INTRODUCTION:Immunoglobulin G4-related disease (IgG4-RD) is a debilitating multiorgan disease characterized by recurring flares leading to organ dysfunction, decreased quality of life, and mortality. Glucocorticoids, the standard of care for IgG4-RD, are associated with substantial treatment-related toxicity. Inebilizumab, an antibody directed against CD19, mediates the rapid and durable depletion of CD19+ B cells thought to be involved in IgG4-RD pathogenesis. We describe the first international, prospective, double-blind, placebo-controlled trial to evaluate the safety and efficacy of B-cell depletion for flare prevention in IgG4-RD (MITIGATE). METHODS:The study was designed by an international panel of physicians with expertise in IgG4-RD. Critical trial design decisions included the selection of participants, definition of clinically meaningful primary and secondary endpoints, accommodation of standard of care, and development of flare diagnostic criteria. The study is approved for conduct in 22 countries. PLANNED OUTCOMES:The primary efficacy endpoint is time from randomization to the occurrence of the first centrally adjudicated and investigator-treated disease flare during the 1-year randomized controlled period. A set of novel, organ-specific flare diagnostic criteria were developed specifically for this trial, incorporating symptoms and signs, laboratory findings, imaging study results, and pathology data. MITIGATE aims to accrue 39 flares for the primary endpoint, which provides sufficient power to detect a relative risk reduction of 65% in the inebilizumab group. It is anticipated that enrollment of 160 participants will achieve this goal. Additional endpoints include safety, annualized flare rate, flare-free complete remission, quality-of-life measures, and cumulative glucocorticoid use. MITIGATE represents the first randomized, double-blind, placebo-controlled trial of any treatment strategy conducted in IgG4-RD. Data from this study will provide insights into the natural history and pathophysiology of IgG4-RD and the efficacy and safety of B-cell depletion as a therapeutic avenue. TRIAL REGISTRATION:NCT04540497.

There is currently no licensed vaccine for respiratory syncytial virus (RSV). Here, we assess the effect of RSV fusion protein (F) conformation on B cell responses in a post hoc comparison of samples from the DS-Cav1 [pre -fusion ( pre-F)] and MEDI7510 [postfusion ( post-F)] vaccine clinical trials. We compared the magnitude and quality of the serological and B cell responses across time points and vaccines. We measured RSV A and B neu-tralization, F-binding immunoglobulin G titers, and competition assays at week 0 (before vaccination) and week 4 (after vaccination) to evaluate antibody specificity and potency. To compare B cell specificity and activation, we used pre-F and post-F probes in tandem with a 17-color immunophenotyping flow cytometry panel at week 0 (before vaccination) and week 1 (after vaccination). Our data demonstrate that both DS-Cav1 and MEDI7510 vaccination robustly elicit F-specific antibodies and B cells, but DS-Cav1 elicited antibodies that more potently neutralized both RSV A and B. The superior potency was mediated by antibodies that bind antigenic sites on the apex of pre-F that are not present on post-F. In the memory (CD27+) B cell compartment, vaccination with DS-Cav1 or MEDI7510 elicited B cells with different epitope specificities. B cells preferentially binding the pre-F probe were activated in DS-Cav1-vaccinated participants but not in MEDI7510-vaccinated participants. Our findings emphasize the importance of using pre-F as an immunogen in humans because of its deterministic role in eliciting highly potent neutralizing antibodies and memory B cells.

