Prevalence and type distribution of human papillomavirus in healthy Japanese women aged 20 to 25 years old enrolled in a clinical study.

Efficacy, immunogenicity and tolerability of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine were evaluated in Japanese women aged 20-25 years, for which results have been reported previously. We analyzed the baseline data from that study and report the prevalence rates of HPV infection in young healthy Japanese women. One thousand and the forty Japanese women aged 20-25 years were enrolled in a phase II, double-blind, controlled, randomized, multicenter study. At study entry, cervical specimens were collected from the women and tested by line probe assay for 25 HPV-types and by HPV-16/18-specific polymerase chain reaction. The most frequently detected HPV-type in baseline cervical specimens was HPV-52 (8.1%), followed by HPV-16 (6.5%), HPV-51 (4.5%), HPV-18 (4.0%) and HPV-31 (3.8%). The proportion of HPV DNA-positive women increased with severity of cytological abnormalities: 26.1% (237/908) in normal cytology, 93.3% (70/75) in low-grade squamous intraepithelial lesion and 100% (7/7) in high-grade squamous intraepithelial lesion. The relative contribution of HPV-16 and HPV-18 was 4.1 and 3.0% for normal cytology cases, and 20.0 and 16.0% in low-grade squamous intraepithelial lesion, respectively. HPV-16 was found in four of seven high-grade squamous intraepithelial lesion cases (57.1%) and five of the six cervical intraepithelial neoplasia 2+ cases (83.3%). Multiple and single HPV infections were observed in 13.5% (140/1039) and 20.7% (215/1039) of all women, respectively. The HPV prevalence rates in Japanese women aged 20-25 years underline the importance of HPV vaccination at a young age and this report should be useful for monitoring changes in HPV prevalence after widespread HPV vaccination in Japanese women.

Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule compared with the licensed 3-dose schedule: results from a randomized study.

The immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix®, GlaxoSmithKline Biologicals) administered according to its licensed vaccination schedule (3-dose, 3D) and formulation (20 µg of each HPV antigen; 20/20F) has previously been demonstrated. This partially-blind, controlled, randomized trial (NCT00541970) evaluated 2-dose (2D) schedules using the licensed 20/20F or an alternative formulation containing 40 µg of each antigen (40/40F), compared with the licensed 3D schedule. Healthy females stratified by age (9-14, 15-19, 20-25 y) were randomized to receive 2 doses of 20/20F at Months (M) 0,6 (n=240), 40/40F at M0,6 (n=241) or 40/40F at M0,2 (n=240), or 3 doses of 20/20F at M0,1,6 (licensed schedule/formulation, n=239). One month after the last dose, the 3D schedule was not immunologically superior to 2D schedules except in the 40/40F M0,2 group for HPV-16 (lower limit of 95% CI geometric mean antibody titer (GMT) ratio [2D/3D] < 0.5). For both HPV-16 and HPV-18, the 2D schedules in girls 9-14 y were immunologically non-inferior to the 3D schedule in women 15-25 y (the age group in which efficacy has been demonstrated) (upper limit of 95% CI for GMT ratio [3D/2D] < 2) one month after the last dose. At Month 24, non-inferiority was maintained for the 2D M0,6 schedules in girls 9-14 y versus the 3D schedule in women 15-25 y. All formulations had acceptable reactogenicity and safety profiles. These results indicate that the HPV-16/18 vaccine on a 2D M0,6 schedule is immunogenic and generally well tolerated in girls 9-14 y and that the 2D schedule is likely adequate for younger females.

Safety, reactogenicity, and immunogenicity of a 12-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine in healthy toddlers: results from a phase I, randomized trial.

