Assessment of an optimized manufacturing process for inactivated quadrivalent influenza vaccine: a phase III, randomized, double-blind, safety and immunogenicity study in children and adults.

BACKGROUND: GSK has modified the licensed monovalent bulk manufacturing process for its split-virion inactivated quadrivalent influenza vaccine (IIV4) to harmonize the process among different strains, resulting in an increased number of finished vaccine doses, while compensating for the change from inactivated trivalent influenza vaccine (IIV3) to IIV4. To confirm the manufacturing changes do not alter the profile of the vaccine, a clinical trial was conducted to compare IIV4 made by the currently licensed process with a vaccine made by the new (investigational) process (IIV4-I). The main objectives were to compare the reactogenicity and safety of IIV4-I versus IIV4 in all age groups, and to demonstrate the non-inferiority of the hemagglutination-inhibition (HI) antibody responses based on the geometric mean titer ratio of IIV4-I versus IIV4 in children. METHODS: The Phase III, randomized, double-blind, multinational study included three cohorts: adults (18-49 years; N = 120), children (3-17 years; N = 821), and infants (6-35 months; N = 940). Eligible subjects in each cohort were randomized 1:1 to receive IIV4-I or IIV4. Both vaccines contained 15 µg of hemagglutinin antigen for each of the four seasonal virus strains. Adults and vaccine-primed children received one dose of vaccine, and vaccine-unprimed children received two doses of vaccine 28 days apart. All children aged ≥9 years were considered to be vaccine-primed and received one dose of vaccine. RESULTS: The primary immunogenicity objective of the study was met in demonstrating immunogenic non-inferiority of IIV4-I versus IIV4 in children. The IIV4-I was immunogenic against all four vaccine strains in each age cohort. The reactogenicity and safety profile of IIV4-I was similar to IIV4 in each age cohort, and there was no increase in the relative risk of fever (≥38 °C) with IIV4-I versus IIV4 within the 7-day post-vaccination period in infants (1.06; 95% Confidence Interval: 0.75, 1.50; p = 0.786). CONCLUSIONS: The study demonstrated that in adults, children, and infants, the IIV4-I made using an investigational manufacturing process was immunogenic with a reactogenicity and safety profile that was similar to licensed IIV4. These results support that the investigational process used to manufacture IIV4-I is suitable to replace the current licensed process. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02207413 ; trial registration date: August 4, 2014.

Quadrivalent Influenza Vaccine Prevents Illness and Reduces Healthcare Utilization Across Diverse Geographic Regions During Five Influenza Seasons: A Randomized Clinical Trial.

BACKGROUND: We evaluated an inactivated quadrivalent influenza vaccine (IIV4) in children 6-35 months of age in a phase III, observer-blind trial. METHODS: The aim of this analysis was to estimate vaccine efficacy (VE) in preventing laboratory-confirmed influenza in each of 5 independent seasonal cohorts (2011-2014), as well as vaccine impact on healthcare utilization in 3 study regions (Europe/Mediterranean, Asia-Pacific and Central America). Healthy children were randomized 1:1 to IIV4 or control vaccines. VE was estimated against influenza confirmed by reverse transcription polymerase chain reaction on nasal swabs. Cultured isolates were characterized as antigenically matched/mismatched to vaccine strains. RESULTS: The total vaccinated cohort included 12,018 children (N = 1777, 2526, 1564, 1501 and 4650 in cohorts 1-5, respectively). For reverse transcription polymerase chain reaction confirmed influenza of any severity (all strains combined), VE in cohorts 1-5 was 57.8%, 52.9%, 73.4%, 30.3% and 41.4%, respectively, with the lower limit of the 95% confidence interval >0 for all estimates. The proportion of vaccine match for all strains combined in each cohort was 0.9%, 79.3%, 72.5%, 24.1% and 28.6%, respectively. Antibiotic use associated with influenza illness was reduced with IIV4 by 71% in Europe, 36% in Asia Pacific and 59% in Central America. CONCLUSIONS: IIV4 prevented influenza in children 6-35 months of age in each of 5 separate influenza seasons in diverse geographical regions. A possible interaction between VE, degree of vaccine match and socioeconomic status was observed. The IIV4 attenuated the severity of breakthrough influenza illness and reduced healthcare utilization, particularly antibiotic use.

Clinical Presentation of Influenza in Children 6 to 35 Months of Age: Findings From a Randomized Clinical Trial of Inactivated Quadrivalent Influenza Vaccine.

