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1.
Front Immunol ; 13: 876306, 2022.
Article in English | MEDLINE | ID: covidwho-1865451

ABSTRACT

The COVID-19 pandemic shows that vaccination strategies building on an ancestral viral strain need to be optimized for the control of potentially emerging viral variants. Therefore, aiming at strong B cell somatic hypermutation to increase antibody affinity to the ancestral strain - not only at high antibody titers - is a priority when utilizing vaccines that are not targeted at individual variants since high affinity may offer some flexibility to compensate for strain-individual mutations. Here, we developed a next-generation sequencing based SARS-CoV-2 B cell tracking protocol to rapidly determine the level of immunoglobulin somatic hypermutation at distinct points during the immunization period. The percentage of somatically hypermutated B cells in the SARS-CoV-2 specific repertoire was low after the primary vaccination series, evolved further over months and increased steeply after boosting. The third vaccination mobilized not only naïve, but also antigen-experienced B cell clones into further rapid somatic hypermutation trajectories indicating increased affinity. Together, the strongly mutated post-booster repertoires and antibodies deriving from this may explain why the third, but not the primary vaccination series, offers some protection against immune-escape variants such as Omicron B.1.1.529.


Subject(s)
B-Lymphocytes , COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , COVID-19/prevention & control , COVID-19 Vaccines/immunology , COVID-19 Vaccines/metabolism , Humans , Pandemics , SARS-CoV-2/genetics , Vaccination/methods , /immunology
2.
Immunity ; 55(5): 781-799, 2022 05 10.
Article in English | MEDLINE | ID: covidwho-1838898

ABSTRACT

Neuroanatomical barriers with physical, chemical, and immunological properties play an essential role in preventing the spread of peripheral infections into the CNS. A failure to contain pathogens within these barriers can result in very serious CNS diseases. CNS barriers are inhabited by an elaborate conglomerate of innate and adaptive immune cells that are highly responsive to environmental challenges. The CNS and its barriers can also be protected by memory T and B cells elicited by prior infection or vaccination. Here, we discuss the different CNS barriers from a developmental, anatomical, and immunological standpoint and summarize our current understanding of how memory cells protect the CNS compartment. We then discuss a contemporary challenge to CNS-barrier system (SARS-CoV-2 infection) and highlight approaches to promote immunological protection of the CNS via vaccination.


Subject(s)
COVID-19 , SARS-CoV-2 , B-Lymphocytes , Humans , Vaccination
3.
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)
B-Lymphocytes , Germinal Center , Lymph Nodes
4.
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
5.
Immunol Cell Biol ; 100(5): 308-311, 2022 05.
Article in English | MEDLINE | ID: covidwho-1807103

ABSTRACT

It is vitally important that we understand whether mRNA vaccines are capable of generating high-affinity, longlived immune memory cells to SARS-CoV-2. To this end, a recent study by Ellebedy, Kim and colleagues provide much-needed insight into the production and quality of humoral immune cells generated by the BNT162b2 vaccine.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , B-Lymphocytes , COVID-19 Vaccines , Humans
6.
Cytometry A ; 101(6): 474-482, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1802168

ABSTRACT

Conventional methods for quantifying and phenotyping antigen-specific lymphocytes can rapidly deplete irreplaceable specimens. This is due to the fact that antigen-specific T and B cells have historically been analyzed in independent assays each requiring millions of cells. A technique that facilitates the simultaneous detection of antigen-specific T and B cells would allow for more thorough immune profiling with significantly reduced sample requirements. To this end, we developed the B and T cell tandem lymphocyte evaluation (BATTLE) assay, which allows for the simultaneous identification of SARS-CoV-2 Spike reactive T and B cells using an activation induced marker (AIM) T cell assay and dual-color B cell antigen probes. Using this assay, we demonstrate that antigen-specific B and T cell subsets can be identified simultaneously using conventional flow cytometry platforms and provide insight into the differential effects of mRNA vaccination on B and T cell populations following natural SARS-CoV-2 infection.


