Non-neutralizing antibody responses following A(H1N1)pdm09 influenza vaccination with or without AS03 adjuvant system

BACKGROUND: Non-neutralizing antibodies inducing complement-dependent lysis (CDL) and antibody-dependent cell-mediated cytotoxicity (ADCC) activity may contribute to protection against influenza infection. We investigated CDL and ADCC responses in healthy adults randomized to receive either non-adjuvanted or AS03-adjuvanted monovalent A(H1N1)pdm09 vaccine (containing 15 microg/3.75 mug of hemagglutinin, respectively) on a 2-dose schedule 21 days apart. METHODS: We conducted an exploratory analysis of a subset of 106 subjects having no prior history of A(H1N1)pdm09 infection or seasonal influenza vaccination enrolled in a previously reported study (NCT00985673). Antibody responses against the homologous A/California/7/2009 (H1N1) vaccine strain and a related A/Brisbane/59/2007 (H1N1) seasonal influenza strain were analyzed up to Day 42. RESULTS: Baseline seropositivity determined with hemagglutination inhibition (HI), CDL and ADCC antibody titers against viral strains was high; A/California/7/2009 (HI [40.4-48.1%]; CDL [34.6-36.0%]; ADCC [92.1-92.3%]); A/Brisbane/59/2007 (HI [73.1-88.9%]; CDL [38.0-42.0%]; ADCC [86.8-97.0%]). CDL seropositivity increased following vaccination with both adjuvanted and non-adjuvanted formulations (A/California/7/2009 [95.9-100%]; A/Brisbane/59/2007 [75.5-79.6%]). At Day 21, increases in CDL and ADCC antibody geometric mean titers against both strains were observed for both formulations. After 2 doses of AS03-adjuvanted vaccine, vaccine responses of 95.8% ( \u3e /=9-fold increase from baseline in CDL titers) and 34.3% ( \u3e /=16-fold increase from baseline in ADCC titers) were seen against A/California/7/2009; and 22.4% and 42.9%, respectively, against A/Brisbane/59/2007. Vaccine responses after 2 doses of the non-adjuvanted vaccine were broadly similar. CONCLUSIONS: Broadly comparable non-neutralizing immune responses were observed following vaccination with non-adjuvanted and AS03-adjuvanted A(H1N1)pdm09 formulations; including activity against a related vaccine strain

Differentiation associated regulation of microRNA expression in vivo in human CD8+ T cell subsets

BACKGROUND: The differentiation of CD8+ T lymphocytes following priming of naïve cells is central in the establishment of the adaptive immune response. Yet, the molecular events underlying this process are not fully understood. MicroRNAs have been recently shown to play a key role in the regulation of haematopoiesis in mouse, but their implication in peripheral lymphocyte differentiation in humans remains largely unknown. METHODS: In order to explore the potential implication of microRNAs in CD8+ T cell differentiation in humans, microRNA expression profiles were analysed using microarrays and quantitative PCR in several human CD8+ T cell subsets defining the major steps of the T cell differentiation pathway. RESULTS: We found expression of a limited set of microRNAs, including the miR-17~92 cluster. Moreover, we reveal the existence of differentiation-associated regulation of specific microRNAs. When compared to naive cells, miR-21 and miR-155 were indeed found upregulated upon differentiation to effector cells, while expression of the miR-17~92 cluster tended to concomitantly decrease. CONCLUSIONS: This study establishes for the first time in a large panel of individuals the existence of differentiation associated regulation of microRNA expression in human CD8+ T lymphocytes in vivo, which is likely to impact on specific cellular functions

T cells, more than antibodies, may prevent symptoms developing from respiratory syncytial virus infections in older adults

Introduction: The immune mechanisms supporting partial protection from reinfection and disease by the respiratory syncytial virus (RSV) have not been fully characterized. In older adults, symptoms are typically mild but can be serious in patients with comorbidities when the infection extends to the lower respiratory tract. Methods: This study formed part of the RESCEU older-adults prospective-cohort study in Northern Europe (2017–2019; NCT03621930) in which a thousand participants were followed over an RSV season. Peripheral-blood samples (taken pre-season, post-season, during illness and convalescence) were analyzed from participants who (i) had a symptomatic acute respiratory tract infection by RSV (RSV-ARTI; N=35) or (ii) asymptomatic RSV infection (RSV-Asymptomatic; N=16). These analyses included evaluations of antibody (Fc-mediated–) functional features and cell-mediated immunity, in which univariate and machine-learning (ML) models were used to explore differences between groups. Results: Pre–RSV-season peripheral-blood biomarkers were predictive of symptomatic RSV infection. T-cell data were more predictive than functional antibody data (area under receiver operating characteristic curve [AUROC] for the models were 99% and 76%, respectively). The pre-RSV season T-cell phenotypes which were selected by the ML modelling and which were more frequent in RSV-Asymptomatic group than in the RSV-ARTI group, coincided with prominent phenotypes identified during convalescence from RSV-ARTI (e.g., IFN-γ+, TNF-α+ and CD40L+ for CD4+, and IFN-γ+ and 4-1BB+ for CD8+). Conclusion: The evaluation and statistical modelling of numerous immunological parameters over the RSV season suggests a primary role of cellular immunity in preventing symptomatic RSV infections in older adults

Safety and Immunogenicity of the PRAME Cancer Immunotherapeutic in Patients with Resected Non–Small Cell Lung Cancer: A Phase I Dose Escalation Study