Objective: Functional HDL (high-density lipoprotein) particles that facilitate cholesterol efflux may be cardioprotective. EL (endothelial lipase) hydrolyzes phospholipids promoting catabolism of HDL and subsequent renal excretion. MEDI5884 is a selective, humanized, monoclonal, EL-neutralizing antibody. We sought to determine the safety, pharmacokinetics, and pharmacodynamic effects of multiple doses of MEDI5884 in patients with stable coronary artery disease. Approach and Results: LEGACY was a phase 2a, double-blind, placebo-controlled, parallel-design trial that randomized 132 patients with stable coronary artery disease receiving high-intensity statin therapy to 3 monthly doses of 1 of 5 dose levels of MEDI5884 (50, 100, 200, 350, or 500 mg SC) or matching placebo. The primary end point was the safety and tolerability of MEDI5884 through the end of the study (day 151). Additional end points included change in HDL cholesterol and cholesterol efflux from baseline to day 91, hepatic uptake of cholesterol at day 91, changes in various other lipid parameters. The incidence of adverse events was similar between the placebo and MEDI5884 groups. In a dose-dependent manner, MEDI5884 increased HDL cholesterol up to 51.4% ( P <0.0001) and global cholesterol efflux up to 26.2% ([95% CI, 14.3–38.0] P <0.0001). MEDI5884 increased HDL particle number up to 14.4%. At the highest dose tested, an increase in LDL (low-density lipoprotein) cholesterol up to 28.7% ( P <0.0001) and apoB (apolipoprotein B) up to 13.1% ( P =0.04) was observed with MEDI5884. However, at the potential target doses for future studies, there was no meaningful increase in LDL cholesterol or apoB. Conclusions: Inhibition of EL by MEDI5884 increases the quantity and quality of functional HDL in patients with stable coronary artery disease on high-intensity statin therapy without an adverse safety signal at the likely dose to be used. These data support further clinical investigation. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03351738.

Cardiovascular disease ( CVD) is the leading global cause of death, and treatments that further reduce CV risk remain an unmet medical need. Epidemiological studies have consistently identified low high-density lipoprotein cholesterol (HDL-C) as an independent risk factor for CVD, making HDL elevation a potential clinical target for improved CVD resolution. Endothelial lipase (EL) is a circulating enzyme that regulates HDL turnover by hydrolyzing HDL phospholipids and driving HDL particle clearance. Using MEDI5884, a first-in-class, EL-neutralizing, monoclonal antibody, we tested the hypothesis that pharmacological inhibition of EL would increase HDL-C by enhancing HDL stability. In nonhuman primates, MEDI5884 treatment resulted in lasting, dose-dependent elevations in HDL-C and circulating phospholipids, confirming the mechanism of EL action. We then showed that a favorable lipoprotein profile of elevated HDL-C and reduced low-density lipoprotein cholesterol (LDL-C) could be achieved by combining MEDI5884 with a PCSK9 inhibitor. Last, when tested in healthy human volunteers, MEDI5884 not only raised HDL-C but also increased HDL particle numbers and average HDL size while enhancing HDL functionality, reinforcing EL neutralization as a viable clinical approach aimed at reducing CV risk.

There are no approved vaccines for respiratory syncytial virus (RSV), and consensus on methods to assess RSV vaccine efficacy has not been established. In this study of an adjuvanted RSV vaccine, we evaluated an RSV disease endpoint using a patient-reported outcome instrument (the inFLUenza Patient-Reported Outcome instrument [FLU-PRO]) and molecular testing for virologic confirmation.In a randomized, blinded efficacy study (NCT02508194), 1900 adult participants aged ≥60 years who had any respiratory symptom lasting ≥24 hours recorded symptoms in a FLU-PRO-based workbook for 21 days, self-collected nasal swabs on illness days 2 to 4, and had a site-collected swab obtained on (approximately) day 4. The endpoint, acute RSV-associated respiratory illness (ARA-RI), required specific symptoms with virologic confirmation.The FLU-PRO demonstrated reliability, ability to detect change, and validity and had high participant adherence and acceptable patient burden in the setting of an RSV prevention trial. The ARA-RI endpoint definition captured all 33 virologically confirmed RSV illnesses for which symptom data were provided, and in 32 of these, at least 1 lower respiratory symptom was reported. Sensitivity analysis with an endpoint requiring ≥2 lower respiratory symptoms captured greater symptom severity but fewer cases. Results of self- and site-collected swabs were highly correlated. Self-swabbing detected 9 additional cases that would have been missed by site swabbing only.These results demonstrated the reliability and validity of the ARA-RI definition and of the FLU-PRO for use in RSV studies. Self-swabbing improved RSV detection.