As a stepping stone toward evaluation in infants, the safety and immunogenicity of an investigational 12-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (12vPHiD-CV) was assessed in toddlers. 12vPHiD-CV contains CRM197-conjugated capsular polysaccharides of serotypes 6A and 19A in addition to capsular polysaccharides of the 10 serotypes in PHiD-CV. In this phase I, double-blind, multicenter study (NCT01485406) conducted in Germany, 61 healthy toddlers aged 12-23 months previously primed with three PHiD-CV doses were randomized (1:1) to receive one dose of 12vPHiD-CV or PHiD-CV. Safety and reactogenicity of 12vPHiD-CV were assessed in terms of occurrence of grade 3 vaccination-related solicited and unsolicited adverse events (AEs) and vaccination-related serious AEs. Immune responses were evaluated 1 month post-vaccination. Grade 3 solicited local AEs (all considered vaccination-related) were reported for two (6.5%, redness) and three (9.7%, swelling) toddlers in the 12vPHiD-CV group and one (3.4%, swelling) in the PHiD-CV group. Grade 3 vaccination-related solicited general AEs were only reported in the PHiD-CV group. No grade 3 unsolicited or serious AEs were reported. For PHiD-CV serotypes, 100% of toddlers in both groups had antibody concentrations ≥0.2 µg/mL 1 month post-vaccination, and antibody geometric mean concentrations increased from pre-boosting. For serotypes 6A and 19A, antibody responses tended to be higher in the 12vPHiD-CV than the PHiD-CV group. A single dose of 12vPHiD-CV administered in toddlers was well tolerated and no safety concerns were identified. Immune responses were comparable to those induced by PHiD-CV when administered in toddlers previously primed with three doses of PHiD-CV.

Efficacy of human papillomavirus type 16/18 AS04-adjuvanted vaccine in Japanese women aged 20 to 25 years: final analysis of a phase 2 double-blind, randomized controlled trial.

BACKGROUND: Human papillomavirus (HPV) type 16/18 AS04-adjuvanted vaccine was shown to be highly immunogenic and generally well tolerated in the interim analysis of a phase 2 double-blind, randomized controlled multicenter study in Japanese healthy women aged 20 to 25 years. Vaccine efficacy, immunogenicity, and safety are assessed in this study through 24 months after the first vaccination. METHODS: Japanese women aged 20 to 25 years were randomly assigned to receive either HPV-16/18 AS04-adjuvanted vaccine (n = 519) or hepatitis A vaccine (n = 521) at 0, 1, and 6 months. Women were assessed for virological, cytological, and histological end points associated with HPV-16/18 and 12 other oncogenic HPV types (types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) in cervical specimens and for the vaccine safety and immunogenicity. Antibody concentrations were measured by an enzyme-linked immunosorbent assay. Primary efficacy analysis was performed in the according-to-protocol cohort for efficacy, primary immunogenicity analysis was performed in the according-to-protocol cohort for immunogenicity, and primary safety analysis was done in the total vaccinated cohort. RESULTS: Vaccine efficacy against persistent infections (6 month definition) associated with HPV-16/18 was 100% (95.5% confidence interval, 71.3-100; P < 0.0001). Vaccine efficacy against cervical intraepithelial neoplasia 1+ associated with 14 oncogenic HPV types was 64.9% (95.5% confidence interval, 4.9-89.0; P = 0.02). At 24 months after the first dose of the vaccine, geometric mean antibody titers against HPV-16 and HPV-18 were 1521.5 enzyme-linked immunosorbent assay U/mL and 627.4 enzyme-linked immunosorbent assay U/mL, respectively. The HPV-16/18 AS04-adjuvanted vaccine had a clinically acceptable safety profile. CONCLUSIONS: The HPV-16/18 AS04-adjuvanted vaccine showed excellent prophylactic efficacy against 6-month persistent infection with HPV-16/18. The HPV-16/18 AS04-adjuvanted vaccine was generally well tolerated and immunogenic in the study population of healthy Japanese women aged 20 to 25 years.

Efficacy of human papillomavirus 16/18 AS04-adjuvanted vaccine in Japanese women aged 20 to 25 years: interim analysis of a phase 2 double-blind, randomized, controlled trial.

