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1.
J Immunol ; 208(10): 2267-2271, 2022 05 15.
Article in English | MEDLINE | ID: covidwho-1835021

ABSTRACT

Understanding the generation of immunity to SARS-CoV-2 in lymphoid tissues draining the site of infection has implications for immunity to SARS-CoV-2. We performed tonsil biopsies under local anesthesia in 19 subjects who had recovered from SARS-CoV-2 infection 24-225 d previously. The biopsies yielded >3 million cells for flow cytometric analysis in 17 subjects. Total and SARS-CoV-2 spike-specific germinal center B cells, and T follicular helper cells, were readily detectable in human tonsils early after SARS-CoV-2 infection, as assessed by flow cytometry. Responses were higher in samples within 2 mo of infection but still detectable in some subjects out to 7 mo following infection. We conclude the tonsils are a secondary lymphoid organ that develop germinal center responses to SARS-CoV-2 infection and could play a role in the long-term development of immunity.


Subject(s)
COVID-19 , Antibodies, Viral , Germinal Center , Humans , Palatine Tonsil , SARS-CoV-2 , T Follicular Helper Cells
2.
Nat Commun ; 13(1): 2460, 2022 05 05.
Article in English | MEDLINE | ID: covidwho-1825071

ABSTRACT

Infection or vaccination leads to the development of germinal centers (GC) where B cells evolve high affinity antigen receptors, eventually producing antibody-forming plasma cells or memory B cells. Here we follow the migratory pathways of B cells emerging from germinal centers (BEM) and find that many BEM cells migrate into the lymph node subcapsular sinus (SCS) guided by sphingosine-1-phosphate (S1P). From the SCS, BEM cells may exit the lymph node to enter distant tissues, while some BEM cells interact with and take up antigen from SCS macrophages, followed by CCL21-guided return towards the GC. Disruption of local CCL21 gradients inhibits the recycling of BEM cells and results in less efficient adaption to antigenic variation. Our findings thus suggest that the recycling of antigen variant-specific BEM cells and transport of antigen back to GC may support affinity maturation to antigenic drift.


Subject(s)
Antigenic Drift and Shift , Memory B Cells , B-Lymphocytes , Germinal Center , Lymph Nodes
3.
Front Immunol ; 13: 844837, 2022.
Article in English | MEDLINE | ID: covidwho-1809397

ABSTRACT

In this work, we evaluated recombinant receptor binding domain (RBD)-based vaccine formulation prototypes with potential for further clinical development. We assessed different formulations containing RBD plus alum, AddaS03, AddaVax, or the combination of alum and U-Omp19: a novel Brucella spp. protease inhibitor vaccine adjuvant. Results show that the vaccine formulation composed of U-Omp19 and alum as adjuvants has a better performance: it significantly increased mucosal and systemic neutralizing antibodies in comparison to antigen plus alum, AddaVax, or AddaS03. Antibodies induced with the formulation containing U-Omp19 and alum not only increased their neutralization capacity against the ancestral virus but also cross-neutralized alpha, lambda, and gamma variants with similar potency. Furthermore, the addition of U-Omp19 to alum vaccine formulation increased the frequency of RBD-specific geminal center B cells and plasmablasts. Additionally, U-Omp19+alum formulation induced RBD-specific Th1 and CD8+ T-cell responses in spleens and lungs. Finally, this vaccine formulation conferred protection against an intranasal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge of K18-hACE2 mice.


Subject(s)
Adjuvants, Immunologic/metabolism , B-Lymphocytes/immunology , Bacterial Outer Membrane Proteins/metabolism , Brucella/metabolism , COVID-19 Vaccines/immunology , COVID-19/immunology , Germinal Center/immunology , SARS-CoV-2/physiology , Alum Compounds/metabolism , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral , Antibody Formation , Bacterial Outer Membrane Proteins/immunology , Brucella/immunology , Disease Resistance , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Spike Glycoprotein, Coronavirus/immunology
4.
Cell ; 185(6): 945-948, 2022 03 17.
Article in English | MEDLINE | ID: covidwho-1748152

ABSTRACT

Long-term protection against SARS-CoV-2 requires effective and durable immunity. In this issue of Cell, two papers closely examine germinal centers, the physiological birthplace of adaptive immunity, to quantify the specificity, breadth, magnitude, and persistence of systemic and local humoral immune responses following natural infection with, or vaccination against, SARS-CoV-2.