International audience; INTRODUCTION:Adjuvant platinum-based chemotherapy is standard treatment for surgically resected stage II to IIIA NSCLC, but the relapse rate is high. The preferentially expressed antigen of melanoma (PRAME) tumor antigen is expressed in two-thirds of NSCLC and offers an attractive target for antigen-specific immunization. A phase I dose escalation study assessed the safety and immunogenicity of a PRAME immunotherapeutic consisting of recombinant PRAME plus proprietary immunostimulant AS15 in patients with surgically resected NSCLC (NCT01159964).METHODS:Patients with PRAME-positive resected stage IB to IIIA NSCLC were enrolled in three consecutive cohorts to receive up to 13 injections of PRAME immunotherapeutic (recombinant PRAME protein dose of 20 μg, 100 μg, or 500 μg, with a fixed dose of AS15). Adverse events, predefined dose-limiting toxicity, and the anti-PRAME humoral response (measured by enzyme-linked immunosorbent assay) were coprimary end points. Anti-PRAME cellular responses were assessed.RESULTS:A total of 60 patients were treated (18 received 20 μg of PRAME, 18 received 100 μg of PRAME, and 24 received 500 μg of PRAME). No dose-limiting toxicity was reported. Adverse events considered by the investigator to be causally related to treatment were grade 1 or 2, and most were injection site reactions or fever. All patients had detectable anti-PRAME antibodies after four immunizations. The percentages of patients with PRAME-specific CD4-positive T cells were higher at the dose of 500 μg compared with lower doses. No predefined CD8-positive T-cell responses were detected.CONCLUSION:The PRAME immunotherapeutic had an acceptable safety profile. All patients had anti-PRAME humoral responses that were not dose related, and 80% of those treated at the highest dose showed a cellular immune response. The dose of 500 μg was selected. However, further development was stopped after negative results with a similar immunotherapeutic in patients with NSCLC

T cells, more than antibodies, may prevent symptoms developing from respiratory syncytial virus infections in older adults

INTRODUCTION: The immune mechanisms supporting partial protection from reinfection and disease by the respiratory syncytial virus (RSV) have not been fully characterized. In older adults, symptoms are typically mild but can be serious in patients with comorbidities when the infection extends to the lower respiratory tract. METHODS: This study formed part of the RESCEU older-adults prospective-cohort study in Northern Europe (2017-2019; NCT03621930) in which a thousand participants were followed over an RSV season. Peripheral-blood samples (taken pre-season, post-season, during illness and convalescence) were analyzed from participants who (i) had a symptomatic acute respiratory tract infection by RSV (RSV-ARTI; N=35) or (ii) asymptomatic RSV infection (RSV-Asymptomatic; N=16). These analyses included evaluations of antibody (Fc-mediated-) functional features and cell-mediated immunity, in which univariate and machine-learning (ML) models were used to explore differences between groups. RESULTS: Pre-RSV-season peripheral-blood biomarkers were predictive of symptomatic RSV infection. T-cell data were more predictive than functional antibody data (area under receiver operating characteristic curve [AUROC] for the models were 99% and 76%, respectively). The pre-RSV season T-cell phenotypes which were selected by the ML modelling and which were more frequent in RSV-Asymptomatic group than in the RSV-ARTI group, coincided with prominent phenotypes identified during convalescence from RSV-ARTI (e.g., IFN-γ+, TNF-α+ and CD40L+ for CD4+, and IFN-γ+ and 4-1BB+ for CD8+). CONCLUSION: The evaluation and statistical modelling of numerous immunological parameters over the RSV season suggests a primary role of cellular immunity in preventing symptomatic RSV infections in older adults

Interstitial lung disease in children - genetic background and associated phenotypes

Interstitial lung disease in children represents a group of rare chronic respiratory disorders. There is growing evidence that mutations in the surfactant protein C gene play a role in the pathogenesis of certain forms of pediatric interstitial lung disease. Recently, mutations in the ABCA3 transporter were found as an underlying cause of fatal respiratory failure in neonates without surfactant protein B deficiency. Especially in familiar cases or in children of consanguineous parents, genetic diagnosis provides an useful tool to identify the underlying etiology of interstitial lung disease. The aim of this review is to summarize and to describe in detail the clinical features of hereditary interstitial lung disease in children. The knowledge of gene variants and associated phenotypes is crucial to identify relevant patients in clinical practice

Immune responses to the adjuvanted recombinant zoster vaccine in immunocompromised adults: a comprehensive overview

Immunocompromised (IC) persons are at increased risk for herpes zoster (HZ) and its complications, mainly due to impairment of cell-mediated immunity (CMI). The adjuvanted recombinant zoster vaccine (RZV) demonstrated efficacy against HZ in autologous hematopoietic stem cell transplant (auto-HSCT) recipients and hematologic malignancy (HM) patients. We review immune responses to RZV in 5 adult IC populations, 4 of which were receiving multiple, concomitant immunosuppressive medications: auto-HSCT and renal transplant recipients, HM and solid tumor patients, and human immunodeficiency virus-infected adults. Although administered in most cases when immunosuppression was near its maximum, including concomitantly with chemotherapy cycles, RZV induced robust and persistent humoral and, more importantly, CMI responses in all 5 IC populations. Based on the overall clinical data generated in older adults and IC individuals, RZV is expected to provide benefit in a broad adult population at risk for HZ