Phase 2, Double-Blind, Placebo-controlled Trial of a c-Jun N-Terminal Kinase Inhibitor in Idiopathic Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis is a fatal and progressive disease with limited treatment options. Objectives: We sought to assess the efficacy and safety of CC-90001, an oral inhibitor of c-Jun N-terminal kinase 1, in patients with idiopathic pulmonary fibrosis. Methods: In a Phase 2, randomized (1:1:1), double-blind, placebo-controlled study (ClinicalTrials.gov ID: NCT03142191), patients received CC-90001 (200 or 400 mg) or placebo once daily for 24 weeks. Background antifibrotic treatment (pirfenidone) was allowed. The primary endpoint was change in the percentage of predicted FVC (ppFVC) from baseline to Week 24; secondary endpoints included safety. Measurements and Main Results: In total, 112 patients received at least one dose of study drug. The study was terminated early because of a strategic decision made by the sponsor. Ninety-one patients (81%) completed the study. The least-squares mean changes from baseline in ppFVC at Week 24 were -3.1% (placebo), -2.1% (200 mg), and -1.0% (400 mg); the differences compared with placebo were 1.1% (200 mg; 95% confidence interval: -2.1, 4.3; P = 0.50) and 2.2% (400 mg; 95% confidence interval: -1.1, 5.4; P = 0.19). Adverse event frequency was similar in patients in the combined CC-90001 arms versus placebo. The most common adverse events were nausea, diarrhea, and vomiting, which were more frequent in patients in CC-90001 arms versus placebo. Fewer patients in the CC-90001 arms than in the placebo arm experienced cough and dyspnea. Conclusions: Treatment with CC-90001 over 24 weeks led to numerical improvements in ppFVC in patients with idiopathic pulmonary fibrosis compared with placebo. CC-90001 was generally well tolerated, which was consistent with previous studies. Clinical trial registered with www.clinicaltrials.gov (NCT03142191).

CC-90001, a c-Jun N-terminal kinase (JNK) inhibitor, in patients with pulmonary fibrosis: design of a phase 2, randomised, placebo-controlled trial.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal interstitial lung disease (ILD); other ILDs have a progressive, fibrotic phenotype (PF-ILD). Antifibrotic agents can slow but not stop disease progression in patients with IPF or PF-ILD. c-Jun N-terminal kinases (JNKs) are stress-activated protein kinases implicated in the underlying mechanisms of fibrosis, including epithelial cell death, inflammation and polarisation of profibrotic macrophages, fibroblast activation and collagen production. CC-90001, an orally administered (PO), one time per day, JNK inhibitor, is being evaluated in IPF and PF-ILD. METHODS AND ANALYSIS: This is a phase 2, randomised, double-blind, placebo-controlled study evaluating efficacy and safety of CC-90001 in patients with IPF (main study) and patients with PF-ILD (substudy). Both include an 8-week screening period, a 24-week treatment period, up to an 80-week active-treatment extension and a 4-week post-treatment follow-up. Patients with IPF (n=165) will be randomised 1:1:1 to receive 200 mg or 400 mg CC-90001 or placebo administered PO one time per day; up to 25 patients/arm will be permitted concomitant pirfenidone use. Forty-five patients in the PF-ILD substudy will be randomised 2:1 to receive 400 mg CC-90001 or placebo. The primary endpoint is change in per cent predicted forced vital capacity from baseline to Week 24 in patients with IPF. ETHICS AND DISSEMINATION: This study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles and local ethical and legal requirements. Results will be reported in a peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT03142191.

Immunogenicity of Inactivated Varicella Zoster Vaccine in Autologous Hematopoietic Stem Cell Transplant Recipients and Patients With Solid or Hematologic Cancer.

BACKGROUND: In phase 3 trials, inactivated varicella zoster virus (VZV) vaccine (ZVIN) was well tolerated and efficacious against herpes zoster (HZ) in autologous hematopoietic stem cell transplant (auto-HSCT) recipients and patients with solid tumor malignancies receiving chemotherapy (STMc) but did not reduce HZ incidence in patients with hematologic malignancies (HMs). Here, we describe ZVIN immunogenicity from these studies. METHODS: Patients were randomized to ZVIN or placebo (4 doses). Immunogenicity was assessed by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and VZV interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay in patients receiving all 4 doses without developing HZ at the time of blood sampling. RESULTS: Estimated geometric mean fold rise ratios (ZVIN/placebo) by gpELISA and IFN-y ELISPOT ~28 days post-dose 4 were 2.02 (95% confidence interval [CI], 1.53-2.67) and 5.41 (95% CI, 3.60-8.12) in auto-HSCT recipients; 1.88 (95% CI, 1.79-1.98) and 2.10 (95% CI, 1.69-2.62) in patients with STMc; and not assessed and 2.35 (95% CI, 1.81-3.05) in patients with HM. CONCLUSIONS: ZVIN immunogenicity was directionally consistent with clinical efficacy in auto-HSCT recipients and patients with STMc even though HZ protection and VZV immunity were not statistically correlated. Despite a lack of clinical efficacy in patients with HM, ZVIN immunogenicity was observed in this population. Immunological results did not predict vaccine efficacy in these 3 populations. CLINICAL TRIAL REGISTRATION: NCT01229267, NCT01254630.

