Immunogenicity and Safety of a 3-Antigen Hepatitis B Vaccine vs a Single-Antigen Hepatitis B Vaccine: A Phase 3 Randomized Clinical Trial.

Importance: There is a need for improved immunogenicity of hepatitis B virus (HBV) vaccines among young adults with risk of infection. Objectives: To demonstrate manufacturing equivalence of a 3-antigen (3A) HBV vaccine, evaluate noninferiority of seroprotection rate (SPR) of 3A-HBV vs single-antigen (1A) HBV after 2 and 3 vaccine doses, and compare safety and reactogenicity between 3A-HBV and 1A-HBV vaccines. Design, Setting, and Participants: This phase 3, double-blinded, randomized clinical trial included healthy adults aged 18 to 45 years randomized to 1 of three 3A-HBV groups or 1 control group receiving 1A-HBV. The trial was conducted at 37 community clinics and academic hospitals in Canada, Europe, the United Kingdom, and the United States between December 2017 and October 2019. Participants were followed up for 48 weeks after the first vaccination. Interventions: Intramuscular administration of 3A-HBV (10 µg) or 1A-HBV (20 µg) on days 0, 28, and 168. Main Outcomes and Measures: Geometric mean concentration (GMC) of serum hepatitis B surface antibodies (anti-HBs) and proportion of participants achieving seroprotection. Results: Of 2838 participants, 1638 (57.8%) were women, 2595 (91.5%) were White, and 161 (5.7%) were Black or African American. A total of 712 participants (25.1%) were randomized to the 1A-HBV group and 2126 (74.9%) to 3A-HBV. The mean (SD) age at informed consent was 33.5 (8.0) years. The study demonstrated 3A-HBV lot-to-lot consistency, as the 2-sided 95% CIs for each pairwise comparison for the anti-HBs GMC ratios were within 0.67 and 1.50 (eg, adjusted GMC ratio, lot A vs lot B: 0.82; 95% CI, 0.67-1.00; lot A vs lot C: 0.95; 95% CI, 0.78-1.15; lot B vs lot C: 1.16; 95% CI, 0.95-1.41). The SPR of the pooled 3A-HBV was noninferior to 1A-HBV and higher than 1A-HBV after 2 vaccinations at day 168 (90.4% [95% CI, 89.0%-91.8%] vs 51.6% [95% CI, 47.5%-55.6%]) and 3 vaccinations at day 196 (99.3% [95% CI, 98.7%-99.6%] vs 94.8% [95% CI, 92.7%-96.4%]). The mean GMC of anti-HBs with 3A-HBV was 7.9 times higher after 2 vaccinations at day 168 and 3.5 times higher after 3 vaccinations at day 196 compared with 1A-HBV (after 2 vaccinations, 3A-HBV: GMC, 118.7 mIU/mL; 95% CI, 108.0-129.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: GMC, 15.0 mIU/mL; 95% CI, 12.9-17.5 mIU/mL; SE, 1.0 mIU/mL; after 3 vaccinations, 3A-HBV: GMC, 5442.4 mIU/mL; 95% CI, 4967.0-5963.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: 1567.2 mIU/mL; 95% CI, 1338.0-1834.0 mIU/mL; SE, 1.0 mIU/mL). Rates of local and systemic reactogenicities were higher with 3A-HBV compared with 1A-HBV (local: 1805 of 2124 [85.0%] vs 469 of 712 [65.9%]; systemic: 1445 [68.0%] vs 428 [60.1%]). Vaccine discontinuation due to adverse events (AE) was uncommon, and serious AEs were infrequent, reported in 42 participants (2.0%) and 3 participants (0.4%) in the 3A-HBV and 1A-HBV groups, respectively. Conclusions and Relevance: In this study, consistently higher antibody concentrations and SPRs were found with 3A-HBV after 2 and 3 doses vs 1A-HBV in adults aged 18 to 45 years old. The safety and efficacy of 3A-HBV shows its usefulness for the prevention of hepatitis B in young healthy adults. Trial Registration: Clinicaltrials.gov Identifier: NCT03408730; EU Clinical Trials Number: 2017-001820-22.

Immunogenicity and safety of a tri-antigenic versus a mono-antigenic hepatitis B vaccine in adults (PROTECT): a randomised, double-blind, phase 3 trial.

