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Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: A randomized clinical trial.

ABSTRACT: BACKGROUND:Cytomegalovirus (CMV) is a leading cause of congenital infection and an important target for vaccine development. METHODS:CMV seronegative girls between 12 and 17 years of age received CMV glycoprotein B (gB) vaccine with MF59 or saline placebo at 0, 1 and 6 months. Blood and urine were collected throughout the study for evidence of CMV infection based on PCR and/or seroconversion to non-vaccine CMV antigens. RESULTS:402 CMV seronegative subjects were vaccinated (195 vaccine, 207 placebo). The vaccine was generally well tolerated, although local and systemic adverse events were significantly more common in the vaccine group. The vaccine induced gB antibody in all vaccine recipients with a gB geometric mean titer of 13,400 EU; 95%CI 11,436, 15,700, after 3 doses. Overall, 48 CMV infections were detected (21 vaccine, 27 placebo). In the per protocol population (124 vaccine, 125 placebo) vaccine efficacy was 43%; 95%CI: -36; 76, p=0.20. The most significant difference was after 2 doses, administered as per protocol; vaccine efficacy 45%, 95%CI: -9; 72, p=0.08. CONCLUSION:The vaccine was safe and immunogenic. Although the efficacy did not reach conventional levels of significance, the results are consistent with a previous study in adult women (Pass et al. N Engl J Med 2009;360:1191) using the same formulation.

SUBMITTER: Bernstein DI

PROVIDER: S-EPMC4701617 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: A randomized clinical trial.

Bernstein David I DI Munoz Flor M FM Callahan S Todd ST Rupp Richard R Wootton Susan H SH Edwards Kathryn M KM Turley Christine B CB Stanberry Lawrence R LR Patel Shital M SM Mcneal Monica M MM Pichon Sylvie S Amegashie Cyrille C Bellamy Abbie R AR

Vaccine 20151202 3

<h4>Background</h4>Cytomegalovirus (CMV) is a leading cause of congenital infection and an important target for vaccine development.<h4>Methods</h4>CMV seronegative girls between 12 and 17 years of age received CMV glycoprotein B (gB) vaccine with MF59 or saline placebo at 0, 1 and 6 months. Blood and urine were collected throughout the study for evidence of CMV infection based on PCR and/or seroconversion to non-vaccine CMV antigens.<h4>Results</h4>402 CMV seronegative subjects were vaccinated ...[more]

PMID: 26657184

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Project description:BackgroundSlowing the decline in participation in physical activity among adolescent girls is a public health priority. This study reports the outcomes from a multi-component school-based intervention (Girls in Sport), focused on promoting physical activity among adolescent girls.MethodsGroup randomized controlled trial in 24 secondary schools (12 intervention and 12 control). Assessments were conducted at baseline (2009) and at 18 months post-baseline (2010). The setting was secondary schools in urban, regional and rural areas of New South Wales, Australia. All girls in Grade 8 in 2009 who attended these schools were invited to participate in the study (N?=?1769). Using a Health Promoting Schools and Action Learning Frameworks, each school formed a committee and developed an action plan for promoting physical activity among Grade 8 girls. The action plan incorporated strategies in three main areas - i) the formal curriculum, ii) school environment, and iii) home/school/community links - based on the results of formative data from target girls and staff and on individual needs of the school. A member of the research team supported each school throughout the intervention. The main outcome measure was accelerometer-derived total physical activity (TPA) spent in physical activity. Data were analyzed from December 2011 to March 2012.Results1518 girls (mean age 13.6y ±0.02) were assessed at baseline. There was a significant decline in TPA from baseline to 18-month follow-up with no differences between girls in the intervention and control schools. Only one-third of schools (4/12) implemented the intervention as per their action plan. Per-protocol analyses on these schools revealed a smaller decline in percentage of time spent in MVPA among girls in the intervention group (adjusted difference 0.5%, 95% CI?=?-0.01, 0.99, P?=?0.05).ConclusionsThe Girls in Sport intervention was not effective in reducing the decline in physical activity among adolescent girls. Lack of implementation by most intervention schools was the main reason for a null effect. Identifying strategies to enhance implementation levels is critical to determining the true potential of this intervention approach.Trial registrationThis study was retrospectively registered with the Australian New Zealand Clinical Trials Registry ACTRN12610001077055 . Date of registration: 7 December 2010.