Cost and utility in immunocompromised subjects who developed herpes zoster during the randomized V212 inactivated varicella-zoster vaccine (ZVIN) trial.

Objectives: Immunocompromised subjects are at increased risk for herpes zoster (HZ) and HZ-related complications, such as post-herpetic neuralgia (PHN). We describe health utilities, health care resource utilization (HCRU), productivity loss and health care costs in recipients of autologous hematopoietic stem-cell transplantation (Auto-HSCT) who developed confirmed HZ in the phase 3 clinical trial. Methods: HCRU, costs, and EQ-5D-3L utility were assessed for 155 confirmed HZ cases observed after receiving inactivated varicella-zoster virus (VZV) vaccine (ZVIN) or placebo. In a prospective, longitudinal 6-month follow up, costs and utilities were analyzed for two health states, HZ without PHN and HZ with PHN. Results: There was a clinically relevant difference in utility between HZ without PHN (mean 0.814) and HZ with PHN (0.729). The disutility for HZ without PHN was estimated to -0.117 and to -0.186 for HZ with PHN. Direct costs (2017 USD) associated with a HZ without PHN episode and HZ with PHN episode was estimated at $3,412 and $3,711, respectively, of which hospitalizations accounted for 90% of the costs. Expert opinion: Both HZ and PHN are associated with considerable disutility in recipients of Auto-HSCT. Costs were comparable to published estimates in other immunocompromised subjects. The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT01229267).

Safety and efficacy of inactivated varicella zoster virus vaccine in immunocompromised patients with malignancies: a two-arm, randomised, double-blind, phase 3 trial.

BACKGROUND: Patients who are immunocompromised because of malignancy have an increased risk of herpes zoster and herpes zoster-related complications. We aimed to investigate the efficacy and safety of an inactivated varicella zoster virus (VZV) vaccine for herpes zoster prevention in patients with solid tumour or haematological malignancies. METHODS: This phase 3, two-arm, randomised, double-blind, placebo-controlled, multicentre trial with an adaptive design was done in 329 centres across 40 countries. The trial included adult patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies, either receiving or not receiving chemotherapy. Patients were randomly assigned (1:1) to receive four doses of VZV vaccine inactivated by γ irradiation or placebo approximately 30 days apart. The patients, investigators, trial site staff, clinical adjudication committee, and sponsor's clinical and laboratory personnel were masked to the group assignment. The primary efficacy endpoint was herpes zoster incidence in patients with solid tumour malignancies receiving chemotherapy, which was assessed in the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of inactivated VZV vaccine or placebo). The primary safety endpoint was serious adverse events up to 28 days after the fourth dose in patients with solid tumour malignancies receiving chemotherapy. Safety endpoints were assessed in all patients who received at least one dose of inactivated VZV vaccine or placebo and had follow-up data. This trial is registered (NCT01254630 and EudraCT 2010-023156-89). FINDINGS: Between June 27, 2011, and April 11, 2017, 5286 patients were randomly assigned to receive VZV vaccine inactivated by γ irradiation (n=2637) or placebo (n=2649). The haematological malignancy arm was terminated early because of evidence of futility at a planned interim analysis; therefore, all prespecified haematological malignancy endpoints were deemed exploratory. In patients with solid tumour malignancies in the modified intention-to-treat population, confirmed herpes zoster occurred in 22 of 1328 (6·7 per 1000 person-years) VZV vaccine recipients and in 61 of 1350 (18·5 per 1000 person-years) placebo recipients. Estimated vaccine efficacy against herpes zoster in patients with solid tumour malignancies was 63·6% (97·5% CI 36·4 to 79·1), meeting the prespecified success criterion. In patients with solid tumour malignancies, serious adverse events were similar in frequency across treatment groups, occurring in 298 (22·5%) of 1322 patients who received the vaccine and in 283 (21·0%) of 1346 patients who received placebo (risk difference 1·5%, 95% CI -1·7 to 4·6). Vaccine-related serious adverse events were less than 1% in each treatment group. Vaccine-related injection-site reactions were more common in the vaccine group than in the placebo group. In the haematological malignancy group, VZV vaccine was well tolerated and estimated vaccine efficacy against herpes zoster was 16·8% (95% CI -17·8 to 41·3). INTERPRETATION: The inactivated VZV vaccine was well tolerated and efficacious for herpes zoster prevention in patients with solid tumour malignancies receiving chemotherapy, but was not efficacious for herpes zoster prevention in patients with haematological malignancies. FUNDING: Merck & Co, Inc.

