Weak immunogenicity of SARS-CoV-2 vaccine in patients with hematologic malignancies

AbstractThis study evaluated the safety and immunogenicity of BNT162b2 vaccine in patients with hematological malignancies. Antibodies blocking spike binding to immobilized ACE-2 (NAb) correlated with anti-Spike (S) IgG d42 titers (Spearman r = 0.865, p < 0.0001), and an anti-S IgG d42 level ≥3100 UA/mL was predictive of NAb ≥ 30%, the positivity cutoff for NAb (p < 0.0001). Only 47% of the patients achieved an anti-S IgG d42 level ≥3100 UA/mL after the two BNT162b2 inocula, compared to 87% of healthy controls. In multivariable analysis, male patients, use of B-cell targeting treatment within the last 12 months prior to vaccination, and CD19+ B-cell level <120/uL, were associated with a significantly decreased probability of achieving a protective anti-S IgG level after the second BNT162b2 inoculum. Finally, using the IFN-γ ELISPOT assay, we found a significant increase in T-cell response against the S protein, with 53% of patients having an anti-S IgG-positive ELISPOT after the second BNT162b2 inoculum. There was a correlation between the anti-S ELISPOT response and IgG d42 level (Spearman r = 0.3026, p = 0.012). These findings suggest that vaccination with two BNT162b2 inocula translates into a significant increase in humoral and cellular response in patients with hematological malignancies, but only around half of the patients can likely achieve effective immune protection against COVID-19.

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Long-term patterns of humoral and cellular response after vaccination against influenza A (H1N1) in patients with hematologic malignancies

European Journal Of Haematology ◽

10.1111/j.1600-0609.2012.01793.x ◽

2012 ◽

Vol 89 (2) ◽

pp. 111-119 ◽

Cited By ~ 4

Author(s):

Jacopo Mariotti ◽

Francesco Spina ◽

Cristiana Carniti ◽

Giovanni Anselmi ◽

Davide Lucini ◽

...

Keyword(s):

Influenza A ◽

Cellular Response ◽

Hematologic Malignancies ◽

Influenza A H1n1 ◽

Humoral And Cellular Response

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Safety Profile of a Virus-Like Particle-Based Vaccine Targeting Self-Protein Interleukin-5 in Horses

Vaccines ◽

10.3390/vaccines8020213 ◽

2020 ◽

Vol 8 (2) ◽

pp. 213 ◽

Cited By ~ 4

Author(s):

Sigridur Jonsdottir ◽

Victoria Fettelschoss ◽

Florian Olomski ◽

Stephanie C. Talker ◽

Jelena Mirkovitch ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Mononuclear Cells ◽

Clinical Signs ◽

T Cell Response ◽

Type I ◽

Cell Responses ◽

Virus Like Particle ◽

Ifn Γ

Background: Insect bite hypersensitivity (IBH) is an eosinophilic allergic dermatitis of horses caused by type I/IVb reactions against mainly Culicoides bites. The vaccination of IBH-affected horses with equine IL-5 coupled to the Cucumber mosaic virus-like particle (eIL-5-CuMVTT) induces IL-5-specific auto-antibodies, resulting in a significant reduction in eosinophil levels in blood and clinical signs. Objective: the preclinical and clinical safety of the eIL-5-CuMVTT vaccine. Methods: The B cell responses were assessed by longitudinal measurement of IL-5- and CuMVTT-specific IgG in the serum and plasma of vaccinated and unvaccinated horses. Further, peripheral blood mononuclear cells (PBMCs) from the same horses were re-stimulated in vitro for the proliferation and IFN-γ production of specific T cells. In addition, we evaluated longitudinal kidney and liver parameters and the general blood status. An endogenous protein challenge was performed in murine IL-5-vaccinated mice. Results: The vaccine was well tolerated as assessed by serum and cellular biomarkers and also induced reversible and neutralizing antibody titers in horses and mice. Endogenous IL-5 stimulation was unable to re-induce anti-IL-5 production. The CD4+ T cells of vaccinated horses produced significantly more IFN-γ and showed a stronger proliferation following stimulation with CuMVTT as compared to the unvaccinated controls. Re-stimulation using E. coli-derived proteins induced low levels of IFNγ+CD4+ cells in vaccinated horses; however, no IFN-γ and proliferation were induced following the HEK-eIL-5 re-stimulation. Conclusions: Vaccination using eIL-5-CuMVTT induces a strong B-cell as well as CuMVTT-specific T cell response without the induction of IL-5-specific T cell responses. Hence, B-cell unresponsiveness against self-IL-5 can be bypassed by inducing CuMVTT carrier-specific T cells, making the vaccine a safe therapeutic option for IBH-affected horses.

