scholarly journals Cellular and humoral immunity to SARS-CoV-2 infection in multiple sclerosis patients on ocrelizumab and other disease-modifying therapies: a multi-ethnic observational study

2022 ◽  
Author(s):  
Ilya Kister ◽  
Yury Patskovsky ◽  
Ryan Curtin ◽  
Jinglan Pei ◽  
Katherine Perdomo ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Humoral Immunity ◽  
T Cell Responses ◽  
Antibody Responses ◽  
Cell Responses ◽  
Disease Modifying Therapies ◽  
Disease Modifying ◽  
Cellular And Humoral Immunity ◽  
Multiple Sclerosis Patients

Objective: To determine the impact of MS disease-modifying therapies (DMTs) on the development of cellular and humoral immunity to SARS-CoV-2 infection. Methods: MS patients aged 18-60 were evaluated for anti-nucleocapsid and anti-Spike RBD antibody with electro-chemiluminescence immunoassay; antibody responses to Spike protein, RBD, N-terminal domain with multiepitope bead-based immunoassays (MBI); live virus immunofluorescence-based microneutralization assay; T-cell responses to SARS-CoV-2 Spike using TruCulture ELISA; and IL-2 and IFNγ ; ELISpot assays. Assay results were compared by DMT class. Spearman correlation and multivariate analyses were performed to examine associations between immunologic responses and infection severity. Results: Between 1/6/2021 and 7/21/2021, 389 MS patients were recruited (mean age 40.3 years; 74% female; 62% non-White). Most common DMTs were ocrelizumab (OCR) - 40%; natalizumab - 17%, Sphingosine 1-phosphate receptor (S1P) modulators -12%; and 15% untreated. 177 patients (46%) had laboratory evidence of SARS-CoV-2 infection; 130 had symptomatic infection, 47 - asymptomatic. Antibody responses were markedly attenuated in OCR compared to other groups (p≤0.0001). T-cell responses (IFNγ) were decreased in S1P (p=0.03), increased in natalizumab (p<0.001), and similar in other DMTs, including OCR. Cellular and humoral responses were moderately correlated in both OCR (r=0.45, p=0.0002) and non-OCR (r=0.64, p<0.0001). Immune responses did not differ by race/ethnicity. COVID-19 clinical course was mostly non-severe and similar across DMTs; 7% (9/130) were hospitalized. Interpretation: DMTs had differential effects on humoral and cellular immune responses to SARS-CoV-2 infection. Immune responses did not correlate with COVID-19 clinical severity in this relatively young and non-disabled group of MS patients.

scholarly journals Marburg virus survivor immune responses are Th1 skewed with limited neutralizing antibody responses

2017 ◽  
Vol 214 (9) ◽  
pp. 2563-2572 ◽  
Author(s):  
Spencer W. Stonier ◽  
Andrew S. Herbert ◽  
Ana I. Kuehne ◽  
Ariel Sobarzo ◽  
Polina Habibulin ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Ebola Virus ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Cd8 T Cell ◽  
Marburg Virus ◽  
Antibody Responses ◽  
Cd4 T Cell ◽  
Cell Responses

Until recently, immune responses in filovirus survivors remained poorly understood. Early studies revealed IgM and IgG responses to infection with various filoviruses, but recent outbreaks have greatly expanded our understanding of filovirus immune responses. Immune responses in survivors of Ebola virus (EBOV) and Sudan virus (SUDV) infections have provided the most insight, with T cell responses as well as detailed antibody responses having been characterized. Immune responses to Marburg virus (MARV), however, remain almost entirely uncharacterized. We report that immune responses in MARV survivors share characteristics with EBOV and SUDV infections but have some distinct differences. MARV survivors developed multivariate CD4+ T cell responses but limited CD8+ T cell responses, more in keeping with SUDV survivors than EBOV survivors. In stark contrast to SUDV survivors, rare neutralizing antibody responses in MARV survivors diminished rapidly after the outbreak. These results warrant serious consideration for any vaccine or therapeutic that seeks to be broadly protective, as different filoviruses may require different immune responses to achieve immunity.

scholarly journals Systems Vaccinology for a Live Attenuated Tularemia Vaccine Reveals Unique Transcriptional Signatures That Predict Humoral and Cellular Immune Responses

Vaccines ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 4 ◽  
Author(s):  
Muktha S. Natrajan ◽  
Nadine Rouphael ◽  
Lilin Lai ◽  
Dmitri Kazmin ◽  
Travis L. Jensen ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Innate Immune ◽  
Antibody Responses ◽  
Cytokine Signaling ◽  
Cell Responses ◽  
Viral Vaccine ◽  
Tularemia Vaccine