Subject(s)
COVID-19 , B-Lymphocytes , Humans , SARS-CoV-2 , T-Lymphocytes , Vaccination
7.
J Exp Med ; 219(6)2022 06 06.
Article in English | MEDLINE | ID: covidwho-1788448

ABSTRACT

Severe SARS-CoV-2 infection is associated with strong inflammation and autoantibody production against diverse self-antigens, suggesting a system-wide defect in B cell tolerance. BND cells are a B cell subset in healthy individuals harboring autoreactive but anergic B lymphocytes. In vitro evidence suggests inflammatory stimuli can breach peripheral B cell tolerance in this subset. We asked whether SARS-CoV-2-associated inflammation impairs BND cell peripheral tolerance. To address this, PBMCs and plasma were collected from healthy controls, individuals immunized against SARS-CoV-2, or subjects with convalescent or severe SARS-CoV-2 infection. We demonstrate that BND cells from severely infected individuals are significantly activated, display reduced inhibitory receptor expression, and restored BCR signaling, indicative of a breach in anergy during viral infection, supported by increased levels of autoreactive antibodies. The phenotypic and functional BND cell alterations significantly correlate with increased inflammation in severe SARS-CoV-2 infection. Thus, autoreactive BND cells are released from peripheral tolerance with SARS-CoV-2 infection, likely as a consequence of robust systemic inflammation.


Subject(s)
COVID-19 , Peripheral Tolerance , Antibodies, Viral , B-Lymphocytes , Humans , Inflammation/metabolism , SARS-CoV-2
8.
Trends Immunol ; 43(5): 343-354, 2022 05.
Article in English | MEDLINE | ID: covidwho-1773408

ABSTRACT

The overarching logos of mammalian memory B cells (MBCs) is to cache the potential for enhanced antibody production upon secondary exposure to cognate antigenic determinants. However, substantial phenotypic diversity has been identified across MBCs, hinting at the existence of unique origins or subfunctions within this compartment. Herein, we discuss recent advancements in human circulatory MBC subphenotyping as driven by high-throughput cell surface marker analysis and other approaches, as well as speculated and substantiated subfunctions. With this in mind, we hypothesize that the relative induction of specific circulatory MBC subsets might be used as a biomarker for optimally durable vaccines and inform vaccination strategies to subvert antigenic imprinting in the context of highly mutable pathogens such as influenza virus or SARS-CoV-2.


Subject(s)
COVID-19 , Vaccines , Animals , Antibodies, Viral , B-Lymphocytes , Humans , Immunologic Memory , Mammals , SARS-CoV-2 , Vaccination
9.
Immunity ; 55(3): 542-556.e5, 2022 03 08.
Article in English | MEDLINE | ID: covidwho-1768197

ABSTRACT

Some patients hospitalized with acute COVID-19 suffer respiratory symptoms that persist for many months. We delineated the immune-proteomic landscape in the airways and peripheral blood of healthy controls and post-COVID-19 patients 3 to 6 months after hospital discharge. Post-COVID-19 patients showed abnormal airway (but not plasma) proteomes, with an elevated concentration of proteins associated with apoptosis, tissue repair, and epithelial injury versus healthy individuals. Increased numbers of cytotoxic lymphocytes were observed in individuals with greater airway dysfunction, while increased B cell numbers and altered monocyte subsets were associated with more widespread lung abnormalities. A one-year follow-up of some post-COVID-19 patients indicated that these abnormalities resolved over time. In summary, COVID-19 causes a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to the ongoing activation of cytotoxic T cells.


Subject(s)
B-Lymphocytes/immunology , COVID-19/immunology , Monocytes/immunology , Respiration Disorders/immunology , Respiratory System/immunology , SARS-CoV-2/physiology , T-Lymphocytes, Cytotoxic/immunology , Adult , Aged , COVID-19/complications , Female , Follow-Up Studies , Humans , Immunity, Cellular , Immunoproteins , Male , Middle Aged , Proteome , Respiration Disorders/etiology , Respiratory System/pathology
10.
Hum Vaccin Immunother ; 18(5): 2048622, 2022 Nov 30.
Article in English | MEDLINE | ID: covidwho-1764459

ABSTRACT

We report a Human Immune System (HIS)-humanized mouse model ("DRAGA": HLA-A2.HLA-DR4.Rag1KO.IL-2 RγcKO.NOD) for COVID-19 research. DRAGA mice express transgenically HLA-class I and class-II molecules in the mouse thymus to promote human T cell development and human B cell Ig-class switching. When infused with human hematopoietic stem cells from cord blood reconstitute a functional human immune system, as well as human epi/endothelial cells in lung and upper respiratory airways expressing the human ACE2 receptor for SARS-CoV-2. The DRAGA mice were able to sustain SARS-CoV-2 infection for at least 25 days. Infected mice showed replicating virus in the lungs, deteriorating clinical condition, and human-like lung immunopathology including human lymphocyte infiltrates, microthrombi and pulmonary sequelae. Among the intra-alveolar and peri-bronchiolar lymphocyte infiltrates, human lung-resident (CD103+) CD8+ and CD4+ T cells were sequestered in epithelial (CD326+) lung niches and secreted granzyme B and perforin, suggesting anti-viral cytotoxic activity. Infected mice also mounted human IgG antibody responses to SARS-CoV-2 viral proteins. Hence, HIS-DRAGA mice showed unique advantages as a surrogate in vivo human model for studying SARS-CoV-2 immunopathological mechanisms and testing the safety and efficacy of candidate vaccines and therapeutics.