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The CD8+ T-Cell Response to Lymphocytic Choriomeningitis Virus Involves the L Antigen: Uncovering New Tricks for an Old Virus

Journal of Virology ◽

10.1128/jvi.02632-06 ◽

2007 ◽

Vol 81 (10) ◽

pp. 4928-4940 ◽

Cited By ~ 74

Author(s):

Maya F. Kotturi ◽

Bjoern Peters ◽

Fernando Buendia-Laysa ◽

John Sidney ◽

Carla Oseroff ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Response ◽

Cellular Response ◽

Lymphocytic Choriomeningitis ◽

Lymphocytic Choriomeningitis Virus ◽

T Cell Response ◽

Ifn Γ ◽

Lcmv Infection

ABSTRACT CD8+ T-cell responses control lymphocytic choriomeningitis virus (LCMV) infection in H-2b mice. Although antigen-specific responses against LCMV infection are well studied, we found that a significant fraction of the CD8+ CD44hi T-cell response to LCMV in H-2b mice was not accounted for by known epitopes. We screened peptides predicted to bind major histocompatibility complex class I and overlapping 15-mer peptides spanning the complete LCMV proteome for gamma interferon (IFN-γ) induction from CD8+ T cells derived from LCMV-infected H-2b mice. We identified 19 novel epitopes. Together with the 9 previously known, these epitopes account for the total CD8+ CD44hi response. Thus, bystander T-cell activation does not contribute appreciably to the CD8+ CD44hi pool. Strikingly, 15 of the 19 new epitopes were derived from the viral L polymerase, which, until now, was not recognized as a target of the cellular response induced by LCMV infection. The L epitopes induced significant levels of in vivo cytotoxicity and conferred protection against LCMV challenge. Interestingly, protection from viral challenge was best correlated with the cytolytic potential of CD8+ T cells, whereas IFN-γ production and peptide avidity appear to play a lesser role. Taken together, these findings illustrate that the LCMV-specific CD8+ T-cell response is more complex than previously appreciated.

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Cultured Human B Cell APCs Expanded Using Il-4 and CD40 Ligand Preferentially Promote a Type 2 T Cell Response to Alloimmune Stimulation.

Blood ◽

10.1182/blood.v104.11.2668.2668 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2668-2668

Author(s):

Abdul Tawab ◽

Yoshiyuki Takahashi ◽

Childs Richard ◽

Kurlander J. Roger

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cell Response ◽

Cd40 Ligand ◽

T Cell Response ◽

Ifn Γ

Abstract In vitro stimulation of human peripheral blood B cells with recombinant IL-4 and CD40 ligand (CD40L) markedly increases their expression of MHC and costimulatory molecules, thus enhancing antigenic peptide presentation to T cells. Because these cells proliferate extensively in vitro (unlike monocytes or dendritic cells), they represent a promising and convenient reagent for the generation and maintenance of antigen-specific T cells for use in a variety of experimental or therapeutic settings. However, the impact of this type of B cell APC on cytokine production by responder T cells has hitherto not been examined. To address this issue, we stimulated normal human T cells with either allogeneic B cells (generated in vitro) or with MNCs obtained from the same donor. After 7 days, T cells were washed and re-challenged with the same APCs. The resulting alloreactive cytokine response was measured using quantitative ELISPOT methods and expressed as the frequencies of IFN-γ, IL-4, and IL-5 producing cells per thousand responder cells added. B cell- and MNC-primed cell lines both produced vigorous lymphokine responses, but B cell-stimulated T cells consistently produced more IL-5 spots (mean of 265 vs. 98/1000 responders, p<0.002) and fewer IFN-γ spots (163 vs 386/1000 cells, p<0.005) than MNC-stimulated cells. Further, the ratio of IFN-γ to IL-5 spots was almost ten-fold lower in B cell-stimulated cultures compared to MNC-induced cultures (0.67 vs. 5.2, p<0.001). ELISPOT studies assessing the ratio of IFN-γ to IL-4 spots and ELISA assays comparing IFN-γ and IL-5 levels from culture supernatants demonstrated the same pattern of marked type 2 skewing by B cells. This pattern was unaffected by the presence of anti-IL-4 antibody suggesting type 2 skewing was not mediated by IL-4. Cytokine skewing produced by B cells or MNC could be partially reversed by swapping MNC and B cells during re-stimulation on day 7, but this plasticity was markedly reduced after 3 (weekly) cycles of B cell or MNC re-stimulation in vitro. Type 2 skewing by B cells was enhanced when monocytes were removed from responder T cell populations by either depleting CD14+ positive cells or by positive selection of T cells prior to stimulation. In contrast, type 2 polarization could be prevented using recombinant IL-12. Not all cells of B-cell origin share the same propensity to type 2 skewing observed with IL-4/CD40L-stimulated B cells; under identical conditions, EBV-transformed B cells stimulated alloimmune T cells to produce a strong type 1 cytokine response comparable to that produced by MNCs. In summary, IL-4/CD40L-stimulated B cells strongly promote a type 2 T cell response during primary alloimmune challenge; this skewing can become fixed after repeated B cell stimulation. Investigators using these cells as APC should be aware of this potential phenomenon, particularly during primary T cell responses. It is also important to consider the factors described above that may exacerbate or ameliorate this effect.