BACKGROUND: The seroprotection rate (SPR) of hepatitis B vaccination in adults is suboptimal. The aim of this study was to compare the SPR of a tri-antigenic hepatitis B vaccine (TAV), with a mono-antigenic vaccine (MAV) in adults of all ages. METHODS: This was a multicentre, double-blind, phase 3, randomised controlled trial (PROTECT) comparing the immunogenicity and safety of TAV with MAV in 28 community and hospital sites in the USA, Finland, Canada, and Belgium. Adults (aged ≥18 years) seronegative for hepatitis B virus (HBV), including those with well-controlled common chronic conditions, were randomly assigned (1:1) and stratified by study centre and age according to a web-based permuted blocked randomisation. Participants received either TAV or MAV which were administered as an intramuscular dose (1 mL) of TAV (10 µg; Sci-B-Vac, VBI Vaccines [SciVac, Rehovot, Israel]) or MAV (20 µg; Engerix-B [GlaxoSmithKline Biologicals, Rixensart, Belgium]) on days 0, 28, and 168 with six study visits and 24 weeks of follow-up after the third vaccination. Participants, investigators, and those assessing outcomes were masked to group assignment. The co-primary outcomes were to show non-inferiority of the SPRs 4 weeks after the third vaccination with TAV versus MAV in adults aged 18 years and older, as well as superiority in adults aged 45 years and older. SPR was defined as the percentage of participants attaining anti-HBs titres of 10 mIU/mL or higher. Non-inferiority of TAV to MAV was concluded if the lower limit of the 95% CI for the between-group difference was greater than -5%. Non-inferiority was assessed in the per-protocol set of participants (aged ≥18 years) and superiority was assessed in all participants (aged ≥45 years) who received at least one vaccination and had at least one evaluable immunogenicity sample after baseline (full analysis set). Safety analyses were a secondary outcome and included all participants who received at least one injection. This trial is registered at Clinicaltrials.gov (NCT03393754) and EudraCT (2017-001819-36) and is closed to new participants. FINDINGS: Between Dec 13, 2017, and April 8, 2019, 1607 participants (796 allocated to TAV and 811 allocated to MAV) were randomly assigned and distributed across age cohorts of 18-44 years (299 of 1607; 18·6%), 45-64 years (716 of 1607; 44·6%), and 65 years and older (592 of 1607; 36·8%). In participants aged 18 years and older, SPR was 91·4% (656 of 718) in the TAV group versus 76·5% (553 of 723) in the MAV group (difference 14·9%, 95% CI 11·2-18·6), showing non-inferiority in the per-protocol set. In participants aged 45 years and older, SPR was 89·4% (559 of 625) in the TAV group versus 73·1% (458 of 627) in the MAV group (difference 16·4%, 95% CI 12·2-20·7), showing superiority in the full analysis set. TAV was associated with higher rates of mild or moderate injection site pain (63·2% [503 of 796] in TAV vs 36·3% [294 of 811] in MAV), tenderness (60·8% [484 of 796] in TAV vs 34·8% [282 of 811] in MAV), and myalgia (34·7% [276 of 796] vs 24·3% [197 of 811] in MAV). Otherwise, the safety profile of TAV was similar to that of MAV. INTERPRETATION: The safety and efficacy of TAV shows its usefulness for the prevention of HBV infection in adults, including those with stable and controlled chronic conditions. FUNDING: VBI Vaccines.

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine.

BACKGROUND: Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. METHODS: This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 µg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. RESULTS: The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. CONCLUSIONS: The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).

Safety and immunogenicity of a novel hexavalent group B streptococcus conjugate vaccine in healthy, non-pregnant adults: a phase 1/2, randomised, placebo-controlled, observer-blinded, dose-escalation trial.