Background: Tularemia is a potential biological weapon due to its high infectivity and ease of dissemination. This study aimed to characterize the innate and adaptive responses induced by two different lots of a live attenuated tularemia vaccine and compare them to other well-characterized viral vaccine immune responses. Methods: Microarray analyses were performed on human peripheral blood mononuclear cells (PBMCs) to determine changes in transcriptional activity that correlated with changes detected by cellular phenotyping, cytokine signaling, and serological assays. Transcriptional profiles after tularemia vaccination were compared with yellow fever [YF-17D], inactivated [TIV], and live attenuated [LAIV] influenza. Results: Tularemia vaccine lots produced strong innate immune responses by Day 2 after vaccination, with an increase in monocytes, NK cells, and cytokine signaling. T cell responses peaked at Day 14. Changes in gene expression, including upregulation of STAT1, GBP1, and IFIT2, predicted tularemia-specific antibody responses. Changes in CCL20 expression positively correlated with peak CD8+ T cell responses, but negatively correlated with peak CD4+ T cell activation. Tularemia vaccines elicited gene expression signatures similar to other replicating vaccines, inducing early upregulation of interferon-inducible genes. Conclusions: A systems vaccinology approach identified that tularemia vaccines induce a strong innate immune response early after vaccination, similar to the response seen after well-studied viral vaccines, and produce unique transcriptional signatures that are strongly correlated to the induction of T cell and antibody responses.

scholarly journals Durability of immune responses to the BNT162b2 mRNA vaccine

2021 ◽  
Author(s):  
Mehul Suthar ◽  
Prabhu S Arunachalam ◽  
Mengyun Hu ◽  
Noah Reis ◽  
Meera Trisal ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Significant Proportion ◽  
T Cell Responses ◽  
Primary Vaccination ◽  
Antibody Responses ◽  
Booster Immunization ◽  
Cell Responses ◽  
Cell Immunity ◽  
Antibody Titers

The development of the highly efficacious mRNA vaccines in less than a year since the emergence of SARS-CoV-2 represents a landmark in vaccinology. However, reports of waning vaccine efficacy, coupled with the emergence of variants of concern that are resistant to antibody neutralization, have raised concerns about the potential lack of durability of immunity to vaccination. We recently reported findings from a comprehensive analysis of innate and adaptive immune responses in 56 healthy volunteers who received two doses of the BNT162b2 vaccination. Here, we analyzed antibody responses to the homologous Wu strain as well as several variants of concern, including the emerging Mu (B.1.621) variant, and T cell responses in a subset of these volunteers at six months (day 210 post-primary vaccination) after the second dose. Our data demonstrate a substantial waning of antibody responses and T cell immunity to SARS-CoV-2 and its variants, at 6 months following the second immunization with the BNT162b2 vaccine. Notably, a significant proportion of vaccinees have neutralizing titers below the detection limit, and suggest a 3rd booster immunization might be warranted to enhance the antibody titers and T cell responses.

scholarly journals Balance of cellular and humoral immunity determines the level of protection by HIV vaccines in rhesus macaque models of HIV infection

2015 ◽  
Vol 112 (9) ◽  
pp. E992-E999 ◽  
Author(s):  
Timothy R. Fouts ◽  
Kenneth Bagley ◽  
Ilia J. Prado ◽  
Kathryn L. Bobb ◽  
Jennifer A. Schwartz ◽  
...  
Keyword(s):  
T Cell ◽  
Rhesus Macaque ◽  
Humoral Immunity ◽  
T Cell Responses ◽  
Hiv Vaccine ◽  
Single Chain ◽  
Hiv Vaccines ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Cellular And Humoral Immunity

A guiding principle for HIV vaccine design has been that cellular and humoral immunity work together to provide the strongest degree of efficacy. However, three efficacy trials of Ad5-vectored HIV vaccines showed no protection. Transmission was increased in two of the trials, suggesting that this vaccine strategy elicited CD4+ T-cell responses that provide more targets for infection, attenuating protection or increasing transmission. The degree to which this problem extends to other HIV vaccine candidates is not known. Here, we show that a gp120-CD4 chimeric subunit protein vaccine (full-length single chain) elicits heterologous protection against simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) acquisition in three independent rhesus macaque repeated low-dose rectal challenge studies with SHIV162P3 or SIVmac251. Protection against acquisition was observed with multiple formulations and challenges. In each study, protection correlated with antibody-dependent cellular cytotoxicity specific for CD4-induced epitopes, provided that the concurrent antivaccine T-cell responses were minimal. Protection was lost in instances when T-cell responses were high or when the requisite antibody titers had declined. Our studies suggest that balance between a protective antibody response and antigen-specific T-cell activation is the critical element to vaccine-mediated protection against HIV. Achieving and sustaining such a balance, while enhancing antibody durability, is the major challenge for HIV vaccine development, regardless of the immunogen or vaccine formulation.