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Cellular and humoral immunogenicity of the mRNA-1273 SARS-CoV-2 vaccine in patients with hematologic malignancies

Blood Advances ◽

10.1182/bloodadvances.2021006101 ◽

2021 ◽

Author(s):

Moraima Jiménez ◽

Elisa Roldan ◽

Candela Fernández- Naval ◽

Guillermo Villacampa ◽

Monica Martinez-Gallo ◽

...

Keyword(s):

T Cell ◽

Cellular Response ◽

Immunosuppressive Agents ◽

Immunosuppressive Treatment ◽

Humoral Response ◽

Hematologic Malignancies ◽

T Cell Response ◽

Cell Counts ◽

Immuno Assay ◽

Anti Cd20

Recent studies have demonstrated a suboptimal humoral response to SARS-CoV-2 mRNA vaccines in patients diagnosed with hematologic malignancies, however data about cellular immunogenicity is scarce. In this study we aimed to evaluate both the humoral and cellular immunogenicity one month after the second dose of the mRNA-1273 vaccine. Antibody titers were measured by the Elecsys and LIAISON Anti-SARS-CoV-2 S assay while T-cell response was assessed by Interferon-Gamma-Release-immuno-Assay technology. Overall, 76.3% (184/241) of patients developed humoral immunity and the cellular response rate was 79% (184/233). Hypogammaglobulinemia, lymphopenia, active hematological treatment and anti-CD20 therapy during the last 6 months were associated with an inferior humoral response. Conversely, age over 65 years, active disease, lymphopenia and immunosuppressive treatment for GvHD were associated with an impaired cellular response. A significant dissociation between humoral and cellular response was observed in patients treated with anti-CD20 therapy, being the humoral response of 17.5% whereas the cellular response was 71.1%. In these patients B-cell aplasia was confirmed while T cell counts were preserved. In contrast, humoral response was observed in 77.3% of patients under immunosuppressive treatment for GvHD, while only 52.4% had cellular response. The cellular and humoral response to the SARS-CoV-2 mRNA-1273 vaccine in patients with hematological malignancies is highly influenced by the presence of treatments like anti-CD20 therapy and immunosuppressive agents. This observation has implications for the further management of these patients.

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Peptide vaccines designed with the aid of immunoinformatic against Caseous Lymphadenitis promotes humoral and cellular response induction in mice

PLoS ONE ◽

10.1371/journal.pone.0256864 ◽

2021 ◽

Vol 16 (11) ◽

pp. e0256864

Author(s):

Daniela Droppa-Almeida ◽

Glenda Amaral da Silva ◽

Lívia Maria do Amorim Costa Gaspar ◽

Beatriz Benny Sungaila Pereyra ◽

Roberto José Meyer Nascimento ◽

...

Keyword(s):