Background: Infections with respiratory syncytial virus (RSV) cause significant morbidity and hospitalization in older adults. We studied the humoral, mucosal and B cell responses of an investigational adjuvanted RSV sF vaccine, MEDI7510, in older adults. Methods: In a substudy of a randomized (1:1), double-blind, placebo-controlled study of MEDI7510 in adults ≥60 years of age, we collected blood and nasal secretions at days 0, 8, 29, 91 and 180 post-vaccination to measure F-specific IgG and IgA antibodies by ELISA, and plasmablasts and memory B cells by IgA/IgG dual-color fluorospot. Results: The 27 vaccine- and 18 placebo-recipients had a mean age of 73 years and included 24 women. Among vaccinees, 93% had significant increases in F-specific plasma IgG 85% had increased plasma IgA; 74% had increased nasal IgG and 26% nasal IgA; 93% had IgG and 89% IgA plasmablasts on Day 8 post-immunization; and 82% had IgG and 7.4% IgA memory B cell responses to the vaccine. Vaccinees <70 years of age and women had the highest responses to the vaccine. Conclusions: This adjuvanted vaccine generated robust humoral immune responses in older adults, including RSV F-specific systemic and mucosal antibodies and memory B cells. Nevertheless, age ≥70 years was associated with decreased immunogenicity of the adjuvanted vaccine.

Introduction: Even with marked lowering of LDL-C, patients with CAD remain at significant risk of CV events. Elevated HDL-C is one of the strongest epidemiologic surrogates for protection against C...

Immunogenicity data from phase 1 vaccine studies can be difficult to interpret, especially in seropositive populations and when multiple assays are used. We developed 3 statistical methods (Youden index [YI] threshold, receiver-operating characteristic relative to baseline [ROC-B], and ROC of postdose levels [ROC-P]) to characterize complex immunogenicity data by assessing the proportion of a study population that achieved values above thresholds. The YI method calculates a single threshold per assay. Both ROC methods construct ROC curves for individual assays and surfaces for assay combinations to assess degree of separation of postdose values from a reference distribution; the ROC-B method uses overall predose values as the reference distribution and the ROC-P method uses pooled postdose values. All methods are applicable to a seropositive population with overlapping distributions of baseline and postdose measurements and can evaluate results of multiple assays jointly. The ROC-P method is also applicable when postdose levels are fully separated from baseline levels, as is common in a seronegative population. These methods were demonstrated using data from a phase 1a study of respiratory syncytial virus vaccines formulated with and without an adjuvant in a seropositive population of adults aged ≥60 years. All 3 methods provided a comprehensive assessment of vaccine immunogenicity effects with results presented in easily interpretable formats. In the example data, the methods demonstrated antigen dose response trend and contribution of adjuvant to response in multiple assays individually and jointly where optimal responses in assay combinations (humoral and cellular) are important.

Objectives: MEDI3902 is a bivalent, bispecific human immunoglobulin G1 kappa monoclonal antibody that binds to both the Pseudomonas aeruginosa PcrV protein involved in host cell cytotoxicity and the Psl exopolysaccharide involved in P. aeruginosa colonization and tissue adherence. MEDI3902 is being developed for the prevention of nosocomial P. aeruginosa pneumonia in high-risk patients. Methods: This phase 1 dose-escalation study (NCT02255760) evaluated the safety, pharmacokinetics, antidrug antibody (ADA) responses and ex vivo anticytotoxicity and opsonophagocytic killing activities of MEDI3902 after a single intravenous infusion in healthy adults aged 18 to 60 years. Fifty-six subjects were randomized in a 3:1 ratio to receive 250, 750, 1500 or 3000 mg of MEDI3902 or placebo and followed for 60 days afterwards. Results: Treatment-emergent adverse events (TEAEs) were mild or moderate in severity; no serious TEAEs were observed. The most common TEAEs were infusion-related reactions. MEDI3902 exhibited approximately linear pharmacokinetics across the 250, 750 and 1500 mg doses and nonlinear pharmacokinetics between the 1500 and 3000 mg doses. One subject in the 3000 mg group tested positive for ADA on day 61 and had a lower MEDI3902 serum concentration from days 43 to 61 than ADA-negative subjects. Serum anticytotoxicity antibody concentrations and opsonophagocytic killing activity were correlated with MEDI3902 serum concentrations across all doses. Conclusions: Phase 1 study results of MEDI3902 in healthy subjects support further evaluation of its safety and efficacy in subjects at risk for P. aeruginosa pneumonia. (C) 2018 The Authors. Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