The Effect of Age on the Immunogenicity of the Live Attenuated Zoster Vaccine Is Predicted by Baseline Regulatory T Cells and Varicella-Zoster Virus-Specific T Cell Immunity.

Older age is associated with increased infectious morbidity and decreased immune responses to vaccines, but the mechanisms that mediate this effect are incompletely understood. The efficacy and immunogenicity of the live attenuated zoster vaccine (ZVL) have a very-well-described negative association with the age of the vaccinee. In a study of 600 ZVL recipients 50 to >80 years of age, we investigated immunological factors that might explain the effect of age on the immunogenicity of ZVL. Using FluoroSpot assays and flow cytometry, we determined that varicella-zoster virus (VZV)-specific peak T helper 1 (VZV-Th1) responses to ZVL were independently predicted by prevaccination VZV-Th1 responses, regulatory T cells (Treg), and PD1-expressing immune checkpoint T cells (Tcheck) but not by the age of the vaccinee. Persistence of VZV-Th1 1 year after vaccination was independently predicted by the factors mentioned above, by peak VZV-Th1 responses to ZVL, and by the age of the vaccinee. We further demonstrated by ex vivo blocking experiments the mechanistic role of PD1 and CTLA4 as modulators of decreased VZV-Th1 responses in the study participants. VZV-specific cytotoxic T cell (VZV-CTL) and T follicular helper responses to ZVL did not correlate with age, but similar to other Th1 responses, VZV-CTL peak and baseline responses were independently correlated. These data expand our understanding of the factors affecting the magnitude and kinetics of T cell responses to ZVL in older adults and show the importance of prevaccination Treg and Tcheck in modulating the immunogenicity of ZVL. This presents new potential interventions to increase vaccine responses in older adults.IMPORTANCE Vaccination is the most effective method to protect older adults against viral infections. However, the immunogenicity of viral vaccines in older adults is notoriously poor. The live attenuated zoster vaccine (ZVL) provides the best example of a gradual decrease of vaccine immunogenicity with every 10-year age increase above 50 years. Here we show that the abundance of regulatory T cells before vaccine administration to older adults has a significant inhibitory effect on immune responses to ZVL and, together with baseline immunity to varicella-zoster virus, explains the effect of age on the immunogenicity of ZVL. Moreover, in vitro blockade of regulatory T cell mechanisms of action with biologic modulators restores immune responses to varicella-zoster virus in vaccinees. Collectively, these observations suggest that immune modulators that block regulatory T cell activity may increase responses to viral attenuated vaccines in older adults.

Persistence of Varicella-Zoster Virus Cell-Mediated Immunity After the Administration of a Second Dose of Live Herpes Zoster Vaccine.

Protection against zoster conferred by zoster vaccine live (ZVL; Zostavax) wanes over time. We compared varicella-zoster virus cell-mediated immunity (VZV-CMI) of adults ≥70 years who received a second dose of ZVL ≥10 years after the initial dose with de novo-immunized age-matched controls. Before and during the first year after vaccination, VZV-CMI was significantly higher in reimmunized compared with de novo vaccinees. At 3 years, VZV-CMI differences between groups decreased and only memory responses remained marginally higher in reimmunized participants. In conclusion, the increase in VZV-CMI generated by reimmunization with ZVL is at least equally persistent compared with de novo immunization.

A post hoc analysis utilizing the FDA toxicity grading scale to assess injection site adverse events following immunization with the live attenuated Zoster Vaccine (ZVL).