Subject(s)
COVID-19 , Immunity, Humoral , Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , Germinal Center , Humans , SARS-CoV-2
5.
Front Immunol ; 13: 838328, 2022.
Article in English | MEDLINE | ID: covidwho-1731785

ABSTRACT

Confirmed SARS-coronavirus-2 infection with gastrointestinal symptoms and changes in microbiota associated with coronavirus disease 2019 (COVID-19) severity have been previously reported, but the disease impact on the architecture and cellularity of ileal Peyer's patches (PP) remains unknown. Here we analysed post-mortem tissues from throughout the gastrointestinal (GI) tract of patients who died with COVID-19. When virus was detected by PCR in the GI tract, immunohistochemistry identified virus in epithelium and lamina propria macrophages, but not in lymphoid tissues. Immunohistochemistry and imaging mass cytometry (IMC) analysis of ileal PP revealed depletion of germinal centres (GC), disruption of B cell/T cell zonation and decreased potential B and T cell interaction and lower nuclear density in COVID-19 patients. This occurred independent of the local viral levels. The changes in PP demonstrate that the ability to mount an intestinal immune response is compromised in severe COVID-19, which could contribute to observed dysbiosis.


Subject(s)
Atrophy/immunology , COVID-19/immunology , Germinal Center/immunology , Intestinal Mucosa/immunology , Peyer's Patches/immunology , B-Lymphocytes/immunology , Humans , Lymphoid Tissue/immunology , Macrophages/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology
6.
Nature ; 604(7904): 141-145, 2022 04.
Article in English | MEDLINE | ID: covidwho-1684082

ABSTRACT

Germinal centres (GC) are lymphoid structures in which B cells acquire affinity-enhancing somatic hypermutations (SHM), with surviving clones differentiating into memory B cells (MBCs) and long-lived bone marrow plasma cells1-5 (BMPCs). SARS-CoV-2 mRNA vaccination induces a persistent GC response that lasts for at least six months in humans6-8. The fate of responding GC B cells as well as the functional consequences of such persistence remain unknown. Here, we detected SARS-CoV-2 spike protein-specific MBCs in 42 individuals who had received two doses of the SARS-CoV-2 mRNA vaccine BNT162b2 six month earlier. Spike-specific IgG-secreting BMPCs were detected in 9 out of 11 participants. Using a combined approach of sequencing the B cell receptors of responding blood plasmablasts and MBCs, lymph node GC B cells and plasma cells and BMPCs from eight individuals and expression of the corresponding monoclonal antibodies, we tracked the evolution of 1,540 spike-specific B cell clones. On average, early blood spike-specific plasmablasts exhibited the lowest SHM frequencies. By contrast, SHM frequencies of spike-specific GC B cells increased by 3.5-fold within six months after vaccination. Spike-specific MBCs and BMPCs accumulated high levels of SHM, which corresponded with enhanced anti-spike antibody avidity in blood and enhanced affinity as well as neutralization capacity of BMPC-derived monoclonal antibodies. We report how the notable persistence of the GC reaction induced by SARS-CoV-2 mRNA vaccination in humans culminates in affinity-matured long-term antibody responses that potently neutralize the virus.


Subject(s)
B-Lymphocytes , BNT162 Vaccine , Germinal Center , Vaccination , Antibodies, Monoclonal , Antibodies, Viral , B-Lymphocytes/cytology , B-Lymphocytes/immunology , BNT162 Vaccine/administration & dosage , BNT162 Vaccine/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , Germinal Center/cytology , Germinal Center/immunology , Humans , RNA, Messenger/genetics , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology
8.
Sci Immunol ; 7(68): eabl5652, 2022 Feb 04.
Article in English | MEDLINE | ID: covidwho-1673340