BACKGROUND: Group B streptococcus (GBS) is a major cause of invasive disease in young infants. Infants born to women with sufficient pre-existing anti-GBS capsular IgG antibodies are at reduced risk of GBS disease, making maternal immunisation a potential strategy for prevention. We aimed to assess the safety and immunogenicity of a novel hexavalent (serotypes Ia, Ib, II, III, IV, and V) GBS conjugate vaccine (GBS6). METHODS: This phase 1/2, placebo-controlled, observer-blinded, dose-escalation trial, was done at four clinical research centres in the USA (Kentucky, Georgia, and two sites in Utah). Healthy, non-pregnant adults aged 18-49 years were randomly assigned using an interactive, web-based response technology system. Within each dose group (low, medium, or high), participants in sentinel cohorts were randomly assigned 2:2:1 and expanded cohort participants were randomly assigned 4:4:1 to receive GBS6 with aluminium phosphate (AlPO4), GBS6 without AlPO4, or placebo (saline control). One 0·5 mL dose of either saline placebo or 5 µg capsular polysaccharide per serotype in the low-dose group, 10 µg capsular polysaccharide per serotype in the medium-dose group, or 20 µg capsular polysaccharide per serotype in the high-dose group was administered by intramuscular injection into the deltoid muscle on day 1. The primary outcome was safety up to 6 months after vaccination, including the proportion of sentinel cohort participants with clinical laboratory abnormalities at 1 week, the proportion of all participants reporting solicited local reactions, systemic events, or use of antipyretic or pain medication within 14 days, adverse events up to 1 month, and medically attended or serious adverse events up to 6 months. The secondary outcome was GBS immunogenicity (serotype-specific IgG geometric mean concentrations at 1 month). This study is registered with ClinicalTrials.gov, NCT03170609. FINDINGS: Between June 5, 2017, and June 25, 2018, 365 participants were randomly assigned and 364 (52 in each dose group) were vaccinated and included in the safety analysis. Unsolicited adverse events were reported by 15 (29%) participants in the 5 µg with AlPO4 group, 13 (25%) in the 5 µg without AlPO4 group, 22 (42%) in the 10 µg with AlPO4 group, 12 (23%) in the 10 µg without AlPO4 group, 25 (48%) in the 20 µg with AlPO4 group, 21 (40%) in the 20 µg without AlPO4 group, and 20 (38%) in the placebo group. The most common unsolicited adverse events were in the system organ class of infections and infestations in any dose or formulation of GBS6 (ranging from six [12%] in the 10 µg without AlPO4 group to 15 [29%] in the 20 µg with AlPO4 group and placebo group). Three participants reported at least one serious adverse event during the study, one each in the 5 µg GBS6 with AlPO4 group (diabetic ketoacidosis, two events; resolved), 10 µg GBS6 with AlPO4 group (died by suicide), and 20 µg GBS6 with AlPO4 group (metrorrhagia; resolved). None of these serious adverse events were considered related to the vaccine. 11 of the 365 participants were excluded from the evaluable immunogenicity population, including one participant who did not receive the vaccine, and ten who at 1 month after vaccination were withdrawn for various reasons. GBS serotype-specific IgG geometric mean concentrations increased by 1 week after vaccination for all GBS6 groups, peaked at 2 weeks, stabilised by 1 month, and declined gradually but remained higher than placebo at 6 months. INTERPRETATION: GBS6 was well tolerated in healthy adults and elicited robust immune responses for all dose levels and formulations that persisted 6 months after vaccination. This study supports further evaluation of GBS6 in pregnant women. FUNDING: Pfizer.

Immunogenicity and safety of lyophilized and liquid dengue tetravalent vaccine candidate formulations in healthy adults: a randomized, phase 2 clinical trial.

Takeda has developed a live-attenuated dengue tetravalent vaccine candidate (TAK-003) which has been shown to be immunogenic with acceptable reactogenicity in phase 1 trials. In agreement with World Health Organization prequalification requirements for dengue vaccines, Takeda has manufactured a lyophilized formulation of TAK-003 that allows stable storage at +2°C to +8°C. This randomized, double-blind, phase 2 study (NCT02193087) was performed in 1002 healthy dengue-naïve adults, 18-49 years of age, across seven centers in the USA to compare the safety and immunogenicity of one or two doses of a lyophilized TAK-003 formulation with the liquid TAK-003 formulation used in previous phase 1 studies. The primary objective was to show immunologic equivalence in terms of geometric mean titers (GMT) of neutralizing antibodies to the four dengue serotypes one month after one dose of the lyophilized and liquid formulations. Secondary assessments were of safety and seropositivity rates, including after a second dose. The primary endpoint was not met, because immunologic equivalence after one dose was only shown for the DENV-2 serotype. Nonetheless, GMTs and seropositivity rates to all four serotypes were achieved with all formulations after two doses and are in line with what was observed in previous studies. Additionally, in view of the acceptable reactogenicity, with no vaccine-related serious adverse events reported, these data support continuing further clinical development of the lyophilized TAK-003 formulation.