BACKGROUND: In an exploratory analysis of an inactivated quadrivalent influenza vaccine (IIV4) trial in children 6-35 months without risk factors for influenza, we evaluated clinical presentation of influenza illness and vaccine impact on health outcomes. METHODS: This phase III trial was conducted in 13 geographically diverse countries across 5 influenza seasons (2011-2014). Children were randomized 1:1 to IIV4 or control. Active surveillance was performed for influenza-like episodes (ILE); influenza was confirmed by reverse transcription polymerase chain reaction (RT-PCR). The total vaccinated cohort was evaluated (N = 12,018). RESULTS: 5702 children experienced ≥1 ILE; 356 (IIV4 group) and 693 (control group) children had RT-PCR-confirmed influenza. Prevalence of ILE was similar in RT-PCR-positive and RT-PCR-negative cases regardless of vaccination. Breakthrough influenza illness was attenuated in children vaccinated with IIV4; moderate-to-severe illness was 41% less likely to be reported in the IIV4 group than the control group [crude odds ratio: 0.59 (95% confidence intervals: 0.44-0.77)]. Furthermore, fever >39°C was 46% less frequent following vaccination with IIV4 than with control [crude odds ratio: 0.54 (95% confidence intervals: 0.39-0.75)] in children with breakthrough illness. Health outcome analysis showed that, each year, IIV4 would prevent 54 influenza cases per 1000 children and 19 children would need to be vaccinated to prevent 1 new influenza case. CONCLUSIONS: In addition to preventing influenza in 50% of participants, IIV4 attenuated illness severity and disease burden in children who had a breakthrough influenza episode despite vaccination.

Safety and persistence of the humoral and cellular immune responses induced by 2 doses of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine administered to infants, children and adolescents: Two open, uncontrolled studies.

In children, 2 AS03-adjuvanted A(H1N1)pdm09 vaccine doses given 21 days apart were previously shown to induce a high humoral immune response and to have an acceptable safety profile up to 42 days following the first vaccination. Here, we analyzed the persistence data from 2 open-label studies, which assessed the safety, and humoral and cell-mediated immune responses induced by 2 doses of this vaccine. The first study was a phase II, randomized trial conducted in 104 children aged 6-35 months vaccinated with the A(H1N1)pdm09 vaccine containing 1.9 µg haemagglutinin antigen (HA) and AS03B (5.93 mg tocopherol) and the second study, a phase III, non-randomized trial conducted in 210 children and adolescents aged 3-17 years vaccinated with the A(H1N1)pdm09 vaccine containing 3.75 µg HA and AS03A (11.86 mg tocopherol). Approximately one year after the first dose, all children with available data were seropositive for haemagglutinin inhibition and neutralising antibody titres, but a decline in geometric mean antibody titres was noted. The vaccine induced a cell-mediated immune response in terms of antigen-specific CD4(+) T-cells, which persisted up to one year post-vaccination. The vaccine did not raise any safety concern, though these trials were not designed to detect rare events. In conclusion, 2 doses of the AS03-adjuvanted A(H1N1)pdm09 vaccine at 2 different dosages had a clinically acceptable safety profile, and induced high and persistent humoral and cell-mediated immune responses in children aged 6-35 months and 3-17 years. These studies have been registered at www.clinicaltrials.gov NCT00971321 and NCT00964158.

The Impact of Childhood Acute Otitis Media on Parental Quality of Life in a Prospective Observational Cohort Study.

BACKGROUND AND OBJECTIVES: Acute otitis media (AOM) not only affects childhood quality of life (QoL), but can also affect parental QoL. We adapted a previously published questionnaire on the effect of childhood recurrent ear, nose and throat infections on parental QoL for use with AOM and used it in an observational, multicentre, prospective study of children with AOM. METHODS: The AOM-specific parental QoL questionnaire grouped 15 items into emotional, daily disturbance, total and overall parental QoL impact scores. The questionnaire was assessed using item-convergent and item-discriminant validity criteria and internal consistency reliability; and then used with parents of children aged <6 years diagnosed with AOM at 73 practices in Germany, Italy, Spain, Sweden and the UK. Bivariate analyses explored the differences in mean parental QoL impact scores by various characteristics. RESULTS: The questionnaire demonstrated good to excellent internal consistency reliability for the various components (Cronbach's α 0.82-0.97). There were 1419 AOM episodes among 5882 healthy children over 1 year, of which 1063 episodes (74.9%) among 852 children had a questionnaire. Parents reported interrupted sleep (68.4%), worry (51.0%), altered daily schedule (44.6%) and less leisure time (41.5%) with a score ≥ 3 (1 = least to 5 = most impact). Factors that adversely affected parental QoL included: increased parental perception of AOM severity, younger child age and multiple AOM episodes. CONCLUSIONS: The AOM-specific parental QoL questionnaire demonstrated good performance across five European countries. Parental QoL was affected by childhood AOM proportionally to severity, number of episodes and younger child age.

13-valent pneumococcal conjugate vaccine given with meningococcal C-tetanus toxoid conjugate and other routine pediatric vaccinations: immunogenicity and safety.