ABSTRACT

T follicular helper (TFH) cells are the conventional drivers of protective, germinal center (GC)­based antiviral antibody responses. However, loss of TFH cells and GCs has been observed in patients with severe COVID-19. As T cell­B cell interactions and immunoglobulin class switching still occur in these patients, noncanonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both TFH-dependent and -independent antibodies were induced against SARS-CoV-2 infection, SARS-CoV-2 vaccination, and influenza A virus infection. Although TFH-independent antibodies to SARS-CoV-2 had evidence of reduced somatic hypermutation, they were still high affinity, durable, and reactive against diverse spike-derived epitopes and were capable of neutralizing both homologous SARS-CoV-2 and the B.1.351 (beta) variant of concern. We found by epitope mapping and B cell receptor sequencing that TFH cells focused the B cell response, and therefore, in the absence of TFH cells, a more diverse clonal repertoire was maintained. These data support an alternative pathway for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GC-derived antibodies that might compensate for GCs damaged by viral inflammation.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , T Follicular Helper Cells/immunology , Amino Acid Sequence , Animals , Antibody Formation/immunology , B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , Germinal Center/immunology , Humans , Lymphocyte Activation/immunology , Mice , T-Lymphocytes, Helper-Inducer
9.
Cell Rep ; 38(8): 110399, 2022 02 22.
Article in English | MEDLINE | ID: covidwho-1664737

ABSTRACT

Follicular helper T (Tfh) cells promote, whereas follicular regulatory T (Tfr) cells restrain, germinal center (GC) reactions. However, the precise roles of these cells in the complex GC reaction remain poorly understood. Here, we perturb Tfh or Tfr cells after SARS-CoV-2 spike protein vaccination in mice. We find that Tfh cells promote the frequency and somatic hypermutation (SHM) of Spike-specific GC B cells and regulate clonal diversity. Tfr cells similarly control SHM and clonal diversity in the GC but do so by limiting clonal competition. In addition, deletion of Tfh or Tfr cells during primary vaccination results in changes in SHM after vaccine boosting. Aged mice, which have altered Tfh and Tfr cells, have lower GC responses, presenting a bimodal distribution of SHM. Together, these data demonstrate that GC responses to SARS-CoV-2 spike protein vaccines require a fine balance of positive and negative follicular T cell help to optimize humoral immunity.


Subject(s)
COVID-19/prevention & control , Germinal Center/immunology , Spike Glycoprotein, Coronavirus/administration & dosage , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Regulatory/immunology , Aging , Animals , Antibodies, Viral/blood , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , COVID-19/virology , Germinal Center/cytology , Germinal Center/metabolism , Immunity, Humoral , Mice , Mice, Inbred C57BL , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/metabolism , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/metabolism , Vaccination , Vaccines, Subunit/immunology
10.
Elife ; 102021 11 17.
Article in English | MEDLINE | ID: covidwho-1662831

ABSTRACT

The poor efficacy of seasonal influenza virus vaccines is often attributed to pre-existing immunity interfering with the persistence and maturation of vaccine-induced B cell responses. We previously showed that a subset of vaccine-induced B cell lineages are recruited into germinal centers (GCs) following vaccination, suggesting that affinity maturation of these lineages against vaccine antigens can occur. However, it remains to be determined whether seasonal influenza vaccination stimulates additional evolution of vaccine-specific lineages, and previous work has found no significant increase in somatic hypermutation among influenza-binding lineages sampled from the blood following seasonal vaccination in humans. Here, we investigate this issue using a phylogenetic test of measurable immunoglobulin sequence evolution. We first validate this test through simulations and survey measurable evolution across multiple conditions. We find significant heterogeneity in measurable B cell evolution across conditions, with enrichment in primary response conditions such as HIV infection and early childhood development. We then show that measurable evolution following influenza vaccination is highly compartmentalized: while lineages in the blood are rarely measurably evolving following influenza vaccination, lineages containing GC B cells are frequently measurably evolving. Many of these lineages appear to derive from memory B cells. We conclude from these findings that seasonal influenza virus vaccination can stimulate additional evolution of responding B cell lineages, and imply that the poor efficacy of seasonal influenza vaccination is not due to a complete inhibition of vaccine-specific B cell evolution.