BACKGROUND: A phase 2 double-blind, controlled, randomized multicenter study with human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine is ongoing in healthy Japanese women aged 20 to 25 years. We assessed the vaccine efficacy in the event-triggered analysis. METHODS: Japanese women aged 20 to 25 years were randomly assigned to receive either HPV-16/18 AS04-adjuvanted (n = 519) or hepatitis A (n = 521) vaccine at 0, 1, and 6 months. The women were assessed for virological and cytological end points associated with HPV-16/18 in cervical specimens and for the vaccine safety and immunogenicity. RESULTS: The mean length of follow-up for women in the primary analysis for efficacy at the time of a prespecified event-triggered interim analysis was 13.6 months after the first vaccination. Vaccine efficacy against HPV-16/18 persistent infections (6-month definition) in the according-to-protocol cohort for efficacy was 100% (99% confidence interval, 20.5-100, P = 0.0037). At 6 months after the third dose of vaccine, geometric mean titers against HPV-16 and HPV-18 were 2899.3 and 1352.2 enzyme-linked immunosorbent assay units per milliliter, respectively, that is, 97- and 60-fold higher than geometric mean titers observed after natural infection. There were no clinically meaningful differences in safety between the HPV and control group. CONCLUSIONS: The HPV-16/18 AS04-adjuvanted vaccine was as efficacious in Japan as in other countries and was generally safe and highly immunogenic in Japanese women.

Immunogenicity, reactogenicity, and safety of human papillomavirus 16/18 AS04-adjuvanted vaccine in Japanese women: interim analysis of a phase II, double-blind, randomized controlled trial at month 7.

A phase II, double-blind, controlled randomized multicenter study with human papillomavirus (HPV) 16/18 AS04 (3-O-desacyl-4'-monophosphoryl lipid A and aluminum hydroxide)-adjuvanted vaccine is ongoing in Japanese women aged 20 to 25 years. An interim analysis was performed at month 7 (1 month after the third dose of vaccine) to determine reactogenicity, safety, and immunogenicity of the vaccine and to evaluate the baseline HPV-16/18 seropositivity and DNA status of women. In the HPV-16/18 group (according-to-protocol cohort for immunogenicity analysis), 100% seroconversion was observed against HPV-16 and HPV-18 at month 6 (5 months after the second dose) and at month 7. At month 7, anti-HPV-16 geometric mean titer (GMT) was 7441.0 enzyme-linked immunosorbent assay units/mL and anti-HPV-18 GMT was 3805.4 enzyme-linked immunosorbent assay units/mL, which is, respectively, 250- and 168-fold higher than GMTs observed after natural infection with HPV-16 or HPV-18. In the total vaccinated cohort, the seropositivity rates against HPV-16 and HPV-18 at study entry were 17.3% and 15.8%, respectively. At the same time point, HPV-16 and HPV-18 DNA was detected in 6.5% and 4.0% of the women, respectively. The immunogenicity of the HPV-16/18 vaccine and the HPV prevalence before vaccination in Japanese women are in line with what was observed in other populations. Injection site symptoms and some general symptoms were reported more frequently in the HPV-16/18 group than in the hepatitis A vaccine group but had no impact on compliance with completion of the vaccination course. Overall, the HPV-16/18 vaccine had a good safety profile, was well tolerated, and is highly immunogenic in the study population of Japanese women.

Safety and immunogenicity of a tetravalent polysaccharide vaccine against meningococcal disease.

BACKGROUND/PURPOSE: Meningococcal disease, including meningitis and sepsis, usually follows an invasive infection by Neisseria meningitidis, and is a major cause of death and morbidity worldwide. Currently available meningococcal vaccines that consist of pure capsular polysaccharides (serogroups A, C, W-135 and Y) are generally safe and efficacious in adults and children aged > 2 years. The purpose of this study was to evaluate the immunogenicity, safety and reactogenicity of a single dose of GlaxoSmithKline Biologicals' Mencevax ACWY vaccine in healthy Taiwanese subjects aged 2-30 years. METHODS: This open, single center, Phase III study was conducted in Taiwan. A single dose of the Mencevax ACWY vaccine was administered to subjects aged 2-30 years. Immunogenicity and safety of the vaccine were evaluated after vaccination. RESULTS: The immunogenicity results obtained 1 month after vaccination with Mencevax ACWY vaccine indicated that the vaccine elicited a good immune response in vaccinees aged 2-30 years. This was both in terms of functional activity directed against meningococcal polysaccharide (A, C, W-135 and Y) as measured by serum bactericidal assay (> 93% activity against all serogroups), and specific IgG concentrations measured by ELISA (> 96% seropositivity to all serogroups). CONCLUSION: The tetravalent polysaccharide Mencevax ACWY meningococcal vaccine was well tolerated and immunogenic in subjects aged 2-30 years in Taiwan.