Subject(s)
COVID-19 , HLA-DR4 Antigen , Animals , B-Lymphocytes , CD8-Positive T-Lymphocytes , Disease Models, Animal , Endothelial Cells , HLA-A2 Antigen/genetics , Humans , Mice , Mice, Inbred NOD , Mice, Transgenic , SARS-CoV-2
11.
J Immunol ; 208(7): 1711-1718, 2022 04 01.
Article in English | MEDLINE | ID: covidwho-1760900

ABSTRACT

COVID-19 has had an unprecedented global impact on human health. Understanding the Ab memory responses to infection is one tool needed to effectively control the pandemic. Among 173 outpatients who had virologically confirmed SARS-CoV-2 infection, we evaluated serum Ab concentrations, microneutralization activity, and enumerated SARS-CoV-2-specific B cells in convalescent human blood specimens. Serum Ab concentrations were variable, allowing for stratification of the cohort into high and low responders. Neither participant sex, the timing of blood sampling following the onset of illness, nor the number of SARS-CoV-2 spike protein-specific B cells correlated with serum Ab concentration. Serum Ab concentration was positively associated with microneutralization activity and participant age, with participants under the age of 30 showing the lowest Ab level. These data suggest that young adult outpatients did not generate as robust Ab memory, compared with older adults. Body mass index was also positively correlated with serum Ab levels. Multivariate analyses showed that participant age and body mass index were independently associated with Ab levels. These findings have direct implications for public health policy and current vaccine efforts. Knowledge gained regarding Ab memory following infection will inform the need for vaccination in those previously infected and allow for a better approximation of population-wide protective immunity.


Subject(s)
Age Factors , Antibody Formation , Body Mass Index , COVID-19 , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , B-Lymphocytes/immunology , COVID-19/immunology , Humans , Outpatients , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology
12.
J Virol ; 96(4): e0160021, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1759291

ABSTRACT

A comprehensive study of the B cell response against SARS-CoV-2 could be significant for understanding the immune response and developing therapeutical antibodies and vaccines. To define the dynamics and characteristics of the antibody repertoire following SARS-CoV-2 infection, we analyzed the mRNA transcripts of immunoglobulin heavy chain (IgH) repertoires of 24 peripheral blood samples collected between 3 and 111 days after symptom onset from 10 COVID-19 patients. Massive clonal expansion of naive B cells with limited somatic hypermutation (SHM) was observed in the second week after symptom onset. The proportion of low-SHM IgG clones strongly correlated with spike-specific IgG antibody titers, highlighting the significant activation of naive B cells in response to a novel virus infection. The antibody isotype switching landscape showed a transient IgA surge in the first week after symptom onset, followed by a sustained IgG elevation that lasted for at least 3 months. SARS-CoV-2 infection elicited poly-germ line reactive antibody responses. Interestingly, 17 different IGHV germ line genes recombined with IGHJ6 showed significant clonal expansion. By comparing the IgH repertoires that we sequenced with the 774 reported SARS-CoV-2-reactive monoclonal antibodies (MAbs), 13 shared spike-specific IgH clusters were found. These shared spike-specific IgH clusters are derived from the same lineage of several recently published neutralizing MAbs, including CC12.1, CC12.3, C102, REGN10977, and 4A8. Furthermore, identical spike-specific IgH sequences were found in different COVID-19 patients, suggesting a highly convergent antibody response to SARS-CoV-2. Our analysis based on sequencing antibody repertoires from different individuals revealed key signatures of the systemic B cell response induced by SARS-CoV-2 infection. IMPORTANCE Although the canonical delineation of serum antibody responses following SARS-CoV-2 infection has been well established, the dynamics of antibody repertoire at the mRNA transcriptional level has not been well understood, especially the correlation between serum antibody titers and the antibody mRNA transcripts. In this study, we analyzed the IgH transcripts and characterized the B cell clonal expansion and differentiation, isotype switching, and somatic hypermutation in COVID-19 patients. This study provided insights at the repertoire level for the B cell response after SARS-CoV-2 infection.