ABSTRACT This is the second phase 1 study of a respiratory syncytial virus (RSV) vaccine containing RSV fusion protein (sF) adjuvanted with glucopyranosyl lipid A (GLA) in a squalene-based 2% stable emulsion (GLA-SE). In this randomized, double-blind study, 261 subjects aged ≥60 years received inactivated influenza vaccine (IIV), a vaccine containing 120 μg sF with escalating doses of GLA (1, 2.5, or 5 μg) in SE, or a vaccine containing 80 μg sF with 2.5 μg GLA in SE. Subjects receiving 120 μg sF with 2.5 or 5 μg GLA were also randomized to receive IIV or placebo. Immunity to RSV was assessed by detection of microneutralizing, anti-F immunoglobulin G, and palivizumab-competitive antibodies and F-specific gamma interferon enzyme-linked immunosorbent spot assay T-cell responses. Higher adjuvant doses increased injection site discomfort, but at the highest dose, the reactogenicity was similar to that of IIV. Significant humoral and cellular immune responses were observed. The 120 μg sF plus 5.0 μg GLA formulation resulted in the highest responses in all subjects and in older subjects. These results confirm previous observations of vaccine tolerability, safety, and immunogenicity and were used to select the 120 μg sF plus 5.0 μg GLA formulation for phase 2 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT02289820.)

In a randomized, placebo-controlled, phase 2b clinical trial, an adjuvanted vaccine containing the respiratory syncytial virus (RSV) fusion protein was immunogenic but did not protect older adults from disease caused by RSV.

Background: Nosocomial pneumonia is a leading cause of hospital-acquired infection. However, evidence is limited regarding resource utilization and healthcare costs associated with nosocomial pneumonia in France. Methods: This retrospective case-control study used a nationwide hospital claims database for cases of nosocomial pneumonia caused by P. aeruginosa or Pseudomonas aeruginosa. Hospital stay costs were retrieved during index hospitalization and at 30-days and 90-days post-discharge. Cost was calculated using Diagnosis Related Group (DRG) codes and daily cost estimates. Results: Of 7,793 patients discharged with S. aureus or P. aeruginosa pneumonia between January 2010 and December 2011, 1,453 and 1,449 cases were included, respectively. Cases were matched with controls in terms of DRG root, age, gender, Charlson comorbidity score, and hospital region. Cases demonstrated significantly higher Charlson comorbidity scores (p<0.01) and almost four times higher mean index hospitalization duration (p<0.001), critical care unit stays (p<0.001), mechanical ventilation procedures (p<0.001), and mortality (p<0.001) compared to matched controls. Univariate analysis indicated significantly higher cost of treating cases compared to controls in terms of DRG (S. aureus cohort: €21,540 vs. €6,426; P. aeruginosa cohort: €20,732 vs. €6,172; p<0.001) and daily valuation costs (S. aureus cohort: €28,063 vs. €5,976; P. aeruginosa cohort: €30,827 vs. €5,819; p<0.001). Multivariate analysis showed that nosocomial pneumonia increased mean DRG costs at 90 days by €13,500 to €16,700 for S. aureus cohort, and by €13,300 to €20,200 for P. aeruginosa cohort. Conclusions: Nosocomial pneumonia due to S. aureus or P. aeruginosa was associated with considerable patient morbidity and hospital costs in France.

