells into the TIM3+ state in the early and late phases of chronic infection as well as during PD-1 immunotherapy. Thus, PD-1 blockade worked after cessation of mTOR inhibition, but simultaneous treatment failed to induce functional TIM3+ cells, reducing efficacy of PD-1 immunotherapy. Our data demonstrate that mTOR regulates T cell exhaustion and have important implications for combination cancer therapies with PD-1 blockade.

Technology meets TILs: Deciphering T cell function in the -omics era.

T cells are at the center of cancer immunology because of their ability to recognize mutations in tumor cells and directly mediate cancer cell killing. Immunotherapies to rejuvenate exhausted T cell responses have transformed the clinical management of several malignancies. In parallel, the development of novel multidimensional analysis platforms, such as single-cell RNA sequencing and high-dimensional flow cytometry, has yielded unprecedented insights into immune cell biology. This convergence has revealed substantial heterogeneity of tumor-infiltrating immune cells in single tumors, across tumor types, and among individuals with cancer. Here we discuss the opportunities and challenges of studying the complex tumor microenvironment with -omics technologies that generate vast amounts of data, highlighting the opportunities and limitations of these technologies with a particular focus on interpreting high-dimensional studies of CD8+ T cells in the tumor microenvironment.

PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program.

Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection1. Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1+TCF1+ stem-like CD8+ T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+ T cells that resemble highly functional effector CD8+ T cells seen after an acute viral infection. The generation of these qualitatively superior CD8+ T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1+TCF1+ stem-like CD8+ T cells, also referred to as precursors of exhausted CD8+ T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8+ T cells emerging from the stem-like CD8+ T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25-CD122-CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer2,3, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.

Herpes simplex virus lymphadenitis is associated with tumor reduction in a patient with chronic lymphocytic leukemia.

BackgroundHerpes simplex virus lymphadenitis (HSVL) is an unusual presentation of HSV reactivation in patients with chronic lymphocytic leukemia (CLL) and is characterized by systemic symptoms and no herpetic lesions. The immune responses during HSVL have not, to our knowledge, been studied.MethodsPeripheral blood and lymph node (LN) samples were obtained from a patient with HSVL. HSV-2 viral load, antibody levels, B and T cell responses, cytokine levels, and tumor burden were measured.ResultsThe patient showed HSV-2 viremia for at least 6 weeks. During this period, she had a robust HSV-specific antibody response with neutralizing and antibody-dependent cellular phagocytotic activity. Activated (HLA-DR+, CD38+) CD4+ and CD8+ T cells increased 18-fold, and HSV-specific CD8+ T cells in the blood were detected at higher numbers. HSV-specific B and T cell responses were also detected in the LN. Markedly elevated levels of proinflammatory cytokines in the blood were also observed. Surprisingly, a sustained decrease in CLL tumor burden without CLL-directed therapy was observed with this and also a prior episode of HSVL.ConclusionHSVL should be considered part of the differential diagnosis in patients with CLL who present with signs and symptoms of aggressive lymphoma transformation. An interesting finding was the sustained tumor control after 2 episodes of HSVL in this patient. A possible explanation for the reduction in tumor burden may be that the HSV-specific response served as an adjuvant for the activation of tumor-specific or bystander T cells. Studies in additional patients with CLL are needed to confirm and extend these findings.FundingNIH grants 4T32CA160040, UL1TR002378, and 5U19AI057266 and NIH contracts 75N93019C00063 and HHSN261200800001E. Neil W. and William S. Elkin Fellowship (Winship Cancer Institute).

Antibody Response to COVID-19 mRNA Vaccine in Patients With Lung Cancer After Primary Immunization and Booster: Reactivity to the SARS-CoV-2 WT Virus and Omicron Variant.