The adjuvanted recombinant zoster vaccine co-administered with a tetanus, diphtheria and pertussis vaccine in adults aged ≥50 years: A randomized trial.

BACKGROUND: This study evaluated immunogenicity and safety of the adjuvanted recombinant zoster vaccine (RZV) and the reduced-antigen-content diphtheria-tetanus-acellular pertussis vaccine (Tdap) when co-administered in adults aged ≥50 years. METHODS: In this open label, multi-center study (NCT02052596), participants were randomized 1:1 to the Co-Administration group (RZV dose 1 and Tdap at Day 0 [D0], RZV dose 2 at Month 2 [M2]) or Control group (Tdap at D0, RZV dose 1 at M2, RZV dose 2 at M4). Co-primary objectives were evaluation of the vaccine response rate (VRR) to RZV in the Co-Administration group, and demonstration of non-inferiority of the humoral responses to RZV and Tdap in the Co-Administration compared to Control group. Reactogenicity and safety of RZV and Tdap were also assessed. RESULTS: VRR to RZV was 97.8% in the Co-Administration group. The non-inferiority criterion was met for the humoral response to RZV and for 4 Tdap antigens, but was not met for the Tdap antigen pertactin. Occurrences of solicited, unsolicited and serious adverse events, and potential immune-mediated diseases were similar between groups. CONCLUSIONS: Co-administration of RZV and Tdap did not interfere with the humoral immune response to RZV or 4 of the 5 Tdap antigens. No safety concerns were identified.

Long-term safety and efficacy of olopatadine-mometasone combination nasal spray in patients with perennial allergic rhinitis.

Background: Safety and efficacy of GSP301 nasal spray, an investigational fixed-dose combination of olopatadine hydrochloride and mometasone furoate, was established in three large, 2-week seasonal allergic rhinitis studies. Objective: To evaluate long-term (52 weeks) safety and efficacy of GSP301 in patients with perennial allergic rhinitis (PAR). Methods: In this randomized, double-blind, parallel-group study, 601 patients (ages ≥ 12 years) with PAR were randomized 4:1:1 to twice-daily GSP301 (olopatadine 665 µg and mometasone 25 µg [pH 3.7]) or two GSP301 vehicle formulations (placebo pH 3.7 or 7.0). Safety (primary end point) was monitored through adverse events (AE), laboratory assessments, vital signs, and physical examinations at weeks 30 and 52. The change from baseline in the average A.M. reflective Total Nasal Symptom Score (rTNSS) and instantaneous Total Nasal Symptom Score (iTNSS), Physician-assessed Nasal Symptom Scores (PNSS), and quality of life were assessed for GSP301 versus placebo pH 3.7 (p < 0.05 was considered statistically significant). Results: At week 52, treatment-emergent AEs (TEAE) occurred in 51.7, 41.4, and 53.5% of patients in the GSP301, placebo pH 3.7 and placebo 7.0 groups, respectively. No clinically meaningful differences were observed in TEAE incidences or other safety assessments across treatments. At weeks 6 and 30, GSP301 provided significant and clinically meaningful improvements in average rTNSS and iTNSS versus placebo pH 3.7 (p < 0.01, all comparisons). Similarly, at week 52, GSP301 provided significant and clinically meaningful improvements in rTNSS (least-squares mean difference -0.91 [95% confidence interval {CI}, -1.35 to -0.47]; p < 0.001), and iTNSS (least-squares mean difference -0.75 [95% CI, -1.17 to -0.33]; p < 0.001) versus placebo pH 3.7, with significant improvements in each individual symptom (p < 0.05, all comparisons). PNSS and quality of life were significantly improved versus placebo pH 3.7 at weeks 6 and 30 (p < 0.05, all comparisons), but these greater improvements did not reach statistical significance at week 52 (PNSS, p = 0.552; quality of life, p = 0.790). Conclusion: Twice-daily GSP301 was well tolerated and provided statistically significant and clinically meaningful improvements in PAR nasal symptoms versus placebo over 52 weeks and demonstrated a favorable safety profile and efficacy.Clinical trial NCT02709538, www.clinicaltrials.gov.