scholarly journals Deficient Resident Memory T Cell and CD8 T Cell Response to Commensals in Inflammatory Bowel Disease

2019 ◽  
Vol 14 (4) ◽  
pp. 525-537 ◽  
Author(s):  
Alistair Noble ◽  
Lydia Durant ◽  
Lesley Hoyles ◽  
Anne L Mccartney ◽  
Ripple Man ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Responses ◽  
Antibody Responses ◽  
Memory T Cell ◽  
Cell Responses ◽  
Inflammatory Bowel ◽  
Cellular And Humoral Immunity

Abstract Background and Aims The intestinal microbiota is closely associated with resident memory lymphocytes in mucosal tissue. We sought to understand how acquired cellular and humoral immunity to the microbiota differ in health versus inflammatory bowel disease [IBD]. Methods Resident memory T cells [Trm] in colonic biopsies and local antibody responses to intraepithelial microbes were analysed. Systemic antigen-specific immune T and B cell memory to a panel of commensal microbes was assessed. Results Systemically, healthy blood showed CD4 and occasional CD8 memory T cell responses to selected intestinal bacteria, but few memory B cell responses. In IBD, CD8 memory T cell responses decreased although B cell responses and circulating plasmablasts increased. Possibly secondary to loss of systemic CD8 T cell responses in IBD, dramatically reduced numbers of mucosal CD8+ Trm and γδ T cells were observed. IgA responses to intraepithelial bacteria were increased. Colonic Trm expressed CD39 and CD73 ectonucleotidases, characteristic of regulatory T cells. Cytokines/factors required for Trm differentiation were identified, and in vitro-generated Trm expressed regulatory T cell function via CD39. Cognate interaction between T cells and dendritic cells induced T-bet expression in dendritic cells, a key mechanism in regulating cell-mediated mucosal responses. Conclusions A previously unrecognised imbalance exists between cellular and humoral immunity to the microbiota in IBD, with loss of mucosal T cell-mediated barrier immunity and uncontrolled antibody responses. Regulatory function of Trm may explain their association with intestinal health. Promoting Trm and their interaction with dendritic cells, rather than immunosuppression, may reinforce tissue immunity, improve barrier function, and prevent B cell dysfunction in microbiota-associated disease and IBD aetiology.

scholarly journals Dose Effects of Recombinant Adenovirus Immunization in Rodents

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 144 ◽  
Author(s):  
Eric A. Weaver
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Recombinant Adenovirus ◽  
T Cell Responses ◽  
Antibody Responses ◽  
Vaccine Platform ◽  
Cell Responses ◽  
Immune Correlates ◽  
Cell Immunity ◽  
Dose Dependent

Recombinant adenovirus type 5 (rAd) has been used as a vaccine platform against many infectious diseases and has been shown to be an effective vaccine vector. The dose of the vaccine varies significantly from study to study, making it very difficult to compare immune responses and vaccine efficacy. This study determined the immune correlates induced by serial dilutions of rAd vaccines delivered intramuscularly (IM) and intranasally (IN) to mice and rats. When immunized IM, mice had substantially higher antibody responses at the higher vaccine doses, whereas, the IN immunized mice showed a lower response to the higher rAd vaccine doses. Rats did not show dose-dependent antibody responses to increasing vaccine doses. The IM immunized mice and rats also showed significant dose-dependent T cell responses to the rAd vaccine. However, the T cell immunity plateaued in both mice and rats at 109 and 1010 vp/animal, respectively. Additionally, the highest dose of vaccine in mice and rats did not improve the T cell responses. A final vaccine analysis using a lethal influenza virus challenge showed that despite the differences in the immune responses observed in the mice, the mice had very similar patterns of protection. This indicates that rAd vaccines induced dose-dependent immune responses, especially in IM immunized animals, and that immune correlates are not as predictive of protection as initially thought.

scholarly journals Heterogenous Cellular and Humoral Immune Trajectories after SARS-CoV-2 Infection: Compensatory Responses in a Population-Based Cohort