When the immune system encounters a disease-causing pathogen, it releases antibodies that can bind to specific regions of the bacterium or virus and help to clear the infection. These proteins are generated by B cells which, upon detecting the pathogen, can begin to mutate and alter the structure of the antibody they produce: the better the antibody is at binding to the pathogen, the more likely the B cell is to survive. This process of evolution produces B cells that make more effective antibodies. After the infection, some of these cells become 'memory B cells' which can be stimulated in to action when the pathogen invades again. Many vaccines also depend on this process to trigger the production of memory B cells that can fight off a specific disease-causing agent. However, it is unclear to what extent memory B cells that already exist are able to continue to evolve and modify their antibodies. This is particularly important for the flu vaccine, as the virus that causes influenza rapidly mutates. To provide high levels of protection, the memory B cells formed following the vaccine may therefore need to evolve to make different antibodies that recognize mutated forms of the virus. It is thought that the low effectiveness of the flu vaccine is partially because the response it triggers does not stimulate additional evolution of memory B cells. To test this theory, Hoehn et al. developed a computational method that can detect the evolution of B cells over time. The tool was applied to samples collected from the blood and lymph nodes (organ where immune cells reside) of people who recently received the flu vaccine. The results were then compared to B cells taken from people after different infections, vaccinations, and other conditions. Hoehn et al. found the degree to which B cells evolve varies significantly between conditions. For example, B cells produced during chronic HIV infections frequently evolved over time, while such evolution was rarely observed during the autoimmune disease myasthenia gravis. The analysis also showed that memory B cells produced by the flu vaccine were able to evolve if recruited to the lymph nodes, but this was rarely detected in B cells in the blood. These findings suggest the low efficacy of the flu vaccine is not due to a complete lack of B cell evolution, but likely due to other factors. For instance, it is possible the evolutionary process it stimulates is not as robust as in other conditions, or is less likely to produce long-lived B cells that release antibodies. More research is needed to explore these ideas and could lead to the development of more effective flu vaccines.


Subject(s)
B-Lymphocytes/immunology , Evolution, Molecular , Germinal Center/immunology , Influenza Vaccines/immunology , Humans , Influenza, Human/virology , Phylogeny , Vaccination
11.
Cell ; 185(6): 1025-1040.e14, 2022 03 17.
Article in English | MEDLINE | ID: covidwho-1649487

ABSTRACT

During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including third-dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination.


Subject(s)
Antibodies, Viral , BNT162 Vaccine , COVID-19 , Germinal Center , Antigens, Viral , COVID-19/prevention & control , Humans , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus , Vaccination
12.
Mol Biol Rep ; 49(3): 2465-2474, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1605165

ABSTRACT

Coronavirus outbreak was declared a pandemic by World Health Organization (WHO) in March 2020. The pandemic has led to a devastating loss of life. It has shown us how infectious diseases can cause human existence at stake, and community health is important. The spike protein is the most immunogenic component of the virus. Most vaccine development strategies have focused on the receptor-binding domain (RBD) in the spike protein because it is the most specific target site that recognizes and interacts with human lung cells. Neutralizing antibodies are generated by the humoral immune system and reduce the viral load by binding to spike protein components. Neutralizing antibodies are the proteins secreted by plasma cells and serve as an important part of the defense mechanism. In the recent Covid-19 infection, neutralizing antibodies can be utilized for both diagnostic such as immune surveillance and therapeutic tools such as plasma therapy. So far, many monoclonal antibodies are in the clinical trial phase, and few of them are already in use. In this review, we have discussed details about neutralizing antibodies and their role in combating Covid-19 disease.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , COVID-19/therapy , SARS-CoV-2/isolation & purification , Animals , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Antigens, Viral/immunology , B-Lymphocytes/immunology , COVID-19/immunology , Clinical Trials as Topic , Enzyme-Linked Immunosorbent Assay , Epitopes/immunology , Forecasting , Germinal Center/immunology , Humans , Immunization, Passive , Immunoglobulin Isotypes/immunology , Immunologic Memory , Immunologic Surveillance , Macaca mulatta , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology
13.
Cell ; 185(4): 603-613.e15, 2022 02 17.
Article in English | MEDLINE | ID: covidwho-1588149

ABSTRACT

SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4+ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses contribute to this outstanding immunogenicity. Using fine-needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we evaluated the T cell receptor sequences and phenotype of lymph node TFH. Mining of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1∗04-restricted response to S167-180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific TFH cells peak one week after the second immunization, S-specific TFH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this efficacious human vaccine.