BACKGROUND: ZOSTAVAX (ZVL; Zoster Virus Live), is a single dose, live, attenuated vaccine licensed for the prevention of herpes zoster (HZ) and post herpetic neuralgia (PHN) in adults ≥50 years of age. Injection site adverse events (AEs) of erythema, swelling and pain were solicited within 5 days post vaccination in the 2 pivotal studies of ZVL; ZEST (ZOSTAVAX Efficacy and Safety Trial) and SPS (Shingles Prevention Study). Protocol specified criteria were used to report the frequency and intensity of injection site AEs in ZEST and SPS studies. Subsequently, the FDA Toxicity Grading Scale provided guidance for uniform assessment of AEs across all adult vaccine clinical trials. The objective of this post-hoc analysis was to categorize the previously reported injection site AEs in two pivotal trials of ZVL according to the current FDA Toxicity Grading Scale. METHODS: The current FDA Toxicity Grading Scale provides a measure for classifying injection site AEs by four grades [Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe) and Grade 4 (life threatening)]. Injection site erythema, swelling, and pain intensity gradings were assigned to the respective FDA Toxicity Grade based on this appropriation. A descriptive analysis of the proportion and risk difference (within 95% confidence intervals) of injection site AEs per the FDA Toxicity Grading Scale is provided. RESULTS: The frequency of injection site AEs (erythema, swelling, pain) after subcutaneous vaccination with ZVL were higher in recipients of ZVL compared with placebo. Majority of the injection site AEs observed were Grade 1 (mild) or Grade 2 (moderate) in intensity. Additionally, Grade 3 (severe) injection site AEs were observed infrequently. CONCLUSIONS: Application of the FDA Toxicity Grading Scale provides a uniform AE assessment tool across different adult vaccines. This post hoc summary of injection site AEs using FDA Toxicity Grading Scale provides further evidence of low frequency of severe injection site AEs post ZVL vaccination.

Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international, multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT. METHODS: In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5-60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010-020150-34). FINDINGS: Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4-74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0·2%, 95% CI -5·1 to 5·5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0·1%, -1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22·6%, 95% CI 18·5-26·6; p<0·0001). INTERPRETATION: This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated. FUNDING: Merck & Co., Inc.

Safety and Immunogenicity of Zoster Vaccine Live in Human Immunodeficiency Virus-Infected Adults With CD4+ Cell Counts >200 Cells/mL Virologically Suppressed on Antiretroviral Therapy.

Background: Herpes zoster (HZ) risk is increased in human immunodeficiency virus (HIV)-infected persons. Live attenuated zoster vaccine (ZV) reduces HZ incidence and severity in adults; safety and immunogenicity data in HIV-infected adults are limited. Methods: We conducted a randomized, double-blind, placebo-controlled trial in HIV-infected adults virally suppressed on antiretroviral therapy (ART). Participants, stratified by CD4+ count (200-349 or ≥350 cells/µL), were randomized 3:1 to receive ZV or placebo on day 0 and week 6. The primary endpoint was serious adverse event or grade 3/4 signs/symptoms within 6 weeks after each dose. Immunogenicity (varicella zoster virus [VZV]-specific glycoprotein enzyme-linked immunosorbent assay and interferon-γ enzyme-linked immunospot assay responses) was assessed at 6 and 12 weeks postvaccination. Results: Of 395 participants (296 ZV vs 99 placebo), 84% were male, 47% white, 29% black, and 22% Hispanic; median age was 49 years. Safety endpoints occurred in 15 ZV and 2 placebo recipients (5.1% [95% confidence interval {CI}, 2.9%-8.2%] vs 2.1% [95% CI, .3%-7.3%]; P = .26). Injection site reactions occurred in 42% of ZV (95% CI, 36.3%-47.9%) vs 12.4% of placebo recipients (95% CI, 6.6%-20.6%) (P < .001). Week 12 median natural log VZV antibody titer was higher for ZV (6.30 [Q1, Q3, 5.64, 6.96]) vs placebo (5.48 [Q1, Q3, 4.63, 6.44]; P < .001) overall and in the high CD4+ stratum (P = .003). VZV antibody titers were similar after 1 or 2 ZV doses. Polymerase chain reaction-confirmed HZ occurred in 2 participants (1 ZV; 1 placebo); none was vaccine strain related. Conclusions: Two doses of ZV in HIV-infected adults suppressed on ART with CD4+ counts ≥200 cells/µL were safe and immunogenic. Clinical Trials Registration: NCT00851786.

Immunogenicity and safety of zoster vaccine live administered with quadrivalent influenza virus vaccine.