Immunogenicity of pneumococcal conjugate vaccine formulations containing pneumococcal proteins, and immunogenicity and reactogenicity of co-administered routine vaccines - A phase II, randomised, observer-blind study in Gambian infants.

BACKGROUND: Two conserved pneumococcal proteins, pneumolysin toxoid (dPly) and pneumococcal histidine triad protein D (PhtD), combined with 10 polysaccharide conjugates from the pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) in two investigational pneumococcal vaccine (PHiD-CV/dPly/PhtD) formulations were immunogenic and well-tolerated when administered to Gambian children. Here, we report immunogenicity of the polysaccharide conjugates, and immunogenicity and reactogenicity of co-administered routine vaccines. METHODS: In this phase II, controlled, observer-blind, single-centre study, healthy infants aged 8-10 weeks were randomised (1:1:1:1:1:1) to six groups. Four groups received 3+0 schedule (2-3-4 months [M]) of PHiD-CV/dPly/PhtD (10 or 30 µg of each protein), PHiD-CV, or 13-valent pneumococcal conjugate vaccine; and two groups received 2+1 schedule (2-4-9 M) of PHiD-CV/dPly/PhtD (30 µg of each protein) or PHiD-CV. All infants received diphtheria-tetanus-whole cell pertussis-hepatitis B-Haemophilus influenzae type b (DTPw-HBV/Hib) and oral trivalent polio vaccines (OPV) at 2-3-4 M, and measles, yellow fever, and OPV vaccines at 9 M. We evaluated immune responses at 2-5-9-12 M; and reactogenicity 0-3 days post-vaccination. RESULTS: 1200 infants were enrolled between June 2011 and May 2012; 1152 completed the study. 1 M post-primary vaccination, for each PHiD-CV serotype except 6B and 23F, ≥97.4% (3+0 schedule) and ≥96.4% (2+1 schedule) of infants had antibody concentrations ≥0.2 µg/mL. Immune responses were comparable between groups within the same vaccination schedules. Observed antibody geometric mean concentrations (GMCs) increased by 1 M post-primary vaccination compared to pre-vaccination. In the following months, GMCs and opsonophagocytic activity titres waned, with an increase post-booster for the 2+1 schedule. Immune responses to protein D and, DTPw-HBV/Hib, OPV, measles, and yellow fever vaccines were not altered by co-administration with pneumococcal proteins. Reactogenicity of co-administered vaccines was comparable between groups and did not raise concerns. CONCLUSION: Immune responses to the 10 PHiD-CV polysaccharide conjugates and co-administered vaccines were not altered by addition of dPly and PhtD. ClinicalTrials.gov identifier NCT01262872.

Immunogenicity and safety of 11- and 12-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccines (11vPHiD-CV, 12vPHiD-CV) in infants: Results from a phase II, randomised, multicentre study.

BACKGROUND: We assessed 2 investigational 11- and 12-valent vaccines, containing capsular polysaccharides of 10 serotypes as in the pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) and CRM197-conjugated capsular polysaccharides of serotypes 19A (11-valent) or 19A and 6A (12-valent). METHODS: In this phase II, partially-blind, multicentre study (NCT01204658), healthy infants were randomised (1:1:1:1) to receive 11vPHiD-CV, 12vPHiD-CV, PHiD-CV, or 13-valent CRM197-conjugate pneumococcal vaccine (PCV13), at 2, 3, and 4 (primary series), and 12-15 months of age (booster dose), co-administered with DTPa-HBV-IPV/Hib. Confirmatory objectives assessed non-inferiority of investigational vaccines to comparators (PHiD-CV for common serotypes; PCV13 for 19A and 6A), in terms of percentage of infants with pneumococcal antibody concentrations ≥0.2 µg/mL and antibody geometric mean concentrations, post-primary vaccination. Reactogenicity and safety were assessed. RESULTS: 951 children received ≥1 primary dose, 919 a booster dose. Pre-defined immunological non-inferiority criteria were met simultaneously for 9/11 11vPHiD-CV serotypes (all except 23F and 19A) and 10/12 12vPHiD-CV serotypes (all except 19A and 6A); thus, non-inferiority objectives were reached. For each PHiD-CV serotype, percentages of children with antibody concentrations ≥0.2 µg/mL were ≥96.7% post-primary (except 6B [≥75.2%] and 23F [≥81.1%]), and ≥98.1% post-booster vaccination. For each PHiD-CV serotype except serotype 1, ≥81.0% and ≥93.9% of children had opsonophagocytic activity titres ≥8, post-primary and booster vaccination. AEs incidence was similar across all groups. SAEs were reported for 117 children (29 in the 11vPHiD-CV group, 26 in the 12vPHiD-CV group, 38 in the PHiD-CV group and 24 in the PCV13 group); 4 SAEs were considered vaccination-related. No fatal events were recorded. CONCLUSION: Addition of 19A and 6A CRM197-conjugates did not alter immunogenicity of the PHiD-CV conjugates; for both investigational vaccines post-booster immune responses to 10 common serotypes appeared similar to those elicited by PHiD-CV. Safety and reactogenicity profiles of the investigational vaccines were comparable to PHiD-CV. Clinical trial registry: NCT01204658.