2021 ◽  
Author(s):  
Dominik Menges ◽  
Kyra D Zens ◽  
Tala Ballouz ◽  
Nicole Caduff ◽  
Daniel Llanas-Cornejo ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Disease Severity ◽  
Cell Subset ◽  
T Cell Responses ◽  
Population Based ◽  
Antibody Responses ◽  
Igg Antibody ◽  
Cell Responses ◽  
Over Time

To better understand the development of immunity against SARS-CoV-2 over time, we evaluated humoral and cellular responses a population-based cohort of SARS-CoV-2-infected individuals covering the full spectrum of COVID-19 up to 217 days after diagnosis. We characterized anti-Spike (S)-IgA and -IgG antibody responses in 431 individuals and found that about 85% develop and maintain anti-S-IgG responses over time. In a subsample of 64 participants selected for a detailed characterization of immune responses, we additionally evaluated anti-Nucleocapsid (N)-IgG antibodies and T cell responses specific to viral Membrane (M), N, and S proteins. Most participants had detectable T cell responses to at least one of the four peptide pools analyzed, which were more frequent than antibody seropositivity. We found a moderate correlation between antibody and T cell responses, which declined over time and suggests important variability in response patterns between individuals. The heterogeneity of immune trajectories was further analyzed using cluster analyses taking into account joint antibody and T cell responses over time. We identified five distinct immune trajectory patterns, which were characterized by specific antibody, T cell and T cell subset patterns along with disease severity and demographic factors. Higher age, male sex, higher disease severity and being a non-smoker was significantly associated with stronger immune responses. Overall, the results highlight that there is a consistent and maintained antibody response among most SARS-CoV-2-infected individuals, while T cell responses appear to be more heterogenous but potentially compensatory among those with low antibody responses.

scholarly journals Impact of multiple sclerosis disease-modifying therapies on SARS-CoV-2 vaccine-induced antibody and T cell immunity

2021 ◽  
Author(s):  
Joseph J. Sabatino ◽  
Kristen Mittl ◽  
William Rowles ◽  
Kira Mcpolin ◽  
Jayant V. Rajan ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
T Cell Responses ◽  
Effective Prevention ◽  
Cell Responses ◽  
Disease Modifying Therapies ◽  
Vaccination Recommendations ◽  
Specific Igg ◽  
Disease Modifying ◽  
Anti Cd20

AbstractVaccine-elicited adaptive immunity is an essential prerequisite for effective prevention and control of coronavirus 19 (COVID-19). Treatment of multiple sclerosis (MS) involves a diverse array of disease-modifying therapies (DMTs) that target antibody and cell-mediated immunity, yet a comprehensive understanding of how MS DMTs impact SARS-CoV-2 vaccine responses is lacking. We completed a detailed analysis of SARS-CoV-2 vaccine-elicited spike antigen-specific IgG and T cell responses in a cohort of healthy controls and MS participants in six different treatment categories. Two specific DMT types, sphingosine-1-phosphate (S1P) receptor modulators and anti-CD20 monoclonal antibodies (mAb), resulted in significantly reduced spike-specific IgG responses. Longer duration of anti-CD20 mAb treatment prior to SARS-CoV-2 vaccination were associated with absent antibody responses. Except for reduced CD4+ T cell responses in S1P-treated patients, spike-specific CD4+ and CD8+ T cell reactivity remained robust across all MS treatment types. These findings have important implications for clinical practice guidelines and vaccination recommendations in MS patients and other immunosuppressed populations.

The Immunomodulatory Role of Lenalidomide on Prevnar® Responses in Patients with Relapsed Multiple Myeloma: A Comprehensive Analysis of the Immune Response

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2772-2772 ◽  
Author(s):  
Kimberly Ann Noonan ◽  
Anna Ferguson ◽  
Carol A. Huff ◽  
Amy Emerling ◽  
Stephanie Mgebroff ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Antibody Responses ◽  
Cell Responses ◽  
Immune Enhancement