Immunogenicity and safety of an AS03-adjuvanted H7N1 vaccine in healthy adults: A phase I/II, observer-blind, randomized, controlled trial.

BACKGROUND: H7 influenza strains have pandemic potential. AS03-adjuvanted H7N1 A/mallard/Netherlands/12/2000 split-virion vaccine formulations were evaluated as model H7-subtype vaccine and tested after H7N9 emerged in China, and caused severe human disease with high mortality. METHODS: In this phase I/II, observer-blind, randomized trial in US and Canada, 420 healthy adults (21-64years) were randomized to receive 1 of 4 H7N1 vaccine formulations (3.75 or 7.5µg hemagglutinin adjuvanted with either AS03A or AS03B), 15µg unadjuvanted H7N1 hemagglutinin, or saline placebo, given as 2-dose series. Immunogenicity was assessed using hemagglutination-inhibition (HI) and microneutralization (MN) assays, at day 42 (21days post-dose 2), month 6, and month 12 (HI only) for the per-protocol cohorts (398, 379 and 368 participants, respectively). Safety is reported up to month 12. RESULTS: Beneficial AS03 adjuvant effect was demonstrated. Committee for Medical Products for Human Use, and Center for Biologics Evaluation and Research (CBER) criteria were met for all adjuvanted formulations at day 42 (H7N1 HI assay); seroprotection (SPR) and seroconversion rates (SCR) were 88.5-94.8%, mean geometric increase (MGI) 19.2-34.9, and geometric mean titers (GMT) 98.3-180.7. Unadjuvanted H7N1 vaccine did not meet CBER criteria. In adjuvanted groups, antibody titers decreased over time; month 12 SPRs and GMTs were low (2.0-18.8% and 8.1-12.2). MN antibodies showed similar kinetics, with titers persisting at higher range than HI at month 6. All adjuvanted groups showed cross-reactivity against H7N9, with HI responses similar to H7N1. The most frequent solicited symptom in adjuvanted groups was injection site pain (71.2-86.7%); grade 3 solicited symptoms were infrequent. Nine participants reported 17 serious adverse events; none were considered causally related to vaccination. CONCLUSIONS: Adjuvanted H7N1 vaccine formulations had an acceptable safety profile and induced an antibody response after 2 doses with cross-reactivity to H7N9. ClinicalTrials.gov: NCT01934127.

Immunogenicity and Safety of an AS03-Adjuvanted H7N9 Pandemic Influenza Vaccine in a Randomized Trial in Healthy Adults.

BACKGROUND: Almost 700 cases of human infection with avian influenza A/H7N9 have been reported since 2013. Pandemic preparedness strategies include H7N9 vaccine development. METHODS: We evaluated an inactivated H7N9 vaccine in an observer-blind study in healthy adults aged 18-64 years. Participants (420) were randomized to receive 1 of 4 AS03-adjuvanted vaccines (low or medium dose of hemagglutinin with AS03A or AS03B), one nonadjuvanted vaccine, or placebo. The coprimary immunogenicity objective determined whether adjuvanted vaccines elicited an immune response against the vaccine-homologous virus, 21 days after the second vaccine dose per US and European licensure criteria in the per-protocol cohort (n = 389). RESULTS: All adjuvanted vaccines met regulatory acceptance criteria. In groups receiving adjuvanted formulations, seroconversion rates were ≥85.7%, seroprotection rates ≥91.1%, and geometric mean titers ≥92.9% versus 23.2%, 28.6%, and 17.2 for the nonadjuvanted vaccine. The AS03 adjuvant enhanced immune response at antigen-sparing doses. Injection site pain occurred more frequently with adjuvanted vaccines (in ≤98.3% of vaccinees) than with the nonadjuvanted vaccine (40.7%) or placebo (20.0%). None of the 20 serious adverse events reported were related to vaccination. CONCLUSIONS: Two doses of AS03-adjuvanted H7N9 vaccine were well tolerated and induced a robust antibody response at antigen-sparing doses in healthy adults. CLINICAL TRIALS REGISTRATION: NCT01999842.