Subject(s)
COVID-19/immunology , COVID-19/virology , Immunity/immunology , SARS-CoV-2/immunology , T Follicular Helper Cells/immunology , Vaccination , Vaccines, Synthetic/immunology , mRNA Vaccines/immunology , Adult , B-Lymphocytes/immunology , BNT162 Vaccine/immunology , COVID-19/blood , Clone Cells , Cohort Studies , Cytokines/metabolism , Female , Germinal Center/immunology , HLA-DP beta-Chains/immunology , Humans , Immunodominant Epitopes/immunology , Jurkat Cells , Lymph Nodes/metabolism , Male , Middle Aged , Peptides/chemistry , Peptides/metabolism , Protein Multimerization , Receptors, Antigen, T-Cell/metabolism
14.
Front Immunol ; 12: 776933, 2021.
Article in English | MEDLINE | ID: covidwho-1581333

ABSTRACT

The efficacy of COVID-19 vaccines appears to depend in complex ways on the vaccine dosage and the interval between the prime and boost doses. Unexpectedly, lower dose prime and longer prime-boost intervals have yielded higher efficacies in clinical trials. To elucidate the origins of these effects, we developed a stochastic simulation model of the germinal center (GC) reaction and predicted the antibody responses elicited by different vaccination protocols. The simulations predicted that a lower dose prime could increase the selection stringency in GCs due to reduced antigen availability, resulting in the selection of GC B cells with higher affinities for the target antigen. The boost could relax this selection stringency and allow the expansion of the higher affinity GC B cells selected, improving the overall response. With a longer dosing interval, the decay in the antigen with time following the prime could further increase the selection stringency, amplifying this effect. The effect remained in our simulations even when new GCs following the boost had to be seeded by memory B cells formed following the prime. These predictions offer a plausible explanation of the observed paradoxical effects of dosage and dosing interval on vaccine efficacy. Tuning the selection stringency in the GCs using prime-boost dosages and dosing intervals as handles may help improve vaccine efficacies.


Subject(s)
B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Clonal Selection, Antigen-Mediated/immunology , Germinal Center/immunology , Host-Pathogen Interactions/immunology , SARS-CoV-2/immunology , Antigens/immunology , B-Lymphocytes/metabolism , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Dose-Response Relationship, Immunologic , Germinal Center/metabolism , Humans , Immunization, Secondary , Models, Theoretical , Vaccination
15.
PLoS Pathog ; 17(12): e1010085, 2021 12.
Article in English | MEDLINE | ID: covidwho-1559373

ABSTRACT

Regulatory T (Treg) cells, which constitute about 5-10% of CD4+T cells expressing Foxp3 transcription factor and CD25(IL-2 receptor α chain), are key regulators in controlling immunological self-tolerance and various immune responses. However, how Treg cells control antigen-specific immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. In this study, we examined the effect of transient breakdown of the immunological tolerance induced by Treg-cell depletion on adaptive immune responses against administered SARS-CoV-2 antigen, spike protein 1 (S1). Notably, without the use of adjuvants, transient Treg-cell depletion in mice induced anti-S1 antibodies that neutralized authentic SARS-CoV-2, follicular helper T cell formation and S1-binding germinal center B cell responses, but prevented the onset of developing autoimmune diseases. To further clarify the mechanisms, we investigated maturation of dendritic cells (DCs), which is essential to initiate antigen-specific immunity. We found that the transient Treg-cell depletion resulted in maturation of both migratory and resident DCs in draining lymph nodes that captured S1-antigen. Moreover, we observed S1-specific CD4+ T cells and CD8+ T cells with interferon-γ production. Thus, captured S1 was successfully presented by DCs, including cross-presentation to CD8+ T cells. These data indicate that transient Treg-cell depletion in the absence of adjuvants induces maturation of antigen-presenting DCs and succeeds in generating antigen-specific humoral and cellular immunity against emerging SARS-CoV-2 antigens. Finally, we showed that SARS-CoV-2 antigen-specific immune responses induced by transient Treg-cell depletion in the absence of adjuvants were compatible with those induced with an effective adjuvant, polyriboinosinic:polyribocytidyl acid (poly IC) and that the combination of transient Treg-cell depletion with poly IC induced potent responses. These findings highlight the capacity for manipulating Treg cells to induce protective adaptive immunity to SARS-CoV-2 with activating antigen-presenting DCs, which may improve the efficacy of ongoing vaccine therapies and help enhance responses to emerging SARS-CoV-2 variants.