Subject(s)
Antibodies, Neutralizing/genetics , Antibodies, Viral/genetics , B-Lymphocytes/immunology , COVID-19/genetics , Immunoglobulin G/genetics , Receptors, Antigen, B-Cell/genetics , SARS-CoV-2/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Humans , Immunoglobulin G/immunology , Receptors, Antigen, B-Cell/immunology
13.
Signal Transduct Target Ther ; 7(1): 61, 2022 02 25.
Article in English | MEDLINE | ID: covidwho-1758178

ABSTRACT

Variants are globally emerging very quickly following pandemic prototypic SARS-CoV-2. To evaluate the cross-protection of prototypic SARS-CoV-2 vaccine against its variants, we vaccinated rhesus monkeys with three doses of prototypic SARS-CoV-2 inactivated vaccine, followed by challenging with emerging SARS-CoV-2 variants of concern (VOCs). These vaccinated animals produced neutralizing antibodies against Alpha, Beta, Delta, and Omicron variants, although there were certain declinations of geometric mean titer (GMT) as compared with prototypic SARS-CoV-2. Of note, in vivo this prototypic vaccine not only reduced the viral loads in nasal, throat and anal swabs, pulmonary tissues, but also improved the pathological changes in the lung infected by variants of Alpha, Beta, and Delta. In summary, the prototypic SARS-CoV-2 inactivated vaccine in this study protected against VOCs to certain extension, which is of great significance for prevention and control of COVID-19.


Subject(s)
Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Cross Protection , SARS-CoV-2/drug effects , Vaccination/methods , Vaccines, Inactivated/administration & dosage , Anal Canal/virology , Animals , B-Lymphocytes/immunology , B-Lymphocytes/virology , COVID-19/immunology , COVID-19/virology , Humans , Immunogenicity, Vaccine , Lung/virology , Macaca mulatta , Male , Nasal Cavity/virology , Pharynx/virology , SARS-CoV-2/growth & development , SARS-CoV-2/pathogenicity , T-Lymphocytes/immunology , T-Lymphocytes/virology , Viral Load/drug effects
14.
Viruses ; 14(3)2022 03 21.
Article in English | MEDLINE | ID: covidwho-1753691

ABSTRACT

BACKGROUND: T and B cell-mediated immunity can be assessed using T cell receptor excision circle (TREC) and Kappa-deleting recombination excision circle (KREC) analysis, respectively, and successful implementation of this method requires evaluation of the correlation between the TREC frequencies and T cell subsets as well as KREC levels and B lymphocyte subsets. The aim of the present study was to evaluate the correlation between the TREC/KREC concentrations and T/B lymphocyte subsets at different stages of COVID-19. METHODS: We examined 33 patients in the acute stage of COVID-19 (including 8 patients with poor outcomes) and 33 COVID-19 survivors. TREC/KREC concentrations were measured using quantitative real-time PCR. T/B lymphocyte subsets were determined using flow cytometry. RESULTS: Blood TREC and KREC levels were found to be significantly lower in the acute stage of COVID-19 compared to control values. Moreover, a zero blood TREC level was a predictor of a poor disease outcome. Reductions in CD3+CD4+CD45RO-CD62L- and CD3+CD8+CD45RO-CD62L- T cell counts (as well as in the main fractions of B1 and B2 B cells) indicated a favorable outcome in COVID-19 patients in the acute stage of the disease. Decreased CD3+CD4+CD45RO-CD62L+ and CD3+CD8+CD45RO-CD62L+ T cell frequencies and increased CD3+CD8+CD45RO-CD62L- cell counts were found to indicate a poor outcome in patients with acute COVID-19. These patients were also found to have increased B1 cell counts while demonstrating no changes in B2 cell counts. The levels of effector T cell subsets an naïve B cells were normal in COVID-19 survivors. The most pronounced correlations between TREC/KREC levels and T/B cell subsets counts were observed in COVID-19 survivors: there were positive correlations with naïve T and B lymphocytes and negative correlations with central and effector memory T cell subsets. CONCLUSIONS: The assessment of correlations between TREC and T cell subsets as well as KREC levels and B cell subset counts in patients with acute COVID-19 and COVID-19 survivors has shown that blood concentrations of TREC and KREC are sensitive indicators of the stage of antigen-independent differentiation of adaptive immunity cells. The results of the TREC and KREC analysis correlated with the stages of COVID-19 and differed depending on the outcome of COVID-19.