No hypothalamic-pituitary-adrenal function effect with beclomethasone dipropionate nasal aerosol, based on 24-hour serum cortisol in pediatric allergic rhinitis.

BACKGROUND: Intranasal corticosteroids are the mainstay of allergic rhinitis (AR) treatment. Their potential to suppress the hypothalamic-pituitary-adrenal axis should be evaluated, especially after long-term daily use in children. OBJECTIVE: To evaluate the effects of treatment with non-aqueous beclomethasone dipropionate (BDP) nasal aerosol on hypothalamic-pituitary-adrenal axis function in children with perennial AR. METHODS: In this double-blinded, placebo-controlled, parallel-group study, patients (6-11 years old) with perennial AR were randomized (2:1) to BDP nasal aerosol at 80 µg/day (n = 67) or placebo (n = 32). The primary end point was change from baseline in 24-hour serum cortisol (SC) weighted mean for BDP nasal aerosol and placebo after 6 weeks of treatment, which was analyzed in the per-protocol population. RESULTS: The per-protocol population included 97 patients (BDP nasal aerosol, n = 66; placebo, n = 31). Baseline geometric mean SC weighted mean values were similar in the 80-µg/day BDP nasal aerosol and placebo groups (5.97 and 6.47 µg/dL, respectively). After 6 weeks' treatment, geometric mean values were 6.19 and 7.13 µg/dL, respectively, with no decrease from baseline in either group. Geometric mean SC ratio of BDP nasal aerosol at 80 µg/day to placebo was 0.91 (95% confidence interval 0.81-1.03), indicating predefined noninferiority. SC concentration-time profiles were similar for the placebo and 80-µg/day BDP nasal aerosol groups at baseline and week 6. BDP nasal aerosol at 80 µg/day was generally well tolerated. CONCLUSION: In pediatric patients with perennial AR, 24-hour SC profiles were comparable for BDP nasal aerosol and placebo, indicating that once-daily BDP nasal aerosol treatment did not significantly affect hypothalamic-pituitary-adrenal axis function. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01697956.

Immunogenicity and Safety of an EB66 Cell-Culture-Derived Influenza A/Indonesia/5/2005(H5N1) AS03-Adjuvanted Vaccine: A Phase 1 Randomized Trial.

BACKGROUND: Cell-culture-derived (CC) influenza vaccine production methods could provide benefits over classical embryonated-egg technology, including a higher production capacity and the faster creation of a supply that meets demand. METHODS: A CC-inactivated split-virus influenza A/Indonesia/5/2005(H5N1) vaccine derived from the EB66 cell line (hereafter, "CC-H5N1") was investigated in a phase 1 randomized, blinded study. Healthy adults (n = 521) received 2 vaccine doses (days 0 and 21) of either investigational CC-H5N1 vaccine (1.9 µg or 3.75 µg of hemagglutinin antigen [HA] with the AS03 adjuvant system or 15 µg of plain HA), embryonated-egg-derived vaccines (3.75 µg of HA with AS03 or 15 µg of plain HA), or placebo. Assessment of the adjuvant effect and immunogenicity was performed using Center for Biologics Evaluation and Research acceptability criteria 21 days after dose 2. Safety was assessed until month 12. RESULTS: AS03-adjuvanted CC-H5N1 elicited a homologous hemagglutination inhibition antibody response that satisfied immunogenicity criteria 21 days after dose 2 and persisted at month 12. Adjuvant effect and immune response against a drift-variant strain were demonstrated. No vaccine-related serious adverse events were reported. The immunogenicity and safety of the CC-H5N1 formulation containing 3.75 µg of HA and AS03 appeared to be similar to those for the licensed egg-derived AS03-adjuvanted control vaccine. CONCLUSIONS: The feasibility of the EB66 cell line to produce an immunogenic influenza vaccine with acceptable safety profile was demonstrated. Antigen sparing was achieved through combination with AS03 adjuvant. This CC-H5N1 might contribute to the rapid access of vaccine in the event of an influenza A(H5N1) pandemic. CLINICAL TRIALS REGISTRATION: NCT01236040.

Effect of intranasal triamcinolone acetonide on basal hypothalamic-pituitary-adrenal axis function in children with allergic rhinitis.