Project description:Importance:Cigarette smoking is the leading cause of preventable morbidity and mortality in the United States and worldwide, and most tobacco users begin smoking in adolescence. Although advances have yielded efficacious pharmacotherapies to complement smoking cessation counseling in adults, far less progress has been made in addressing tobacco use in adolescence. Objective:To evaluate the efficacy and safety of varenicline tartrate for smoking cessation in adolescents and young adults. Design, Setting, and Participants:This 2-group randomized, placebo-controlled, double-blind intention-to-treat clinical trial enrolled a volunteer sample of treatment-seeking adolescent and young adult cigarette smokers (n?=?157) aged 14 to 21 years at an outpatient clinical site in Charleston, South Carolina, from August 15, 2012, to October 20, 2017. Follow-up was completed on January 25, 2018. Data were analyzed from March 19, 2018, to August 11, 2018, with further revisions completed April 10, 2019. Interventions:Participants were randomized in a 1:1 ratio to a 12-week course of varenicline (n?=?77) or placebo (n?=?80). All participants received weekly smoking cessation counseling. Main Outcomes and Measures:The preselected primary efficacy outcome was urine cotinine level-confirmed 7-day abstinence at the end of treatment. Secondary efficacy outcomes included weekly abstinence throughout active treatment, abstinence at posttreatment follow-up visits, and time to first 7-day abstinence. The primary safety outcome was the frequency of treatment-emergent adverse events. Results:A total of 157 participants were enrolled (94 male [59.9%]; mean [SD] age, 19.1 [1.5] years). The varenicline and placebo groups did not differ in the primary outcome of cotinine-confirmed self-reported 7-day abstinence at the end of treatment (varenicline group, 4 of 45 [8.9%]; placebo group, 4 of 45 [8.9%]; risk ratio [RR], 0.97; 95% CI, 0.29-2.99; P?=?.96). However, among secondary outcomes, the varenicline group achieved self-reported earlier abstinence of at least 7 days (hazard ratio, 1.91; 95% CI, 1.12-3.27) and demonstrated higher rates of self-reported weekly abstinence during the full course of treatment (RR, 1.81; 95% CI, 1.09-2.99; P?=?.02) and at posttreatment follow-up (RR, 1.82; 95% CI, 1.01-3.28; P?=?.02). Study medication was generally well tolerated, and treatment-emergent adverse events did not differ between groups (any adverse events, 55 [71.4%] in the varenicline group vs 60 [75.0%] in the placebo group; RR, 0.95; 95% CI, 0.79-1.15; P?=?.61). Conclusions and Relevance:When added to weekly cessation counseling for adolescent cigarette smokers, varenicline, compared with placebo, was well tolerated but did not improve end-of-treatment abstinence. However, varenicline may hasten abstinence and yield improvements in posttreatment abstinence outcomes. Trial Registration:ClinicalTrials.gov identifier: NCT01509547.