Cellular Response ◽

Small Ruminants ◽

Study Groups ◽

Economic Losses ◽

Caseous Lymphadenitis ◽

Peptide Vaccines ◽

Tnf Α ◽

Ifn Γ ◽

Humoral And Cellular Response ◽

Immunodominant Epitopes

Caseous Lymphadenitis (CLA) is a chronic disease that affects also small ruminants. CLA is caused by Corynebacterium pseudotuberculosis and is responsible for high economic losses due to the formation of superficial and visceral granulomas, the latter is considered as asymptomatic CLA causing high levels of dissemination. Several vaccination strategies, in which the use of synthetic peptides stands out. Thus, this work aimed to evaluate the protective potential of peptide vaccines designed to determine the immunodominant epitopes of CP40 against CLA in mice. The animals were divided into eight groups separated in controls (G1—PBS, G2—Saponin and G9—rCP40) and experimental (G3—pep1, G4- pep2, G5-pep3, G6-pep4, G7-pep5 and G8-pep6), these were vaccinated on days 0 and 15 by a subcutaneous route. 60 days after the first immunization, all animals were challenged with C. pseudotuberculosis. On days 0, 15, 60, and 120 after the first immunization, blood samples were taken to measure immunoglobulins. On the same day of the challenge, the splenocytes were isolated and assayed for the production of IL-2, IL-4, IL-6, IFN-γ, TNF-α, IL-17, and IL-10. After vaccinations, the animals were challenged and all of them were affected by the disease which led to their death. The G6 and G8 groups provided 10% protection and the G7 provided 20%. The G3 and G4 groups provided 30% and 40% protection respectively. The peptides showed the production of Total IgG antibodies and cytokines (IL-2, IL-4, IL-6, IFN-γ, and TNF-α), indicating a possible activation of the Th1 type response. However, groups G3, G5, G6, and G8 showed production of IL-17. None of the study groups showed IL-10 production. The immunogenicity of the peptides was not enough to protect these animals and it is believed that the use of adjuvants based on PAMPs may improve the immune response offered by these peptides.

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Impact of Prior Influenza and Pneumoccocal Vaccines on Humoral and Cellular Response to SARS-CoV-2 BNT162b2 Vaccination

Vaccines ◽

10.3390/vaccines9060615 ◽

2021 ◽

Vol 9 (6) ◽

pp. 615

Author(s):

Vincenzo Puro ◽

Concetta Castilletti ◽

Chiara Agrati ◽

Delia Goletti ◽

Sara Leone ◽

...

Keyword(s):

Immune Response ◽

Cellular Response ◽

Large Scale ◽

Univariate Analysis ◽

Multivariable Analysis ◽

Pneumococcal Vaccination ◽

Interferon Γ ◽

Direct Care ◽

Neutralization Titer ◽

Ifn Γ

Vaccination against SARS-CoV-2 is considered the most effective method of prevention to contain the pandemic. While highly effective SARS-CoV-2 vaccines are being applied on a large-scale, whether and to what extent the strength of the vaccine-induced immune response could be further potentiated is still an object of debate. Several reports studied the effect of different vaccines on the susceptibility and mortality of COVID-19, with conflicting results. We aimed to evaluate whether previous influenza and/or pneumococcal vaccination had an impact on the specific immune response to the SARS-CoV-2 BNT162b2 mRNA vaccine. The study population consists of 710 workers from our Institute who completed the BNT162b2 schedule and have been tested at least once after the second dose, from 27 December 2020 up to 15 April 2021. Of these, 152 (21.4%) had received an influenza and 215 (30.3%) a concomitant influenza and pneumococcal vaccination, a median of 102 days before the second dose of BNT162b2. Overall, 100% of workers were tested for anti-Spike receptor-binding domain (anti-S/RBD) antibodies, 224 workers for neutralization titer (Micro-neutralization assay, MNA), and 155 workers for a spike-specific T cell interferon-γ response (IFN-γ). The levels of anti-S/RBD, MNA and IFN-γ were evaluated and compared according to sex, age, involvement in direct care of COVID-19 patients, and previous influenza/pneumococcal vaccination. At the univariate analysis, no statistically significant association was observed with regard to a previous influenza and pneumococcal vaccination. A significant lower anti-S/RBD response was observed according to an older age and male sex, while MNA titers were significantly associated to sex but not to age. At the multivariable analysis, workers receiving a concomitant influenza and pneumococcal vaccination or only influenza showed a 58% (p 0.01) and 42% (p 0.07) increase in MNA titers, respectively, compared to those who did not receive an influenza/pneumococcal vaccination. Female workers showed an 81% MNA and a 44% anti-S/RBD increase compared to male workers (p < 0.001). Compared to workers aged 21 to 49 years, those aged 50 or older were associated with a reduction in the anti-S/RBD (16%; p 0.005), MNA (31%; p 0.019), and IFN.g (32%) immune response. Maintaining the influenza and pneumococcal immunization program for the coming season, in which COVID-19 could still be spreading, remains strongly recommended to protect those who are more vulnerable and to limit the potential burden of these infections on the healthcare system.