Introduction: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants worldwide and also causes significant disease in the elderly. Despite 60years of RSV research and vaccine development, there is only one approved medicine to prevent RSV infections. Palivizumab, a monoclonal antibody (mAb) against the RSV fusion (F) protein, is indicated for preterm infants and children at high-risk for RSV infections. It is an active time in RSV vaccine and mAb development with 14 vaccines and 2 mAbs currently being tested in clinical trials as of 13 February 2017. Active vaccination of women in the third trimester or passive immunization of infants with a mAb are particularly attractive approaches as the most severe disease occurs within the first 6months of life.Areas covered: Here, we review current approaches for preventing RSV in the young and old, describe proposed clinical endpoints for studies in pediatric and adult clinical trials and highlight results from recent and ongoing clinical studies.Expert commentary: With 16 candidates in clinical development, approval of the first RSV vaccine or mAb for the prevention of RSV in all infants or the elderly is likely to occur in the next five years.

Background: Respiratory syncytial virus (RSV) causes significant illness in older adults resulting in substantial health and economic impact. A successful vaccine would reduce morbidity in this growing segment of the population.Methods: In this double-blind phase 1 study, subjects 60 years of age and older were enrolled by cohort and randomized to receive vaccines containing escalating doses (20,50, or 80 mu g) of soluble RSV fusion protein (sF) alone or adjuvanted with 2.5 mu g of glucopyranosyl lipid A, a toll-like receptor-4 agonist, in 2% stable emulsion (GLA-SE). Each cohort included 20 vaccine and 4 placebo recipients. Immune responses were evaluated using assays for RSV microneutralizing, anti-F IgG, and palivizumab competitive antibodies and for F-specific interferon (IFN)-gamma enzyme-linked immunospot (ELISPOT) responses.Results: The inclusion of adjuvant increased local reactogenicity, with the majority of subjects who received sF and adjuvant reporting low-grade injection site pain or tenderness. At all doses, the safety profile was acceptable for further development. Immune responses were antigen dose-dependent, and the inclusion of adjuvant increased both humoral and cellular immune responses, with responses statistically higher than for placebo recipients in all 4 assays. At the highest dosage level with adjuvant, half of the subjects had a >= 3-fold rise from day 0 in RSV neutralizing antibody titers, and all had a >= 3-fold rise in antibody levels by anti-F IgG and palivizumab competitive antibody assays on day 29. For the day 8 IFN gamma ELISPOT assay, 74% of subjects in the highest dosing cohort had a >= 3-fold rise from baseline.Conclusions: The safety and immunogenicity results from this study support inclusion of the GLA-SE adjuvant in this RSV vaccine for older adults and also support assessment of the efficacy of the vaccine in a larger clinical trial. (C) 2016 The Authors. Published by Elsevier Ltd.

L'invention concerne des methodes permettant d'augmenter l'immunite contre le virus respiratoire syncytial (VRS) chez un sujet humain. Les methodes consistent a administrer au sujet une dose intramusculaire unique d'une composition contenant environ 20 µg, environ 50 μg, 80 μg ou environ 120 µg de la proteine F soluble du VRS. La composition contient en outre un adjuvant constitue de GLA (pour "glucopyranosyl lipid A") dans une emulsion stable a base de squalene. La proteine F soluble (sF) du VRS correspond aux acides amines 1-524 de la proteine F soluble du VRS issue de la souche A2 humaine depourvue de domaine transmembranaire (SEQ ID NO : 1). Dans certains modes de realisation, le sujet est humain et est âge d'au moins environ 60 ans, ou entre au moins environ 60 ans et environ 87 ans. Dans d'autres modes de realisation, la methode permettant d'augmenter l'immunite contre le VRS chez un sujet resulte en une augmentation de la reponse immunitaire cellulaire de polarisation Th1 chez le sujet, en une induction d'anticorps neutralisants contre VRS chez le sujet, en une diminution des titres viraux de VRS chez le sujet, en l'induction d'une reponse immunitaire contre le VRS chez le sujet, et/ou en la prevention d'une infection a VRS chez le sujet.