Project description:A vaccine to prevent maternal acquisition of human cytomegalovirus (HCMV) during pregnancy is a primary strategy to reduce the incidence of congenital disease. The MF59-adjuvanted glycoprotein B (gB) protein subunit vaccine (gB/MF59) is the most efficacious vaccine tested to date for this indication. We previously identified that gB/MF59 vaccination elicited poor neutralizing antibody responses and an immunodominant response against gB antigenic domain 3 (AD-3). Thus, we sought to test novel gB vaccines to improve functional antibody responses and reduce AD-3 immunodominance. Groups of juvenile New Zealand White rabbits were administered 3 sequential doses of the full-length gB protein with an MF59-like squalene-based adjuvant, the gB ectodomain protein (lacking AD-3) with squalene adjuvant, or lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA encoding full-length gB. All vaccines were highly immunogenic with similar kinetics and comparable peak gB-binding and functional antibody responses. The AD-3-immunodominant IgG response following human gB/MF59 vaccination was closely mimicked in rabbits. Though gB ectodomain subunit vaccination eliminated targeting of epitopes in AD-3, it did not improve vaccine-elicited neutralizing or nonneutralizing antibody functions. gB nucleoside-modified mRNA-LNP-immunized rabbits exhibited an enhanced durability of vaccine-elicited antibody responses. Furthermore, the gB mRNA-LNP vaccine enhanced the breadth of IgG binding responses against discrete gB peptides. Finally, low-magnitude gB-specific T cell activity was observed in the full-length gB protein and mRNA-LNP groups, though not in ectodomain-vaccinated rabbits. Altogether, these data suggest that the use of gB nucleoside-modified mRNA-LNP vaccines is a viable strategy for improving on the partial efficacy of gB/MF59 vaccination and should be further evaluated in preclinical models.IMPORTANCE Human cytomegalovirus (HCMV) is the most common infectious cause of infant birth defects, resulting in permanent neurological disability for one newborn child every hour in the United States. After more than a half century of research and development, we remain without a clinically licensed vaccine or immunotherapeutic to reduce the burden of HCMV-associated disease. In this study, we sought to improve upon the glycoprotein B protein vaccine (gB/MF59), the most efficacious HCMV vaccine evaluated in a clinical trial, via targeted modifications to either the protein structure or vaccine formulation. Utilization of a novel vaccine platform, nucleoside-modified mRNA formulated in lipid nanoparticles, increased the durability and breadth of vaccine-elicited antibody responses. We propose that an mRNA-based gB vaccine may ultimately prove more efficacious than the gB/MF59 vaccine and should be further evaluated for its ability to elicit antiviral immune factors that can prevent HCMV-associated disease.

Project description:BACKGROUND:Adolescent females with ovarian failure require estrogen therapy for induction of puberty and other important physiologic effects. Currently, health care providers have varying practices without evidence-based standards, thus investigating potential differences between oral and transdermal preparations is essential. The purpose of this study was to compare the differential effects of treatment with oral conjugated equine estrogen (OCEE), oral 17? estradiol (OBE), or transdermal 17? estradiol (TBE) on biochemical profiles and feminization in girls with ovarian failure. STUDY DESIGN:20 prepubertal adolescent females with ovarian failure, ages 12-18 years, were randomized to OCEE (n?=?8), OBE (n?=?7), or TBE (n?=?5) for 24 months. Estrogen replacement was initiated at a low dose (0.15 mg OCEE, 0.25 mg OBE, or 0.0125 mg TBE) and doubled every 6 months to a maximum dose of 0.625 mg/d OCEE, 1 mg/d OBE, or 0.05 mg/d TBE. At 18 months, micronized progesterone was added to induce menstrual cycles. Biochemical markers including sex hormones, inflammatory markers, liver enzymes, coagulation factors, and lipids were obtained at baseline and 6 month intervals. Differences in levels of treatment parameters between the groups were evaluated with one-way analysis of variance (ANOVA). The effect of progesterone on biochemical markers was evaluated with the paired t-test. RESULTS:Mean (±SE) estradiol levels at maximum estrogen dose (18 months) were higher in the TBE group (53?±?19 pg/mL) compared to OCEE (14?±?5 pg/mL) and OBE (12?±?5 pg/mL) (p???0.01). The TBE and OBE groups had more effective feminization (100% Tanner 3 breast stage at 18 months). There were no statistical differences in other biochemical markers between treatment groups at 18 months or after the introduction of progesterone. CONCLUSIONS:Treatment with transdermal 17? estradiol resulted in higher estradiol levels and more effective feminization compared to oral conjugated equine estrogen but did not result in an otherwise different biochemical profile in this limited number of heterogeneous patients. OBE and TBE provide safe and effective alternatives to OCEE to induce puberty in girls, but larger prospective randomized trials are required. TRIAL REGISTRATION: CLINICAL TRIALS IDENTIFIER:NCT01023178.

Dataset Information

Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: A randomized clinical trial.

Publications

Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: A randomized clinical trial.

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