Subject(s)
Adaptive Immunity/immunology , Antigens, Viral/immunology , COVID-19/immunology , Forkhead Transcription Factors/immunology , SARS-CoV-2/immunology , Animals , Antigen Presentation/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/virology , Chlorocebus aethiops , Dendritic Cells/immunology , Female , Germinal Center/immunology , Humans , Immune Tolerance , Mice , Mice, Inbred C57BL , Mice, Inbred MRL lpr , T-Lymphocytes, Regulatory/immunology , Vero Cells
16.
Nat Rev Immunol ; 22(1): 7-18, 2022 01.
Article in English | MEDLINE | ID: covidwho-1555659

ABSTRACT

The germinal centre (GC) response is critical for the generation of affinity-matured plasma cells and memory B cells capable of mediating long-term protective immunity. Understanding whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination elicits a GC response has profound implications for the capacity of responding B cells to contribute to protection against infection. However, direct assessment of the GC response in humans remains a major challenge. Here we summarize emerging evidence for the importance of the GC response in the establishment of durable and broad immunity against SARS-CoV-2 and discuss new approaches to modulate the GC response to better protect against newly emerging SARS-CoV-2 variants. We also discuss new findings showing that the GC B cell response persists in the draining lymph nodes for at least 6 months in some individuals following vaccination with SARS-CoV-2 mRNA-based vaccines.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/virology , Germinal Center/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Viral/immunology , COVID-19/prevention & control , Humans , /immunology
17.
Mucosal Immunol ; 14(5): 1144-1159, 2021 09.
Article in English | MEDLINE | ID: covidwho-1550272

ABSTRACT

Increased IgE is a typical feature of allergic rhinitis. Local class-switch recombination has been intimated but B cell precursors and mechanisms remain elusive. Here we describe the dynamics underlying the generation of IgE-antibody secreting cells (ASC) in human nasal polyps (NP), mucosal tissues rich in ASC without germinal centers (GC). Using VH next generation sequencing, we identified an extrafollicular (EF) mucosal IgD+ naïve-like intermediate B cell population with high connectivity to the mucosal IgE ASC. Mucosal IgD+ B cells, express germline epsilon transcripts and predominantly co-express IgM. However, a small but significant fraction co-express IgG or IgA instead which also show connectivity to ASC IgE. Phenotypically, NP IgD+ B cells display an activated profile and molecular evidence of BCR engagement. Transcriptionally, mucosal IgD+ B cells reveal an intermediate profile between naïve B cells and ASC. Single cell IgE ASC analysis demonstrates lower mutational frequencies relative to IgG, IgA, and IgD ASC consistent with IgE ASC derivation from mucosal IgD+ B cell with low mutational load. In conclusion, we describe a novel mechanism of GC-independent, extrafollicular IgE ASC formation at the nasal mucosa whereby activated IgD+ naïve B cells locally undergo direct and indirect (through IgG and IgA), IgE class switch.


Subject(s)
Antibody Formation/immunology , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , Immunoglobulin D/immunology , Immunoglobulin E/immunology , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Adult , Antibody Formation/genetics , Antibody-Producing Cells/immunology , Antibody-Producing Cells/metabolism , Computational Biology , Gene Expression Profiling , Germinal Center/immunology , High-Throughput Nucleotide Sequencing , Humans , Hypersensitivity/etiology , Hypersensitivity/metabolism , Immunoglobulin Class Switching/genetics , Immunoglobulin Class Switching/immunology , Immunoglobulin Isotypes/genetics , Immunoglobulin Isotypes/immunology , Immunophenotyping , Nasal Polyps/etiology , Nasal Polyps/metabolism , Nasal Polyps/pathology , Pollen/immunology , Seasons , Somatic Hypermutation, Immunoglobulin
18.
Cell Rep ; 37(6): 109961, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1507742