Subject(s)
B-Lymphocyte Subsets , COVID-19 , B-Lymphocytes , DNA , Humans , Receptors, Antigen, T-Cell
15.
Cell Rep Med ; 3(2): 100523, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1751231

ABSTRACT

To understand the determinants of long-term immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the concurrent impact of vaccination and emerging variants, we follow a prospective cohort of 332 patients with coronavirus disease 2019 (COVID-19) over more than a year after symptom onset. We evaluate plasma-neutralizing activity using HIV-based pseudoviruses expressing the spike of different SARS-CoV-2 variants and analyze them longitudinally using mixed-effects models. Long-term neutralizing activity is stable beyond 1 year after infection in mild/asymptomatic and hospitalized participants. However, longitudinal models suggest that hospitalized individuals generate both short- and long-lived memory B cells, while the responses of non-hospitalized individuals are dominated by long-lived B cells. In both groups, vaccination boosts responses to natural infection. Long-term (>300 days from infection) responses in unvaccinated participants show a reduced efficacy against beta, but not alpha nor delta, variants. Multivariate analysis identifies the severity of primary infection as an independent determinant of higher magnitude and lower relative cross-neutralization activity of long-term neutralizing responses.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Severity of Illness Index , Adult , Aged , B-Lymphocytes/immunology , COVID-19/blood , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/therapeutic use , Female , Follow-Up Studies , Humans , Immunologic Memory , Kinetics , Longitudinal Studies , Male , Middle Aged , Prospective Studies , Spike Glycoprotein, Coronavirus/immunology , Treatment Outcome , Vaccination/methods , Young Adult
16.
Trends Biotechnol ; 40(4): 463-481, 2022 04.
Article in English | MEDLINE | ID: covidwho-1735006

ABSTRACT

Humoral immunity is divided into the cellular B cell and protein-level antibody responses. High-throughput sequencing has advanced our understanding of both these fundamental aspects of B cell immunology as well as aspects pertaining to vaccine and therapeutics biotechnology. Although the protein-level serum and mucosal antibody repertoire make major contributions to humoral protection, the sequence composition and dynamics of antibody repertoires remain underexplored. This limits insight into important immunological and biotechnological parameters such as the number of antigen-specific antibodies, which are for example, relevant for pathogen neutralization, microbiota regulation, severity of autoimmunity, and therapeutic efficacy. High-resolution mass spectrometry (MS) has allowed initial insights into the antibody repertoire. We outline current challenges in MS-based sequence analysis of antibody repertoires and propose strategies for their resolution.


Subject(s)
Antibodies , High-Throughput Nucleotide Sequencing , Antibodies/chemistry , Antigens , B-Lymphocytes , High-Throughput Nucleotide Sequencing/methods , Mass Spectrometry
17.
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
18.
Front Immunol ; 13: 827889, 2022.
Article in English | MEDLINE | ID: covidwho-1731779

ABSTRACT

It is well established that pregnancy induces deep changes in the immune system. This is part of the physiological adaptation of the female organism to the pregnancy and the immunological tolerance toward the fetus. Indeed, over the three trimesters, the suppressive T regulatory lymphocytes are progressively more represented, while the expression of co-stimulatory molecules decreases overtime. Such adaptations relate to an increased risk of infections and progression to severe disease in pregnant women, potentially resulting in an altered generation of long-lived specific immunological memory of infection contracted during pregnancy. How potent is the immune response against SARS-CoV-2 in infected pregnant women and how long the specific SARS-CoV-2 immunity might last need to be urgently addressed, especially considering the current vaccinal campaign. To address these questions, we analyzed the long-term immunological response upon SARS-CoV-2 infection in pregnant women from delivery to a six-months follow-up. In particular, we investigated the specific antibody production, T cell memory subsets, and inflammation profile. Results show that 80% developed an anti-SARS-CoV-2-specific IgG response, comparable with the general population. While IgG were present only in 50% of the asymptomatic subjects, the antibody production was elicited by infection in all the mild-to-critical patients. The specific T-cell memory subsets rebalanced over-time, and the pro-inflammatory profile triggered by specific SARS-CoV-2 stimulation faded away. These results shed light on SARS-CoV-2-specific immunity in pregnant women; understanding the immunological dynamics of the immune system in response to SARS-CoV-2 is essential for defining proper obstetric management of pregnant women and fine tune gender-specific vaccinal plans.