BACKGROUND:Staphylococcus aureus and Pseudomonas aeruginosa are major causes of pneumonia in intensive care unit (ICU) patients. Limited data exist regarding the health economic impact of S. aureus and P. aeruginosa pneumonias in the ICU setting.METHODS:We conducted a retrospective observational cohort study using a 29.6 million enrollee US medical and pharmacy administrative claims database. ICU patients with S. aureus or P. aeruginosa infection per International Classification of Diseases, 9th ed. coding between 01/01/2007-8/31/2012 were compared with ICU patients without any pneumonia or infections of interest. Primary outcomes were costs in 2012 US dollars, healthcare utilization and all-cause mortality associated with hospital-acquired S. aureus or P. aeruginosa pneumonia, and the relative odds of incurring higher costs due to a comorbid condition.RESULTS:Patients with S. aureus or P. aeruginosa pneumonia had longer mean hospital (37.9 or 55.4 vs 7.2 days, P < .001) and ICU stays (6.9 or 14.8 vs 1.1 days, P < .001), a higher rate of mechanical ventilation (62.6 % or 62.3 % vs 7.4 %, P < .001), higher mortality (16.0 % or 20.2 % vs 3.1 %, P < .001), and higher total mean hospitalization costs ($146,978 or $213,104 vs $33,851, P < .001) vs controls. Pneumonia survivors had significantly increased risk of rehospitalization within 30 days (27.2 % or 31.1 % vs 15.3 %, P < .001). Comorbid conditions were not associated with increased cost in the pneumonia cohorts.CONCLUSIONS:Healthcare costs and resource utilization were high among ICU patients with S. aureus or P. aeruginosa pneumonia. Reducing the incidence of these infections could lead to substantial cost savings in the United States.

Background: Influenza B viruses from 2 lineages cocirculate annually. Because the single B strain contained in trivalent vaccines may not match the major circulating strain, adding a second B virus could enhance protection. This study compared the safety and immunogenicity of an investigational quadrivalent Ann Arbor strain live attenuated influenza vaccine (Q/LAIV) with that of 2 trivalent vaccines (T/LAIV), each containing a B strain from a different lineage.Methods: This randomized, double-blind study was designed to demonstrate the immunologic noninferiority of Q/LAIV compared with T/LAIV in children 2-17 years of age by comparing postdose geometric mean titers of hemagglutination inhibition antibodies. Children were randomized 3:1:1 to receive Q/LAIV or 1 of 2 T/LAIV vaccines. Those subjects who were 9-17 years of age received 1 dose, and those 2-8 years of age received 2 doses 1 month apart. Serum immune responses were evaluated 1 month after dose 1 (dose 2 for influenza vaccine-naive subjects aged 2-8 years).Results: Q/LAIV was noninferior to T/LAIV: upper bounds for all four 95% confidence intervals for the postdose geometric mean titer ratios (T/LAIV divided by Q/LAIV) were <= 1.5, the predefined noninferiority margin. The overall seroresponse rates (4-fold rise) were comparable between treatment groups. Safety events were comparable, except that fever was more common after dose 1 in Q/LAIV subjects (5.1%) than in T/LAIV subjects (3.1%) 2-8 years of age.Conclusions: The immunogenicity of Q/LAIV was noninferior to that of T/LAIV in children aged 2-17 years; safety was also comparable. Q/LAIV may broaden the protection against influenza B strains provided by current trivalent influenza vaccines.

Expert Rev. Vaccines 11(11), 1293-1303 (2012) Influenza B is responsible for significant morbidity in children and adults worldwide. For more than 25 years, two antigenically distinct lineages of influenza B viruses, B/Yamagata and B/Victoria, have cocirculated globally. Current influenza vaccine formulations are trivalent and contain two influenza subtype A strains (A/H1N1 and A/H3N2) but only one B strain. In a half of recent influenza seasons, the predominant circulating influenza B lineage was different from that contained in trivalent influenza vaccines. A quadrivalent live-attenuated influenza vaccine (Q/LAIV) that contains two B strains, one from each lineage, has been developed to help provide broad protection against influenza B. Q/LAIV was recently approved for use in the USA in eligible individuals 2-49 years of age. This review summarizes clinical trial data in support of Q/LAIV.