Primary vaccination with a new heptavalent DTPw-HBV/Hib-Neisseria meningitidis serogroups A and C combined vaccine is well tolerated.

OBJECTIVE: Safety and reactogenicity of a new heptavalent DTPw-HBV/Hib-MenAC (diphtheria, tetanus, whole cell pertussis-hepatitis B virus/Haemophilus influenzae type b-Neisseria meningitidis serogroups A and C) vaccine was compared with a widely used pentavalent DTPw-HBV/Hib vaccine. METHODS: Three phase III randomized studies comparable in design and methodology, in which healthy infants received DTPw-HBV/Hib-MenAC (N=1334) or DTPw-HBV/Hib (N=446) at 2, 4, and 6 months, were pooled for analysis. Solicited symptoms were recorded for 4 days, and unsolicited adverse events for 31 days after each dose. Serious adverse events (SAEs) were recorded throughout the studies. RESULTS: There were no significant differences between the two groups in the proportion of subjects with fever >39.5 degrees C or >40.0 degrees C (p<0.005). Compared to group DTPw-HBV/Hib, a significantly higher percentage of subjects in group DTPw-HBV/Hib-MenAC reported fever >39 degrees C (21.2% vs. 14.8%, p=0.004). Fever subsided quickly, did not lead to differences in attendance to medical services and did not increase from dose to dose. Sixty-seven SAEs were reported, 56/1334 (4.2%) in group DTPw-HBV/Hib-MenAC and 11/446 (2.5%) in the DTPw-HBV/Hib group. CONCLUSION: Overall, the heptavalent and pentavalent vaccines had similar safety profiles. The difference observed in percentage of subjects with fever >39 degrees C did not lead to differences in medically attended visits for fever.

Immunogenicity and Safety of 10-valent Pneumococcal Nontypeable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) Administered to Children With Sickle Cell Disease Between 8 Weeks and 2 Years of Age: A Phase III, Open, Controlled Study.

BACKGROUND: Immunogenicity, safety and reactogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) were evaluated in children with sickle cell disease (SCD), who are at increased risk for infections. METHODS: In this phase III, open-label, single-center, controlled study in Burkina Faso (NCT01175083), children with SCD (S) or without SCD (NS) were assigned to 6 groups (N = 300): children 8-11 weeks of age (<6 months; <6S and <6NS groups) received 3 primary doses and a booster dose of PHiD-CV coadministered with routine childhood vaccines; children 7-11 months of age (7-11S and 7-11NS groups) received 2 primary doses and a booster dose of PHiD-CV; children 12-23 months of age (12-23S and 12-23NS groups) received 2 catch-up doses of PHiD-CV. Pneumococcal antibody responses were measured using 22F-inhibition enzyme-linked immunosorbent assay and functional opsonophagocytic activity. Responses to other antigens were measured by enzyme-linked immunosorbent assay. Adverse events were recorded. RESULTS: One month postprimary vaccination, for each vaccine serotype ≥98% of infants in the <6S and <6NS groups had antibody concentrations ≥0.2 µg/mL, except for 6B (≥85%) and 23F (≥89%). Immune responses to PHiD-CV after age-appropriate vaccination in children <2 years did not appear influenced by SCD. All infants were seroprotected/seropositive for diphtheria, tetanus and Bordetella pertussis antigens postprimary and booster vaccination. Safety and reactogenicity profiles were similar in children with or without SCD. CONCLUSIONS: PHiD-CV was immunogenic with an acceptable safety profile in children with and without SCD starting vaccination at 8 weeks to 23 months of age.