ABSTRACT

Following infection or immunization, memory B cells (MBCs) and long-lived plasma cells provide humoral immunity that can last for decades. Most principles of MBC biology have been determined with hapten-protein carrier models or fluorescent protein immunizations. Here, we examine the temporal dynamics of the germinal center (GC) B cell and MBC response following mouse influenza A virus infection. We find that antiviral B cell responses within the lung-draining mediastinal lymph node (mLN) and the spleen are distinct in regard to duration, enrichment for antigen-binding cells, and class switching dynamics. While splenic GCs dissolve after 6 weeks post-infection, mLN hemagglutinin-specific (HA+) GCs can persist for 22 weeks. Persistent GCs continuously differentiate MBCs, with "peak" and "late" GCs contributing equal numbers of HA+ MBCs to the long-lived compartment. Our findings highlight critical aspects of persistent GC responses and MBC differentiation following respiratory virus infection with direct implications for developing effective vaccination strategies.


Subject(s)
Antibodies, Viral/immunology , Germinal Center/immunology , Immunologic Memory , Influenza A virus/physiology , Orthomyxoviridae Infections/immunology , T-Box Domain Proteins/physiology , Animals , Cell Differentiation , Female , Lymphocyte Activation , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Orthomyxoviridae Infections/pathology , Orthomyxoviridae Infections/virology
19.
Immunity ; 54(12): 2877-2892.e7, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1499988

ABSTRACT

Adjuvants are critical for improving the quality and magnitude of adaptive immune responses to vaccination. Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines have shown great efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the mechanism of action of this vaccine platform is not well-characterized. Using influenza virus and SARS-CoV-2 mRNA and protein subunit vaccines, we demonstrated that our LNP formulation has intrinsic adjuvant activity that promotes induction of strong T follicular helper cell, germinal center B cell, long-lived plasma cell, and memory B cell responses that are associated with durable and protective antibodies in mice. Comparative experiments demonstrated that this LNP formulation outperformed a widely used MF59-like adjuvant, AddaVax. The adjuvant activity of the LNP relies on the ionizable lipid component and on IL-6 cytokine induction but not on MyD88- or MAVS-dependent sensing of LNPs. Our study identified LNPs as a versatile adjuvant that enhances the efficacy of traditional and next-generation vaccine platforms.


Subject(s)
B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Germinal Center/immunology , SARS-CoV-2/physiology , T-Lymphocytes, Helper-Inducer/immunology , /immunology , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adjuvants, Immunologic , Animals , HEK293 Cells , Humans , Immunity, Humoral , Interleukin-6/genetics , Interleukin-6/metabolism , Liposomes/administration & dosage , Mice , Mice, Inbred BALB C , Nanoparticles/administration & dosage , Protein Subunits/genetics , /genetics
20.
J Infect Dis ; 224(11): 1861-1872, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1493829

ABSTRACT

Germinal centers (GCs) elicit protective humoral immunity through a combination of antibody-secreting cells and memory B cells, following pathogen invasion or vaccination. However, the possibility of a GC response inducing protective immunity against reinfection following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unknown. We found GC activity was consistent with seroconversion observed in recovered macaques and humans. Rechallenge with a different clade of virus resulted in significant reduction in replicating virus titers in respiratory tracts in macaques with high GC activity. However, diffuse alveolar damage and increased fibrotic tissue were observed in lungs of reinfected macaques. Our study highlights the importance of GCs developed during natural SARS-CoV-2 infection in managing viral loads in subsequent infections. However, their ability to alleviate lung damage remains to be determined. These results may improve understanding of SARS-CoV-2-induced immune responses, resulting in better coronavirus disease 2019 (COVID-19) diagnosis, treatment, and vaccine development.


Subject(s)
COVID-19 , Germinal Center , Immunity, Humoral , Reinfection/immunology , Animals , Antibodies, Viral , COVID-19/immunology , Humans , Lung/pathology , Lung/virology , Macaca , Seroconversion
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