OBJECTIVES: Randomized, blinded, placebo-controlled trial to evaluate the safety and immunogenicity of ZOSTAVAX™ (ZV) administered concomitantly with quadrivalent inactivated influenza vaccine (IIV4) in adults≥50years of age (NCT02519855). METHODS: Overall, 440 participants were randomized into the Concomitant Group (CG) and 442 into the Sequential Group (SG). The CG received ZV and IIV4 at separate injection sites on Day 1 and matching placebo at Week 4. The SG received placebo and IIV4 (2015-2016 influenza season) at separate injection sites on Day 1 and ZV at Week 4. IMMUNOGENICITY ENDPOINTS: Varicella-zoster virus (VZV) antibody geometric mean titer (GMT) and geometric mean fold-rise (GMFR) from baseline to 4weeks postvaccination, measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and adjusted for age and prevaccination titer. Influenza strain-specific GMT at baseline and 4weeks postvaccination was measured by hemagglutination inhibition (HAI) assay. SAFETY ENDPOINTS: Injection-site and systemic adverse experiences (AEs) within 28days following any vaccination and serious AEs throughout the study. RESULTS: The adjusted VZV antibody GMT ratio (CG/SG) was 0.87 (95%CI: 0.80, 0.95), meeting the prespecified noninferiority criterion. The VZV antibody GMFR in the CG was 1.9 (95%CI: 1.76, 2.05), meeting the acceptability criterion. Influenza antibody GMT ratios for A/H1N1, A/H3N2, B/Yamagata and B/Victoria were 1.02 (95%CI: 0.88, 1.18), 1.10 (95%CI: 0.94, 1.29), 1.00 (95%CI: 0.88, 1.14), and 0.99 (95%CI: 0.87, 1.13), respectively. The frequency of vaccine-related injection-site and systemic AEs was comparable between groups. No vaccine-related serious AE was observed. CONCLUSION: The concomitant administration of ZV and IIV4 to adults≥50years of age induced VZV-specific and influenza-specific antibody responses that were comparable to those following administration of either vaccine alone, and was generally well tolerated.

Herpes zoster vaccine live: A 10 year review of post-marketing safety experience.

BACKGROUND: Zoster vaccine is a single dose live, attenuated vaccine (ZVL) indicated for individuals ≥50 years-old for the prevention of herpes zoster (HZ). Safety data from clinical trials and post-licensure studies provided reassurance that ZVL is generally safe and well tolerated. The objective of this review was to provide worldwide post-marketing safety information following 10 years of use and >34 million doses distributed. METHODS: All post-marketing adverse experience (AE) reports received worldwide between 02-May-2006 and 01-May-2016 from healthcare professionals following vaccination with ZVL and submitted to the MSD AE global safety database, were analyzed. RESULTS: A total of 23,556 AE reports, 93% non-serious, were reported. Local injection site reactions (ISRs), with a median time-to-onset of 2 days, were the most frequently reported AEs followed by HZ. The majority of HZ reports were reported within 2 weeks of vaccination and considered, based on time-to-onset, pathogenesis of HZ, and data from clinical trials, to be caused by wild-type varicella-zoster virus (VZV). HZ confirmed by PCR analysis to be VZV Oka/Merck vaccine-strain was identified in an immunocompetent individual 8 months postvaccination and in 4 immunocompromised individuals. Disseminated HZ was reported very rarely (<1%) with 38% occurring in immunocompromised individuals. All reports of disseminated HZ confirmed by PCR as VZV Oka/Merck vaccine-strain were in individuals with immunosuppressive conditions and/or therapy at the time of vaccination. CONCLUSIONS: The safety profile of ZVL, following 10 years of post-marketing use, was favorable and consistent with that observed in clinical trials and post-licensure studies.

Safety and Immunogenicity of Inactivated Varicella-Zoster Virus Vaccine in Adults With Autoimmune Disease: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Immunogenicity and safety of inactivated zoster vaccine (ZVIN) were evaluated in adults with autoimmune disease. METHODS: Adults with autoimmune disease treated with immunosuppressive therapy (biologic or nonbiologic) were randomized to receive 4 doses of ZVIN, ZVIN containing a higher quantity of antigen, or placebo. To measure varicella-zoster virus (VZV)-specific immune responses using glycoprotein enzyme-linked immunosorbent assay (gpELISA) and interferon-gamma enzyme-linked immunospot (IFN-γ ELISPOT), blood samples were collected at baseline, post-doses 2, 3, and 4. The primary hypothesis was that ZVIN would elicit significant VZV-specific immune responses, measured by gpELISA or ELISPOT, at approximately 28 days post-dose 4. Safety and tolerability was assessed through 28 days post-dose 4. RESULTS: ZVIN elicited a statistically significant VZV-specific immune response approximately 28 days post-dose 4, measured by gpELISA (estimated geometric mean fold rise from baseline [GMFR] = 1.6 [95% confidence interval [CI], 1.4,1.7], P value < .0001) and IFN-γ ELISPOT (estimated GMFR = 2.0 [95% CI, 1.6,2.6], P value < .0001); both results met the prespecified success criterion. Overall, 57% (164/289) of all ZVIN and 21% (13/62) of placebo recipients reported ≥1 injection-site adverse events (AEs), and 52% (149/289) and 47% (29/62) reported ≥1 systemic AEs, respectively. Eight ZVIN and 1 placebo recipients experienced serious AEs, including 2 events (ZVIN group) determined by the investigator to be vaccine related (keratitis; amnesia). Overall frequency of AEs decreased with subsequent doses of vaccine. CONCLUSIONS: In adults with autoimmune disease, ZVIN was well tolerated and elicited statistically significant VZV-specific immune responses approximately 28 days post-dose 4, measured by gpELISA and IFN-γ ELISPOT. CLINICAL TRIALS REGISTRATION: NCT01527383.