Efficacy of a novel, protein-based pneumococcal vaccine against nasopharyngeal carriage of Streptococcus pneumoniae in infants: A phase 2, randomized, controlled, observer-blind study.

BACKGROUND: Conserved pneumococcal proteins are potential candidates for inclusion in vaccines against pneumococcal diseases. In the first part of a two-part study, an investigational vaccine (PHiD-CV/dPly/PhtD-30) containing 10 pneumococcal serotype-specific polysaccharide conjugates (10VT) combined with pneumolysin toxoid and pneumococcal histidine triad protein D (30µg each) was well tolerated by Gambian children. Part two, presented here, assessed the efficacy of two PHiD-CV/dPly/PhtD formulations against pneumococcal nasopharyngeal carriage (NPC) prevalence in infants. METHODS: In this phase 2, randomized, controlled, observer-blind trial, healthy infants aged 8-10weeks, recruited from a peri-urban health center, were randomized (1:1:1:1:1:1) into six groups. Four groups received PHiD-CV/dPly/PhtD (10 or 30µg of each protein), PHiD-CV, or 13-valent pneumococcal conjugate vaccine at ages 2-3-4months (3+0 infant schedule) and two groups PHiD-CV/dPly/PhtD-30 or PHiD-CV at 2-4-9months (2+1 infant schedule). The primary objective was impact on non-10VT NPC at ages 5-9-12months. Secondary objectives included confirmatory analysis of protein dose superiority and safety/reactogenicity. Impact on pneumococcal NPC acquisition, bacterial load, and ply and phtD gene sequencing were explored. RESULTS: 1200 infants were enrolled between June 2011 and May 2012. Prevalences of pneumococcal (60-67%) and non-10VT (55-61%) NPC were high at baseline. Across all post-vaccination time points, efficacy of PHiD-CV/dPly/PhtD-10 and PHiD-CV/dPly/PhtD-30 against non-10VT NPC (3+0 schedule) was 1.1% (95% CI -21.5, 19.5) and 2.1% (-20.3, 20.3), respectively; efficacy of PHiD-CV/dPly/PhtD-30 (2+1 schedule) was 0.5% (-22.1, 18.9) versus PHiD-CV. No differences were observed in pneumococcal NPC acquisition, clearance, or bacterial load. Both protein-based vaccines elicited immune responses to pneumococcal proteins. CONCLUSIONS: In this high carriage prevalence setting, inclusion of pneumococcal proteins in the PHiD-CV/dPly/PhtD investigational vaccine had no impact on pneumococcal NPC in infants, regardless of protein dose or schedule. Future evaluations will assess its impact against pneumococcal disease endpoints. FUNDING: PATH, GlaxoSmithKline Biologicals SA. ClinicalTrials.gov identifier NCT01262872.

Immunogenicity and reactogenicity of a three-dose primary vaccination course with a combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-haemophilus influenzae type b vaccine coadministered with a meningococcal C conjugate vaccine.

AIM: To evaluate the immunogenicity and safety of 3 doses of the combined diphtheria-tetanus toxoids-acellular pertussis-hepatitis B virus-inactivated poliovirus/Haemophilus influenzae type b (DTPa-HBV-IPV/Hib) vaccine (Infanrix hexa) when coadministered with a CRM197-conjugated meningococcal C vaccine (Meningitec) at different injection sites during the same visit or during separate visits. METHODS: Healthy infants were randomized in an open randomized multicenter study to receive either the DTPa-HBV-IPV/Hib and meningococcal C conjugate vaccines during the same vaccination visit at 2, 4 and 6 months of age (coadministration group) or the DTPa-HBV-IPV/Hib vaccine at 2, 4 and 6 months of age and the meningococcal C conjugate vaccine at 3, 5 and 7 months of age (separate administration group). RESULTS: The immunogenicity analysis included 452 infants, 228 in the coadministration group and 224 in the separate administration group. One month after primary vaccination, 99.1% of subjects in both groups achieved anti-polyribosylribitol phosphate antibody concentrations >/=0.15 microg/mL. The vaccine response against pertussis antigens was at least 99.1% in both groups. For all other DTPa-HBV-IPV/Hib vaccine antigens, at least 97.8% of all subjects of both groups were seroprotected. In addition, 99.5% of all subjects had meningococcal C bactericidal antibody titers >/=1/8 and 99.1% >/=1/128. Coadministration of both vaccines did not result in an increased local or general reactogenicity compared with separate administration. CONCLUSION: Coadministration of the combined DTPa-HBV-IPV/Hib vaccine and the meningococcal C conjugate vaccine during the same vaccination visit was immunogenic and safe.