Abstract Aim: Pre-clinical data suggest that lenalidomide imparts an immunomodulatory effect. This clinical trial in relapsed myeloma patients examined the ability of lenalidomide to augment both endogenous as well as vaccine-specific immune responses in vivo. Methods: Relapsed, lenalidomide naïve, patients treated with 3 or less prior regimens were eligible for the study. Prevnar®, a pneumococcal vaccine, was given either before or during administration of lenalidomide in two cohorts of patients. Cohort A received their first vaccination prior to administration of drug, and the second vaccine on cycle 2, day 15 of lenalidomide. Cohort B were first vaccinated on cycle 2, day 15 and then cycle 4, day 15. Patients were treated with 25mg of lenalidomide daily days 1–21 every 28 days for 6 cycles. Pneumococcal serotype titres as well as CRM-197 T cell responses quantified the B and T cell responses, respectively, to Prevnar vaccination and were correlated with lenalidomide administration. Systemic immune responsiveness was determined by delayed type hypersensitivity (DTH) responses to Candida and tetanus and quantification of cytokines in the peripheral blood (PBL) serum and bone marrow (BM) plasma. Results: A median two-fold increase in antibody responses to Prevnar was observed in cohort B, whereas cohort A demonstrated an 80% decrease in antibody titres. Antibody responses in the bone marrow were more pronounced than in blood and were greatest in Cohort B. 1.8% of the total T cell population proliferated to CRM-197 in Cohort B vs. 0% in Cohort A. Increases in DTH responses were seen in 50% of patients post lenalidomide. Luminex was utilized to measure cytokine levels pre and post lenalidomide. Globally, IL-6 levels were greatly reduced in both the BM (88% reduction) and PBL (77% reduction) samples. Both IFNγ and IL-17 were undetectable in the PBL samples, but were elevated and unchanged respectively in BM samples. Levels of IL-10 peaked in both cohorts after the first vaccination but were ultimately reduced with the administration of lenalidomide, and overall the levels were higher in the BM than PBL samples. MCP-1 and MIP-1β levels showed an overall decrease over the course of the trial. There was no alteration of IL2, IL-4, IL-5, TNFα, IL-7, IL-1 β, IL-12, IL-13, G-CSF or GM-CSF levels with the administration of lenalidomide. Conclusions: This is the first comprehensive examination of the immunomodulatory effect of lenalidomide on global and vaccine specific in vivo immune responses. We show that the most potent immune response was observed when both prime and boost vaccines were administered while receiving lenalidomide. Immune enhancement by lenalidomide was seen in both the blood and BM compartments. Of note, the serologic titres were greater in the BM than blood and the T cell responses (when observed) appeared greater in the BM. These data provide evidence of the important role of bone marrow niche in the maintenance of immune memory responses. The increased DTH response to both Candida and tetanus provides in vivo evidence of lenalidomide-mediated immune enhancement. Taken together, these data demonstrate that lenalidomide augments in vivo immune responses in patients with advanced/relapsed multiple myeloma. This study provides the rationale for utilizing this drug in combination with cancer vaccines to augment anti-tumor efficacy or with infectious vaccines. Figure Figure

scholarly journals Fusion-Expressed CTB Improves Both Systemic and Mucosal T-Cell Responses Elicited by an Intranasal DNA Priming/Intramuscular Recombinant Vaccinia Boosting Regimen

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Sugan Qiu ◽  
Xiaonan Ren ◽  
Yinyin Ben ◽  
Yanqin Ren ◽  
Jing Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Female Genital Tract ◽  
T Cell Responses ◽  
Antibody Responses ◽  
Cell Responses ◽  
Cholera Toxin Subunit B ◽  
Subunit B ◽  
Fusion Antigen ◽  
Female Genital

Previous study showed that CTB (Cholera toxin subunit B) can be used as a genetic adjuvant to enhance the systemic immune responses. To further investigate whether it can also be used as a genetic adjuvant to improve mucosal immune responses, we constructed DNA and recombinant Tiantan vaccinia (rTTV) vaccines expressing OVA-CTB fusion antigen. Female C57BL/6 mice were immunized with an intranasal DNA priming/intramuscular rTTV boosting regimen. OVA specific T-cell responses were measured by IFN-γELISPOT and specific antibody responses were determined by ELISA. Compared to the nonadjuvant group (pSV-OVA intranasal priming/rTTV-OVA intramuscular boosting), pSV-OVA-CTB intranasal priming/rTTV-OVA-CTB intramuscular boosting group significantly improved the magnitudes of T-cell responses at spleen (1562±567SFCs/106splenocytes versus330±182SFCs/106splenocytes,P<0.01), mesenteric LN (96±83SFCs/106lymphocytes versus1±2SFCs/106lymphocytes,P<0.05), draining LNs of respiratory tract (109±60SFCs/106lymphocytes versus2±2SFCs/106lymphocytes,P<0.01) and female genital tract (89±48SFCs/106lymphocytes versus23±21SFCs/106lymphocytes,P<0.01). These results collectively demonstrated that fusion-expressed CTB could act as a potent adjuvant to improve both systemic and mucosal T-cell responses.

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