Studies with herpes zoster vaccines in immune compromised patients.

INTRODUCTION: The active component of the herpes zoster vaccine (ZVL), licensed for people ≥50 years of age, is a live attenuated varicella-zoster virus. ZVL is contraindicated for immune compromised individuals, with limited regard to the degree of immunosuppression. Areas covered: This review evaluates phase I and II and observational studies for ZVL, and published reports of the off-label use of ZVL, for conditions and therapies for which investigators considered the risk-benefit for using ZVL to be favorable. It also discusses exploratory trials of ZVL for additional immune compromising conditions, and summarizes clinical guidelines from many countries and professional societies that are based upon recent investigations. Studies in immune compromised patients of investigational vaccines that do not contain live virus are reviewed. Expert commentary: It is likely that past and ongoing research with ZVL will define immune compromising diseases and/or therapies for which the risk-benefit for using ZVL vaccine is favorable. The main variables to consider in this assessment in immune compromised patients are safety, immunogenicity, protection against herpes zoster, and persistence of protection. Vaccination against herpes zoster prior to suppressing immunity is an important clinical strategy, although efficacy of this approach has not been evaluated in a clinical trial.

A randomized, clinical trial to assess the relative efficacy and tolerability of two doses of etoricoxib versus naproxen in patients with ankylosing spondylitis.

BACKGROUND: This study evaluated two doses of etoricoxib (60 and 90 mg) vs. naproxen 1000 mg in subjects with ankylosing spondylitis (AS). METHODS: This was a 2-part, double-blind, active comparator-controlled non-inferiority study in subjects ≥18 years of age with AS. In Part I, subjects were randomized to naproxen 1000 mg; etoricoxib 60 mg, and 90 mg. In Part II, naproxen and etoricoxib 90 mg subjects continued on the same treatment; subjects on etoricoxib 60 mg either continued on 60 mg or escalated to 90 mg. Part I (6 weeks) assessed the efficacy of A) etoricoxib 60 mg vs. naproxen and B) 90 mg vs. naproxen according to the time-weighted average change from baseline in Spinal Pain Intensity (SPI; 0-100 mm VAS) (primary endpoint). The non-inferiority margin was set at 8 mm for SPI. In Part II (20 weeks) we evaluated the potential benefit of increasing from 60 to 90 mg (predefined minimum clinically important difference = 6 mm in SPI) for inadequate responders (<50 % improvement from baseline in SPI) on etoricoxib 60 mg in Part I. RESULTS: In total, 1015 subjects were randomized to receive etoricoxib 60 mg (N = 702), etoricoxib 90 mg (N = 156), and naproxen 1000 mg (N = 157); 70.9 % were male and the mean age was 45.2 years. There were 919 subjects who completed Part I and all continued to Part II. In Part I, SPI change was non-inferior for both etoricoxib doses vs. naproxen. In both Part I and II, the incidence of adverse events (AEs), drug-related AEs, and serious adverse events (SAEs) were similar between the 3 treatment groups. CONCLUSION: Both doses of etoricoxib were non-inferior to naproxen. All treatments were well tolerated. Etoricoxib 60 and 90 mg effectively control pain in patients with AS, with 60 mg once daily as the lowest effective dose for most patients. TRIAL REGISTRATION: Clinical Trials Registry # NCT01208207 . Registered on 22 September 2010.

Evaluation of two doses of etoricoxib, a COX-2 selective non-steroidal anti-inflammatory drug (NSAID), in the treatment of Rheumatoid Arthritis in a double-blind, randomized controlled trial.