Subject(s)
COVID-19/immunology , Immunologic Memory/immunology , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/virology , SARS-CoV-2/immunology , Adult , Animals , Antibodies, Viral/immunology , Antibody Formation/immunology , B-Lymphocytes/immunology , Cell Line , Chlorocebus aethiops , Female , Humans , Pregnancy , Pregnant Women , Prospective Studies , Spike Glycoprotein, Coronavirus/immunology , Vero Cells , Young Adult
19.
J Immunother Cancer ; 10(3)2022 03.
Article in English | MEDLINE | ID: covidwho-1731296

ABSTRACT

Vaccination against COVID-19 is critical for immuno-compromised individuals, including patients with cancer. Systemic reactogenicity, a manifestation of the innate immune response to vaccines, occurs in up to 69% of patients following vaccination with RNA-based COVID-19 vaccines. Tumor regression can occur following an intense immune-inflammatory response and novel strategies to treat cancer rely on manipulating the host immune system. Here, we report spontaneous regression of metastatic salivary gland myoepithelial carcinoma in a patient who experienced grade 3 systemic reactogenicity, following vaccination with the mRNA-1273 COVID-19 vaccine. Histological and immunophenotypic inspection of the postvaccination lung biopsy specimens showed a massive inflammatory infiltrate with scant embedded tumor clusters (<5%). Highly multiplexed imaging mass cytometry showed that the postvaccination lung metastasis samples had remarkable immune cell infiltration, including CD4+ T cells, CD8+ T cells, natural killer cells, B cells, and dendritic cells, which contrasted with very low levels of these cells in the prevaccination primary tumor and lung metastasis samples. CT scans obtained 3, 6, and 9 months after the second vaccine dose demonstrated persistent tumor shrinkage (50%, 67%, and 73% reduction, respectively), suggesting that vaccination stimulated anticancer immunity. Insight: This case suggests that the mRNA-1273 COVID-19 vaccine stimulated anticancer immunity and tumor regression.


Subject(s)
Immunity, Innate , Immunogenicity, Vaccine , Lung Neoplasms/immunology , Myoepithelioma/immunology , Parotid Neoplasms/surgery , B-Lymphocytes , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Female , Humans , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/secondary , Middle Aged , Myoepithelioma/diagnostic imaging , Myoepithelioma/secondary , Parotid Neoplasms/pathology
20.
Front Immunol ; 13: 798813, 2022.
Article in English | MEDLINE | ID: covidwho-1725390

ABSTRACT

A successful vaccination would represent the most efficient means to control the pandemic of Coronavirus Disease-19 (COVID-19) that led to millions of deaths worldwide. Novel mRNA-based vaccines confer protective immunity against SARS-CoV-2, but whether immunity is immediately effective and how long it will remain in recipients are uncertain. We sought to assess the effectiveness of a two-dose regimen since the boosts are often delayed concerning the recommended intervals. Methods: A longitudinal cohort of healthcare workers (HCW, N = 46; 30.4% men; 69.6% women; mean age 36.05 ± 2.2 years) with no SARS-CoV-2 infection as documented by negative polymerase chain reaction was immunophenotyped in PBMC once a week for 4 weeks from the prime immunization (Pfizer mRNA BNT162b2) and had received 2 doses, to study the kinetic response. Results: We identified three risk groups to develop SARS-CoV-2 infection IgG+-based (late responders, R-; early responders, R+; pauci responders, PR). In all receipts, amplification of B cells and NK cells, including IL4-producing B cells and IL4-producing CD8+ T cells, is early stimulated by the vaccine. After the boost, we observed a growing increase of NK cells but a resistance of T cells, IFNγ-producing CD4+T cells, and IFNγ-producing NK cells. Also, hematologic parameters decline until the boost. The positive association of IFNγ-producing NK with IFNγ-producing CD4+T cells by the multiple mixed-effect model, adjusted for confounders (p = 0.036) as well as the correlation matrix (r = 0.6, p < 0.01), suggests a relationship between these two subsets of lymphocytes. Conclusions: These findings introduce several concerns about policy delay in vaccination: based on immunological protection, B cells and the persistent increase of NK cells during 2 doses of the mRNA-based vaccine could provide further immune protection against the virus, while CD8+ T cells increased slightly only in the R+ and PR groups.


Subject(s)
/immunology , Immunization , Interferon-gamma/immunology , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adult , B-Lymphocytes/immunology , COVID-19/immunology , COVID-19/prevention & control , Female , Humans , Interleukin-4/immunology , Leukocytes, Mononuclear/immunology , Lymphocyte Subsets/immunology , Male , Th1-Th2 Balance
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