Safety and immunogenicity of 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in Nigerian children: Booster dose and 2-dose catch-up regimens in the second year of life.

In a previous study, 3-dose primary vaccination of Nigerian infants with the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) was immunogenic for vaccine pneumococcal serotypes, with comparable tolerability between PHiD-CV and control groups. In an open-label study (ClinicalTrials.gov, NCT01153893), 68 primed children received a PHiD-CV booster dose co-administered with a diphtheria-tetanus-acellular pertussis (DTPa) booster dose at 15-21 months and 36 children unprimed for pneumococcal vaccination received two PHiD-CV catch-up doses (first dose co-administered with DTPa booster dose) at 15-21 and 17-23 months. Adverse events were recorded and immune responses were measured before and one month after vaccination. In both groups, pain was the most frequent solicited local symptom and fever was the most frequent solicited general symptom after the booster dose and each catch-up dose. Few grade 3 solicited symptoms and no vaccine-related serious adverse events were reported. After booster vaccination, for each vaccine serotype, at least 98.5% of children had an antibody concentration ≥ 0.2 µg/ml and at least 94.0% had an opsonophagocytic activity (OPA) titer ≥ 8. After 2-dose catch-up, for each vaccine serotype, at least 97.1% had an antibody concentration ≥ 0.2 µg/ml, except for serotypes 6B (82.9%) and 23F (88.6%), and at least 91.4% had an OPA titer ≥8, except for serotypes 6B (77.4%) and 19F (85.3%). PHiD-CV induced antibody responses against protein D in both groups. In conclusion, PHiD-CV administered to Nigerian toddlers as a booster dose or 2-dose catch-up was well tolerated and immunogenic for vaccine pneumococcal serotypes and protein D.

Safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine in HIV-positive women in South Africa: a partially-blind randomised placebo-controlled study.

In developing countries, risk of human papillomavirus (HPV) infection may be increased by the high prevalence of human immunodeficiency virus (HIV) infection. We evaluated the safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine in HIV-infected women in South Africa. Asymptomatic HIV-positive women aged 18-25 years (N=120) were stratified by CD4⁺ T-cell count and randomised (1:1) to receive HPV-16/18 vaccine (Cervarix®; GlaxoSmithKline Vaccines) or placebo (Al[OH]3) at 0, 1 and 6 months (double-blind). HIV-negative women (N=30) received HPV-16/18 vaccine (open label). Anti-HPV-16/18 antibody and CD4⁺ T-cell responses, CD4⁺ T-cell count, HIV viral load, HIV clinical stage and safety were evaluated for 12 months. The safety and reactogenicity profile of the HPV-16/18 vaccine was comparable in HIV-positive and HIV-negative women. Irrespective of baseline HPV status, all HIV-positive and HIV-negative women who received the HPV-16/18 vaccine were seropositive for both HPV-16 and HPV-18 after the second vaccine dose (month 2) and remained seropositive for both antigens at month 12. Anti-HPV-16/18 antibody titres at month 12 remained substantially above levels associated with natural infection. The HPV-16/18 vaccine induced sustained anti-HPV-16/18 CD4⁺ T-cell responses in both HIV-positive and HIV-negative women. No impact of baseline CD4⁺ T-cell count or HIV viral load was observed on the magnitude of the immune response in HIV-positive women. In HIV-positive women, CD4⁺ T-cell count, HIV viral load and HIV clinical stage were unaffected by HPV-16/18 vaccine administration. In conclusion, the HPV-16/18 AS04-adjuvanted vaccine appears immunogenic and well-tolerated in women with HIV infection. Study ID: 107863/NCT00586339.