BACKGROUND: Treatment with non-steroidal anti-inflammatory drugs (NSAID) is a common component of treatment regimens for rheumatoid arthritis (RA). Etoricoxib is a COX-2 selective NSAID that has demonstrated efficacy in the treatment of RA at a dose of 90 mg. The current study further evaluated the efficacy of etoricoxib 60 mg and 90 mg in RA patients with active disease. METHODS: This was a 2-part, double-blind, placebo-controlled study in RA (NCT01208181). Patients were required to have a diagnosis of RA (according to ARA 1987 revised classification criteria) and were to demonstrate symptom flare upon discontinuation of previous NSAID treatment prior to randomization. Part I was a 6-week, placebo-controlled period to assess the efficacy of etoricoxib 90 mg and etoricoxib 60 mg, each compared to placebo, as well as to each other. Part II was a 6-week period to evaluate the potential benefit of dose escalation from etoricoxib 60 mg to etoricoxib 90 mg after 6 weeks exposure to etoricoxib 60 mg in Part I compared to maintaining a steady dose of etoricoxib 60 mg throughout Parts I and II. Primary endpoints were Disease Activity Score evaluating 28 joints and C reactive protein level (DAS28-CRP) index and Patient Global Assessment of Pain (Pain) score (0-100 mm VAS) after 6 weeks of treatment in Part I. Adverse events were monitored throughout the study. RESULTS: In total, 1404 patients were randomized in a 2:7:7:8 ratio; 1228 patients completed Part I and 713 patients continued to Part II. Both etoricoxib doses were superior to placebo on both primary efficacy endpoints (p = 0.004 for 60 mg and p = 0.034 for 90 mg for DAS28-CRP; p < 0.001 for both doses for PGAP) in Part I. Further in Part I, etoricoxib 90 mg was not significantly different from 60 mg for DAS28-CRP, but did demonstrate a small, but statistically significant decrease in baseline PGAP score vs. 60 mg (p = 0.019). In Part II, there was no significant decrease in PGAP score after increasing to 90 mg in subjects with inadequate pain relief on 60 mg as compared to subjects who stayed on 60 mg. The incidence of AEs and SAEs were similar between etoricoxib 60 mg and 90 mg in both Part I and II. CONCLUSION: Both etoricoxib 90 mg and 60 mg are superior to placebo in relieving the symptoms of RA. Etoricoxib 90 mg vs 60 mg resulted in a statistically significant, though small, improvement in PGAP score, but not DAS28-CRP. Dose escalation from 60 mg to 90 mg in pain inadequate responders did not significantly improve efficacy. These results confirm the efficacy and tolerability of etoricoxib 90mg in patients with RA. In addition, this study demonstrated that etoricoxib 60 mg is also efficacious and well-tolerated in RA. CLINICAL TRIAL REGISTRATION: NCT01208181 (registered September 22, 2010).

Osteoarthritis patients with pain improvement are highly likely to also have improved quality of life and functioning. A post hoc analysis of a clinical trial.

BACKGROUND: This analysis evaluated whether osteoarthritis patients achieving the greatest pain control and lowest pain states also have the greatest improvement in functioning and quality of life. METHODS: Patients (n=419) who failed prior therapies and who were switched to etoricoxib 60mg were categorized as pain responders or non-responders at 4 weeks based on responder definitions established by the Initiative on Methods, Measurement, and Pain (IMMPACT) criteria, including changes from baseline of ≥15%, ≥30%, ≥50%, ≥70% and a final pain status of ≤3/10 (no worse than mild pain). Pain was assessed at baseline and 4 weeks using 4 questions from the Brief Pain Inventory (BPI) (worst pain, least pain, average pain, and pain right now), and also using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale. We examined the relationship between pain responses with changes from baseline in two functional measures (the BPI Pain Interference questions and the WOMAC Function Subscale) as well as changes from baseline in quality of life (assessed on the SF-36 Physical and Mental Component Summaries). We also sought to understand whether these relationships were influenced by the choice of the pain instrument used to assess response. We contrast the mean difference in improvements in the functional and quality of life instruments based on pain responder status (responder versus non-responder) and the associated 95% confidence limits around this difference. RESULTS: Patients with better pain responses were much more likely to have improved functional responses and improved quality of life, with higher mean changes in these outcomes versus pain non-responders, regardless of the choice of IMMPACT pain response definition (e.g., using any of 15%, 30%, 50%, 70% change from baseline) or the final pain state of ≤3/10. There was an evident gradient, where higher levels of pain response were associated with greater mean improvements in function and quality of life. The finding that greater pain responses led to greater functional improvements and quality of life gains was not dependent on the manner in which pain was evaluated. Five different pain instruments (e.g., the 4 questions on pain from the BPI pain questionnaire and the WOMAC pain subscale) consistently demonstrated that pain responders had statistically significantly greater improvements in function and quality of life compared to pain non-responders. This suggests these results are likely to be generalizable to any validated pain measure for osteoarthritis. CONCLUSIONS: Pain is an efficient outcome measure for predicting broader patient response in osteoarthritis. Patients who do not achieve timely, acceptable pain states over 4 weeks were less likely to experience functional or quality of life improvements. IMPLICATIONS: Good pain improvements in osteoarthritis with a valid pain instrument are a proxy for good improvements in both function and quality of life. Therefore proper osteoarthritis pain assessment can lead to efficient evaluations in the clinic.