BACKGROUND: As multiple vaccines are administered concomitantly during routine pediatric immunizations, it is important to ascertain the potential interference of any new vaccine on the immune response to the concomitantly administered vaccines. Immune responses to meningococcal serogroup C-tetanus toxoid conjugate vaccine (MnCC-TT) and the diphtheria and tetanus antigens in routine pediatric vaccines (diphtheria, tetanus, acellular pertussis-hepatitis B virus-inactivated poliovirus/Haemophilus influenza type b [DTaP-HBV-IPV/Hib] and DTaP-IPV+Hib) when given concomitantly with the 13-valent pneumococcal conjugate vaccine (PCV13) were compared with responses when given with PCV7. In addition, the immunogenicity and safety of PCV13 were assessed. METHODS: Healthy infants were randomized to receive PCV13 or PCV7 (ages 2, 4, 6 and 15 months), concomitant with MnCC-TT (2, 4 and 15 months), DTaP-HBV-IPV/Hib (2, 4 and 6 months), and DTaP-IPV+Hib (15 months). RESULTS: Immune responses to MnCC-TT and to the diphtheria and tetanus antigens administered with PCV13 were noninferior to the responses observed when the vaccines were administered with PCV7; ≥96.6 (postinfant) and ≥99.4% (posttoddler) subjects achieved prespecified immune response levels to each antigen in each group. After the infant series, ≥93.0% of subjects receiving PCV13 achieved pneumococcal anticapsular immunoglobulin G concentrations ≥0.35 µg/mL for all serotypes except serotype 3 (86.2%), increasing to 98.1-100% for most serotypes (serotype 3: 93.6%) after the toddler dose. Local and systemic reactions were similar between groups. CONCLUSIONS: Immune responses to MnCC-TT, and other childhood vaccines (DTaP-HBV-IPV/Hib, DTaP-IPV+Hib) were noninferior when concomitantly administered with PCV13 compared with PCV7. PCV13 does not interfere with MnCC-TT. PCV13 is highly immunogenic with a favorable safety profile.

Immunogenicity and safety of AS03-adjuvanted 2009 influenza A H1N1 vaccine in children 6-35 months.

We report on the evaluation of the immunogenicity and reactogenicity/safety of AS03-adjuvanted vaccine against pandemic influenza A/H1N1/2009 in young children. In this open-label, randomized study, 157 healthy children aged 6-35 months received two doses (21 days apart) of split-virion inactivated A/California/7/2009 H1N1 vaccine containing either (i) 1.9microg hemagglutinin (HA) and AS03(B) (5.93mg tocopherol) (N=104) or (ii) 3.75mug HA and AS03(A) (11.86mg tocopherol) (N=53). At 21 days following the first dose of AS03(B)-adjuvanted vaccine (1.9microg HA) the percentage of children with hemagglutination-inhibition titers of >or=40 against the vaccine strain rose from 3.0% before vaccination to 100%. The seroconversion rate was 99% and the geometric mean titer (GMT) increased from 6 to 313. After the second dose the GMT increased further to 2008. The higher dose AS03(A)-adjuvanted 3.75microg HA vaccine did not further increase the immune response. Solicited symptoms reported within 7 days following vaccination were mainly mild to moderate. After the first dose of AS03(B)-adjuvanted vaccine (1.9microg HA) the most common solicited symptoms were pain at the injection site (35.6%) and irritability (31.7%). Fever (axillary >or=37.5 degrees C) was reported with an incidence of 20.2%. After the second dose reactogenicity tended to increase (injection site pain: 41.3%; irritability: 46.2%; fever >or=37.5 degrees C: 67.3%). Spontaneously reported adverse events with an intensity that prevented normal activities were documented for 2.9-6.7% of doses with only one event (vomiting) considered related to vaccination. There was one serious adverse event reported in the AS03(A)-adjuvanted 3.75microg HA vaccine group (traumatic brain injury) which was not considered as related to vaccination. In conclusion, these data suggest that a first dose of AS03(B)-adjuvanted A/H1N1/2009 vaccine containing 1.9microg HA in children 6-35 months old is highly immunogenic and that the overall reactogenicity profile is acceptable although reactions including fever tend to increase after a second dose.

Reactogenicity and immunogenicity of combined Haemophilus influenzae type b-meningococcal serogroup C conjugate vaccine booster dose coadministered with measles, mumps, and rubella vaccine.

A booster dose of Haemophilus influenzae type b-Neisseria meningitidis serogroup C conjugate (Hib-MenC-TT) vaccine simultaneously administered with measles, mumps, and rubella (MMR) vaccine in 13- to 14-month-old Spanish toddlers, primed with 3 doses of a combined Diphteria-Tetanus-Acellular Pertusis DTPa-Hib-containing vaccine and a MenC-CRM197 conjugate vaccine, had a good reactogenicity profile and induced similar Hib and MenC booster responses and MMR seropositivity rates as the vaccines given alone.

Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine coadministered with combined diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine to girls and young women.

PURPOSE: Many countries recommend human papillomavirus (HPV) vaccination in female adolescents at an age when other vaccines are routinely administered. This open, randomized, multicenter study (108464/NCT00426361) evaluated coadministration of HPV-16/18 AS04-adjuvanted vaccine with diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine (dTpa-IPV). METHODS: Healthy females aged 10-18 years were randomized to receive HPV vaccine at months 0, 1, and 6 (n = 248), HPV vaccine coadministered with dTpa-IPV at month 0 and HPV vaccine at months 1 and 6 (n = 255), or dTpa-IPV at month 0 followed by HPV vaccine at months 1, 2, and 7 (n = 248). Immunogenicity was evaluated at months 0, 1, and 7 or 8 (depending on group). Vaccine reactogenicity and safety were also assessed. RESULTS: Coadministered dTpa-IPV and HPV vaccine was noninferior to dTpa-IPV alone in terms of seroprotection against diphtheria (99.2% and 100%), tetanus (100% and 100%) and poliovirus types 1, 2, and 3 (> or = 99.6%), and geometric mean antibody concentrations (ELISA Units/mL) for pertussis toxoid (84 vs. 75), filamentous hemagglutinin (612 and 615) and pertactin (426 and 360) at month 1. Coadministered dTpa-IPV and HPV vaccine was noninferior to HPV vaccine alone in terms of seroconversion rates for HPV-16 (99.5% and 100%) and HPV-18 (99.5% and 100%) and geometric mean antibody titers (ELISA Units/mL) for HPV-16 (15,608 and 18,965) and HPV-18 (6,597 and 6,902) at month 7. Coadministration was generally well tolerated. The reactogenicity of dTpa-IPV and the first dose of HPV vaccine was similar. CONCLUSIONS: Results from this study support coadministration of the HPV-16/18 AS04-adjuvanted vaccine with dTpa-IPV vaccine in females aged 10-18 years.

Desarrollo de sitio periimplantario mediante regeneración ósea guiada e injerto conectivo en el sector anterior / Peri-implant Site Development using Guided Bone Regeneration and Connective Tissue Graft in the Anterior Region

Condiciones desfavorables del reborde alveolar debido a atrofia, enfermedad periodontal o traumatismos pueden generar deficiencias de volumen óseo, produciendo como consecuencia una relación corona/implante inadecuada y un aspecto estético desfavorable. La presente serie de casos propone el uso de la técnica asociada a un injerto de tejido conectivo como método de desarrollo de sitio periimplantario, con el fin de corregir deficiencias del reborde alveolar, para permitir la posterior instalación de un implante óseo integrado. Ocho pacientes con indicación de extracción de una pieza anterior, asociada a ausencia de la tabla vestibular y a una pérdida de tejidos duros y blandos, fueron sometidos a un procedimiento de regeneración ósea guiada mediante el uso de una mezcla de xenoinjerto y hueso autólogo en conjunto con una membrana reabsorbible e injerto conectivo autólogo. A los 6 meses postratamiento, fue colocado el implante, y provisionalizado inmediatamente. En todos los casos se logró una mejora y una equiparación de los contornos periimplantarios con las piezas vecinas. No existieron complicaciones posoperatorias, la regeneración de tejidos fue exitosa en todos los casos intervenidos, y todos los implantes se integraron correctamente. La regeneración ósea guiada en conjunto con un injerto de tejido conectivo fue un método efectivo para el desarrollo de sitio periimplantario previo a la colocación de implantes en el sector anterior del maxilar.

Unfavorable conditions of the alveolar ridge, due to atrophy, periodontal disease or trauma, can lead to osseous volume deficiencies, producing an inadequate crown / implant relationship and an unfavorable esthetic appearance. The present case series proposes the use of guided bone regeneration (GBR) associated with a connective tissue graft, as a method for peri-implant site development, to correct alveolar ridge deficiencies, and to allow the subsequent placement of an osseointegrated implant. Eight patients with the indication of an anterior tooth extraction, associated with a loss of the vestibular plate and a hard and soft tissue deficiency, were treated with a GBR procedure using a mixture of xenograft-autogenous bone in conjunction with a resorbable membrane and an autogenous connective tissue graft. At 6 months post-treatment, the implant was installed and immediately provisionalized. In all the cases, an improvement and matching of the tissue contours with the neighboring teeth was achieved. There were no postoperative complications. The tissue regeneration was successful in all the cases, and all the implants achieved a correct integration. GBR, in conjunction with a connective tissue graft, was an effective method to perform a peri-implant site development prior to the implant installation in the maxillary anterior region.