Intranasal corticosteroids are the most effective medication class for controlling allergic rhinitis (AR) symptoms. However, limited data are available on their effects on basal hypothalamic-pituitary-adrenal (HPA) axis function in children. This study was designed to determine the effect of 6-week triamcinolone acetonide aqueous (TAA-AQ) nasal spray treatment on HPA axis function by measuring 24-hour serum cortisol area under the curve (AUC(0-24h)) in children with AR aged 2-11 years. This phase 4, multicenter, double-blind, placebo-controlled, parallel-group study randomized children with AR to receive TAA-AQ (110 µg, 2-11 years old, or 220 µg, 6-11 years old) or placebo. At pre- and posttreatment domiciled visits, 24-hour serum cortisol and reflective total nasal symptom scores (rTNSSs) were assessed. Safety assessment included treatment-emergent adverse events (TEAEs) at each visit and trough levels of 24-hour serum cortisol. A total of 140 subjects (mean age, 7.2 years; males, 59%) were randomized; 66 from each group completed treatment. The ratio of TAA-AQ to placebo for change from baseline in serum cortisol AUC(0-24h) was 0.966 (95% confidence interval, 0.892-1.045). Reduction from baseline in mean rTNSS was significantly greater in the TAA-AQ than in the placebo group (difference: least square mean ± SE = -0.85 ± 0.24; p = 0.0007). The safety profile was similar (TEAEs, TAA-AQ, 27.5%; placebo, 25.4%), and so was the mean change in serum cortisol trough level (TAA-AQ, -0.4 µg/dL; placebo, -0.1 µg/dL; p = 0.1818 for treatment difference) from pre- to posttreatment. TAA-AQ was safe, well tolerated, and not associated with clinically meaningful suppression of serum cortisol AUC(0-24h) in children with AR. Clinical trial NCT01154153, www.clinicaltrials.gov.

Efficacy and safety of beclomethasone dipropionate nasal aerosol in pediatric patients with seasonal allergic rhinitis.

BACKGROUND: Aerosolized intranasal corticosteroid formulations are desirable for many patients with allergic rhinitis (AR), especially children, who wish to avoid the "wet feeling" and "drip down the throat" associated with aqueous formulations. Beclomethasone dipropionate (BDP) hydrofluoroalkane nasal aerosol has been shown to be safe and effective in adolescents and adults with AR. OBJECTIVE: To evaluate the efficacy and safety of BDP nasal aerosol in pediatric patients with moderate to severe seasonal AR. METHODS: In this double-blinded, placebo-controlled study, children (6-11 years of age) with seasonal AR were randomized to once-daily treatment with BDP nasal aerosol 80 µg (n = 239) or 160 µg (n = 242) or placebo (n = 234). The primary end point was change from baseline in average morning and evening reflective total nasal symptom score over the 2-week treatment period. RESULTS: Treatment with BDP nasal aerosol showed significantly greater improvements in average morning and evening reflective total nasal symptom score vs placebo (80 µg, -0.71; 160 µg, -0.76; P < .001 for the 2 comparisons). Similarly, significantly greater improvements in average morning and evening instantaneous total nasal symptom score were seen with BDP nasal aerosol vs placebo (80 µg, -0.63; 160 µg, -0.73; P < .001 for the 2 comparisons). The incidence of adverse events from BDP nasal aerosol was comparable to that from placebo. CONCLUSION: BDP nasal aerosol (80 or 160 µg/d) provided significant and clinically meaningful nasal symptom relief and an established overall safety profile similar to that of placebo, suggesting that it is an effective and well-tolerated treatment option for pediatric patients with moderate to severe seasonal AR. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT012073190.

Efficacy and safety of levocetirizine in improving symptoms and health-related quality of life in US adults with seasonal allergic rhinitis: a randomized, placebo-controlled study.