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Drug-specific Treg cells are induced during desensitization procedure for rituximab and tocilizumab in patients with anaphylaxis

Scientific Reports ◽

10.1038/s41598-021-91851-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Alessandra Vultaggio ◽

Francesca Nencini ◽

Susanna Bormioli ◽

Elena Silvestri ◽

Laura Dies ◽

...

Keyword(s):

Cell Response ◽

Cellular Response ◽

Adaptive Immune Response ◽

Treg Cells ◽

T Cell Response ◽

In Vitro Assays ◽

Specific Effector ◽

Humoral And Cellular Response

AbstractBiologic agents (BA) are able to induce an adaptive immune response in a proportion of exposed patients with the onset of anti-drug antibodies (ADA), which are usually responsible for hypersensitivity reactions (HR). Drug desensitization (DD) for BA allows transient clinical tolerance to the drug in reactive patients. The paper aimed to analyse the modification of drug-specific immune responses along DD in two patients with previous ADA-mediated HR (anaphylaxis) to rituximab and tocilizumab. The in vivo and in vitro assays of humoral and cellular response to drugs were carried out in a longitudinal manner throughout the DD cycles. We observed a progressive decrease of the pre-procedure ADA titer with negativization during the DD cycles in both patients. The monitoring of the drug-specific effector cell response showed the decrease in the BA-induced proliferation, while T cell response to unrelated antigens resulted unmodified along the DD cycles. Lastly, the increase of circulating drug-specific Treg cells mainly producing IL-35 were shown during the DD treatment. This study provides evidence that DD treatment to two BA inhibits humoral and cellular anti-drug response by increasing regulatory T cells and cytokines in an antigen-restricted manner. These modifications could contribute to the safety of the procedure.

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Cryptosporidium parvum-Specific CD4 Th1 Cells from Sensitized Donors Responding to Both Fractionated and Recombinant Antigenic Proteins

Infection and Immunity ◽

10.1128/iai.72.3.1306-1310.2004 ◽

2004 ◽

Vol 72 (3) ◽

pp. 1306-1310 ◽

Cited By ~ 15

Author(s):

Maria Angeles Gomez Morales ◽

Raffaella Mele ◽

Alessandra Ludovisi ◽

Fabrizio Bruschi ◽

Fabio Tosini ◽

...

Keyword(s):

T Cell ◽

Cryptosporidium Parvum ◽

Cellular Response ◽

Mononuclear Cells ◽

Early Stage ◽

T Cell Response ◽

Interleukin 4 ◽

Cell Mediated Immunity ◽

Human T Cell ◽

Ifn Γ

ABSTRACT T-cell-mediated immunity plays a central role in the host response to Cryptosporidium parvum. Human T-cell clones (TCC) were isolated from peripheral blood mononuclear cells of five healthy donors with prior cryptosporidiosis by use of a C. parvum crude extract, two antigen fractions obtained by ion-exchange chromatography (IEC1 and IEC2), and two recombinant peptides (SA35 and SA40) from C. parvum sporozoites. The T-cell lines derived from the one recently infected donor had a higher proportion (26 to 38%) of T cells exhibiting the γ/δ T-cell receptor (γ/δ-TCR) than those from donors who had recovered from cryptosporidiosis several years earlier, suggesting that the γ/δ T-cell population is involved in the early stage of the infection. The specific TCC had the α/β-TCR, had the phenotype CD45RO+ CD4+ CD8−, and were characterized by either hyperproduction of gamma interferon (IFN-γ) alone, with a Th1 profile, or IFN-γ hyperproduction together with interleukin-4 (IL-4) or IL-5 production, with a Th0 profile. SA35, SA40, IEC1, and IEC2 may be considered good targets of the cellular response against C. parvum and may play a role in maintaining the T-cell-mediated memory response to this parasite. Furthermore, the SA35 and SA40 peptides may be regarded as immunodominant antigens involved in the maintenance of the T-cell response in healthy C. parvum-sensitized persons.

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B cell numbers predict humoral and cellular response upon SARS‐CoV ‐2 vaccination among patients treated with rituximab

Arthritis & Rheumatology ◽

10.1002/art.42060 ◽

2021 ◽

Author(s):

Ana L. Stefanski ◽

Hector Rincon‐Arevalo ◽

Eva Schrezenmeier ◽

Kirsten Karberg ◽

Franziska Szelinski ◽

...

Keyword(s):

B Cell ◽

Cellular Response ◽

Cell Numbers ◽

Humoral And Cellular Response

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