PURPOSE: To examine COVID-19 mRNA vaccine-induced binding and neutralizing antibody responses in patients with non-small-cell lung cancer (NSCLC) to SARS-CoV-2 614D (wild type [WT]) strain and variants of concern after the primary 2-dose and booster vaccination. METHODS: Eighty-two patients with NSCLC and 53 healthy volunteers who received SARS-CoV-2 mRNA vaccines were included in the study. Blood was collected longitudinally, and SARS-CoV-2-specific binding and neutralizing antibody responses were evaluated by Meso Scale Discovery assay and live virus Focus Reduction Neutralization Assay, respectively. RESULTS: A majority of patients with NSCLC generated binding and neutralizing antibody titers comparable with the healthy vaccinees after mRNA vaccination, but a subset of patients with NSCLC (25%) made poor responses, resulting in overall lower (six- to seven-fold) titers compared with the healthy cohort (P = < .0001). Although patients age > 70 years had lower immunoglobulin G titers (P = < .01), patients receiving programmed death-1 monotherapy, chemotherapy, or a combination of both did not have a significant impact on the antibody response. Neutralizing antibody titers to the B.1.617.2 (Delta), B.1.351 (Beta), and in particular, B.1.1.529 (Omicron) variants were significantly lower (P = < .0001) compared with the 614D (WT) strain. Booster vaccination led to a significant increase (P = .0001) in the binding and neutralizing antibody titers to the WT and Omicron variant. However, 2-4 months after the booster, we observed a five- to seven-fold decrease in neutralizing titers to WT and Omicron viruses. CONCLUSION: A subset of patients with NSCLC responded poorly to the SARS-CoV-2 mRNA vaccination and had low neutralizing antibodies to the B.1.1.529 Omicron variant. Booster vaccination increased binding and neutralizing antibody titers to Omicron, but antibody titers declined after 3 months. These data highlight the concern for patients with cancer given the rapid spread of SARS-CoV-2 Omicron variant.

Distinct phenotypic states and spatial distribution of CD8+ T cell clonotypes in human brain metastases.

Metastatic disease in the brain is difficult to control and predicts poor prognosis. Here, we analyze human brain metastases and demonstrate their robust infiltration by CD8+ T cell subsets with distinct antigen specificities, phenotypic states, and spatial localization within the tumor microenvironment. Brain metastases are densely infiltrated by T cells; the majority of infiltrating CD8+ T cells express PD-1. Single-cell RNA sequencing shows significant clonal overlap between proliferating and exhausted CD8+ T cells, but these subsets have minimal clonal overlap with circulating and other tumor-infiltrating CD8+ T cells, including bystander CD8+ T cells specific for microbial antigens. Using spatial transcriptomics and spatial T cell receptor (TCR) sequencing, we show these clonally unrelated, phenotypically distinct CD8+ T cell populations occupy discrete niches within the brain metastasis tumor microenvironment. Together, our work identifies signaling pathways within CD8+ T cells and in their surrounding environment that may be targeted for immunotherapy of brain metastases.

Persistence of Virus-Specific Antibody after Depletion of Memory B Cells.

Humoral immunity is a major component of the adaptive immune response against viruses and other pathogens with pathogen-specific antibody acting as the first line of defense against infection. Virus-specific antibody levels are maintained by continual secretion of antibody by plasma cells residing in the bone marrow. This raises the important question of how the virus-specific plasma cell population is stably maintained and whether memory B cells are required to replenish plasma cells, balancing their loss arising from their intrinsic death rate. In this study, we examined the longevity of virus-specific antibody responses in the serum of mice following acute viral infection with three different viruses: lymphocytic choriomeningitis virus (LCMV), influenza virus, and vesicular stomatitis virus (VSV). To investigate the contribution of memory B cells to the maintenance of virus-specific antibody levels, we employed human CD20 transgenic mice, which allow for the efficient depletion of B cells with rituximab, a human CD20-specific monoclonal antibody. Mice that had resolved an acute infection with LCMV, influenza virus, or VSV were treated with rituximab starting at 2 months after infection, and the treatment was continued for up to a year postinfection. This treatment regimen with rituximab resulted in efficient depletion of B cells (>95%), with virus-specific memory B cells being undetectable. There was an early transient drop in the antibody levels after rituximab treatment followed by a plateauing of the curve with virus-specific antibody levels remaining relatively stable (half-life of 372 days) for up to a year after infection in the absence of memory B cells. The number of virus-specific plasma cells in the bone marrow were consistent with the changes seen in serum antibody levels. Overall, our data show that virus-specific plasma cells in the bone marrow are intrinsically long-lived and can maintain serum antibody titers for extended periods of time without requiring significant replenishment from memory B cells. These results provide insight into plasma cell longevity and have implications for B cell depletion regimens in cancer and autoimmune patients in the context of vaccination in general and especially for COVID-19 vaccines. IMPORTANCE Following vaccination or primary virus infection, virus-specific antibodies provide the first line of defense against reinfection. Plasma cells residing in the bone marrow constitutively secrete antibodies, are long-lived, and can thus maintain serum antibody levels over extended periods of time in the absence of antigen. Our data, in the murine model system, show that virus-specific plasma cells are intrinsically long-lived but that some reseeding by memory B cells might occur. Our findings demonstrate that, due to the longevity of plasma cells, virus-specific antibody levels remain relatively stable in the absence of memory B cells and have implications for vaccination.