Cellular and Humoral Responses to a Second Dose of Herpes Zoster Vaccine Administered 10 Years After the First Dose Among Older Adults.

BACKGROUND: Herpes zoster vaccine (ZV) was administered as a second dose to 200 participants ≥ 70 years old who had received a dose of ZV ≥ 10 years previously (NCT01245751). METHODS: Varicella zoster virus (VZV) antibody titers (measured by a VZV glycoprotein-based enzyme-linked immunosorbent assay [gpELISA]) and levels of interferon γ (IFN-γ) and interleukin 2 (IL-2; markers of VZV-specific cell-mediated immunity [CMI], measured by means of ELISPOT analysis) in individuals aged ≥ 70 years who received a booster dose of ZV were compared to responses of 100 participants aged 50-59 years, 100 aged 60-69 years, and 200 aged ≥ 70 years who received their first dose of ZV. The study was powered to demonstrate noninferiority of the VZV antibody response at 6 weeks in the booster-dose group, compared with the age-matched first-dose group. RESULTS: Antibody responses were similar at baseline and after vaccination across all age and treatment groups. Both baseline and postvaccination VZV-specific CMI were lower in the older age groups. Peak gpELISA titers and their fold rise from baseline generally correlated with higher baseline and postvaccination VZV-specific CMI. IFN-γ and IL-2 results for subjects ≥ 70 years old were significantly higher at baseline and after vaccination in the booster-dose group, compared with the first-dose group, indicating that a residual effect of ZV on VZV-specific CMI persisted for ≥ 10 years and was enhanced by the booster dose. CONCLUSIONS: These findings support further investigation of ZV administration in early versus later age and of booster doses for elderly individuals at an appropriate interval after initial immunization against HZ. CLINICAL TRIALS REGISTRATION: NCT01245751.

Conditional IL-2 Gene Deletion: Consequences for T Cell Proliferation.

To explore the role of interleukin-2 (IL-2) in T cell proliferation, and to circumvent the IL-2 deficiency autoimmune syndrome of conventional il2 gene deletion, mice were created to allow conditional il2 gene deletion when treated with the estrogen analog, tamoxifen (TAM) as adults. Splenocytes from four different mouse strains, C57Bl/6 wild type (WT), conventional IL-2(-/-), TAM-treated Cre recombinase-negative (Cre-)/IL2fl/fl, and Cre recombinase-positive (Cre+)/IL2fl/fl, were activated with anti-CD3 and anti-CD28, and monitored for CD4+ and CD8+ T cell lymphocyte blastogenesis, aerobic glycolysis, BrdU incorporation into newly synthesized DNA, and CFSE dye dilution to monitor cell division. IL-2 production was monitored by quantitative ELISA and multiple additional cytokines were monitored by quantitative protein-bead arrays. Splenocytes from conventional IL-2(-/-) and TAM-treated Cre+ mice resulted in undetectable IL-2 production by ELISA, so that both strains were IL-2-deficient. As monitored by flow cytometry, activated CD4+ and CD8+ T cells from WT, Cre+, and Cre- mice all underwent blastogenesis, whereas far fewer cells from conventional IL-2(-/-) mice did so. By comparison, only cells from IL-2 sufficient WT and Cre- mice switched to aerobic glycolysis as evidenced by a drop in media pH. Blastogenesis was mirrored by BrdU incorporation and CFSE dye dilution by CD4+ and CD8+ T cells from WT, Cre+, and Cre- mice, which were all equivalent, while proliferation of cells from conventional IL-2(-/-) mice was compromised. Splenocytes from IL-2 deficient conventional IL-2(-/-) mice produced low or undetectable other γ(c)-chain cytokines (IL-4, IL-7, IL-9, IL-13, IL-15, and IL-21), whereas production of these γ(c)-chain cytokines from IL-2-deficient conditional IL-2(-/-) Cre+ mice were comparable with WT and Cre- mice. These results indicate that CD4+ and CD8+ T cell blastogenesis cannot be attributable to IL-2 alone, but a switch to aerobic glycolysis was attributable to IL-2, and proliferation after CD3/CD28 activation is dependent on γ(c)-chain cytokines, and not CD3/28 triggering per se.

Effective adoptive therapy of tap-deficient lymphoma using diverse high avidity alloreactive T cells.

High avidity for antigen and diversity of T cell receptor (TCR) repertoire are essential for effective immunity against cancer. We have previously created a transgenic mouse strain with increased TCR avidity in a diverse T cell population. In this report, we show that strong alloreactive responses of transgenic T cells against targets with low MHC class I expression can be used for effective adoptive transfer of tumor immunity in vivo. Alloreactive transgenic T cells could be an effective therapeutic approach counteracting tumor evasion of the immune system.