BACKGROUND: Levocetirizine, a second-generation antihistamine for symptomatic treatment of allergic rhinitis and chronic idiopathic urticaria, has not been previously studied in US patients. OBJECTIVE: To assess the efficacy and safety of levocetirizine in improving symptoms and health-related quality of life in US adults with seasonal allergic rhinitis (SAR). METHODS: This multicenter, double-blind trial randomized adults with SAR, sensitized to at least 1 grass allergen, to receive levocetirizine, 5 mg, or placebo once daily in the evening for 2 weeks. The primary end point was the 24-hour reflective Total 5-Symptom Score (T5SS; sum of rhinorrhea, sneezing, nasal congestion, and nasal and ocular pruritus) during the entire treatment period. Secondary assessments included the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), Work Productivity and Activity Impairment-Allergy Specific (WPAI-AS) questionnaire, and Epworth Sleepiness Scale (ESS), each assessed at week 1, week 2, and the end of treatment. RESULTS: The intent-to-treat population comprised 287 patients taking levocetirizine and 290 taking placebo, with no significant between-group differences at baseline. Levocetirizine resulted in significantly greater improvement from baseline vs placebo in the T5SS (P < .001), overall RQLQ score (P < .001), general and work-related WPAI-AS subscores (P < .05), and ESS score (P < .001). Overall incidence of treatment-emergent adverse events was 14.4% for levocetirizine and 18.4% for placebo. The incidence of somnolence and fatigue was 0.7% and 1.8% with levocetirizine and 1.0% and 0% with placebo, respectively. CONCLUSIONS: Levocetirizine was well tolerated and was significantly more effective than placebo in improving the naso-ocular symptoms and health-related quality of life in US patients with SAR.

Pharmacokinetics, safety and tolerability of an oral suspension of fexofenadine for children with allergic rhinitis.

Allergic rhinitis (AR) is a common chronic condition in children and may impact a child's quality of life. Increasing treatment compliance may improve quality of life. An oral suspension of fexofenadine hydrochloride (HCl) has been developed to ease administration to children and may, therefore, improve treatment compliance. The purpose of this study was to assess the pharmacokinetic behavior, safety, and tolerability of a single dose of fexofenadine HCl oral suspension administered to children aged 2-5 years with allergic rhinitis. Children (aged 2-5 years) with AR were recruited in a multicenter, open-label, single-dose study. Fexofenadine HCl (30 mg) was administered as a 6-mg/mL suspension (5 mL). Plasma samples were collected up to 24 hours postdose. Adverse events (AEs); electrocardiograms (ECGs); vital signs; and clinical laboratory tests for hematology, blood chemistry, and urinalysis were analyzed to evaluate safety and tolerability. Fifty subjects completed the study. Mean maximum plasma concentration of fexofenadine was 224 ng/mL, and mean area under the plasma concentration curve was 898 ng . hour/mL. Treatment-emergent AEs were mild in intensity and reported in a total of seven subjects. No trends or clinically meaningful changes in mean ECG, vital sign, or clinical laboratory test data occurred during the study. In children aged 2-5 years, the exposure after a 30-mg dose of fexofenadine HCl suspension was similar to the exposures previously seen after a 30- and 60-mg dose of fexofenadine HCl in children aged 6-11 years and in adults, respectively. The suspension was also well tolerated.

Accuracy of IgE antibody laboratory results.

BACKGROUND: Studies have demonstrated that the magnitude of sensitization as evidenced by specific IgE (sIgE) levels provides significant information as to whether a sensitized individual is likely to be truly reactive. However, it is not clear that quantitative sIgE results provided by different laboratories using different technologies are comparable. OBJECTIVE: To investigate whether similar results were obtained from Clinical Laboratory Improvement Act-certified laboratories that used 3 common systems for sIgE antibody determination with serum samples and mouse-human IgE chimeric antibodies with known specificity and quantity. METHODS: Sixty samples for peanut and 20 for soy were submitted for sIgE determination on 3 different systems: ImmunoCAP, Immulite, and Turbo radioallergosorbent test (RAST). Mouse-human chimeric IgE antibodies specific for the major birch allergen Bet v 1 and for the dust mite allergen Der p 2 were also included. RESULTS: A qualitative evaluation using a cutoff of 0.35 kUA/L showed some differences in the ability to detect sIgE sensitization, with the Turbo RAST being most variable. However, considerable differences were found with quantitative evaluation, with Immulite overestimating and Turbo RAST underestimating sIgE compared with ImmunoCAP. Similar discrepancies were seen with the mouse-human chimeric IgE antibody samples. CONCLUSION: These findings have potentially serious clinical implications, since each of these systems is widely used. It is therefore important that all laboratories clarify which system they are using. Just because 2 systems present their results in the same units does not mean that the results are necessarily correct or interchangeable.