Randomized trial: immunogenicity and safety of coadministered human papillomavirus-16/18 AS04-adjuvanted vaccine and combined hepatitis A and B vaccine in girls.

PURPOSE: This randomized, open, controlled, multicenter study (110886/NCT00578227) evaluated human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (HPV-16/18 vaccine) coadministered with inactivated hepatitis A and B (HAB) vaccine. Coprimary objectives were to demonstrate noninferiority of hepatitis A, hepatitis B, and HPV-16/18 immune responses at month 7 when vaccines were coadministered, compared with the same vaccines administered alone. METHODS: Healthy girls (9-15 years) were age-stratified (9, 10-12, and 13-15 years) and randomized to receive HPV (n = 270), HAB (n = 271), or HPV + HAB (n = 272). Vaccines were administered at months 0, 1, and 6. Immunogenicity was evaluated at months 0 and 7. RESULTS: The hepatitis A immune response was noninferior for HPV + HAB, versus HAB, for seroconversion rates (100% in each group) and geometric mean antibody titers (GMTs) (95% CI) (4,504.2 [3,993.0-5,080.8] and 5,288.4 [4,713.3-5,933.7] mIU/mL, respectively). The hepatitis B immune response was noninferior for HPV + HAB, versus HAB, for anti-HBs seroprotection rates (98.3% and 100%); GMTs were 3,136.5 [2,436.0-4,038.4] and 5,646.5 [4,481.3-7,114.6] mIU/mL, respectively. The HPV-16/18 immune response was noninferior for HPV + HAB, versus HPV, for seroconversion rates (99.6% and 100% for both antigens) and GMTs (22,993.5 [20,093.4-26,312.0] and 26,981.9 [23,909.5-30,449.1] EL.U/mL for HPV-16; 8,671.2 [7,651.7-9,826.6] and 11,182.7 [9,924.8-12,600.1] EL.U/mL for HPV-18, respectively). No subject withdrew because of adverse events. No vaccine-related serious adverse events were reported. Immune responses and reactogenicity were similar in girls aged 9 years compared with the entire study population. CONCLUSIONS: Results support coadministration of HPV-16/18 vaccine with HAB vaccine in girls aged 9-15 years. The HPV-16/18 vaccine was immunogenic and generally well tolerated in 9-year-old girls.

Randomized trial of the immunogenicity and safety of the Hepatitis B vaccine given in an accelerated schedule coadministered with the human papillomavirus type 16/18 AS04-adjuvanted cervical cancer vaccine.

The human papillomavirus type 16/18 (HPV-16/18) AS04-adjuvanted cervical cancer vaccine is licensed for females aged 10 years and above and is therefore likely to be coadministered with other licensed vaccines, such as hepatitis B. In this randomized, open-label study, we compared the immunogenicity of the hepatitis B vaccine administered alone (HepB group) or with the HPV-16/18 AS04-adjuvanted vaccine (HepB+HPV group) in healthy women aged 20 to 25 years (clinical trial NCT00637195). The hepatitis B vaccine was given at 0, 1, 2, and 12 months (an accelerated schedule which may be required by women at high risk), and the HPV-16/18 vaccine was given at 0, 1, and 6 months. One month after the third dose of hepatitis B vaccine, in the according-to-protocol cohort (n = 72 HepB+HPV; n = 76 HepB), hepatitis B seroprotection rates (titer of ≥10 mIU/ml) were 96.4% (95% confidence interval [CI], 87.5 to 99.6) and 96.9% (CI, 89.2 to 99.6) in the HepB+HPV and HepB groups, respectively, in women initially seronegative for anti-hepatitis B surface antigen (HBs) and anti-hepatitis B core antigen (HBc). Corresponding geometric mean titers of anti-HBs antibodies were 60.2 mIU/ml (CI, 40.0 to 90.5) and 71.3 mIU/ml (CI, 53.9 to 94.3). Anti-HBs antibody titers rose substantially after the fourth dose of hepatitis B vaccine. All women initially seronegative for anti-HPV-16 and anti-HPV-18 antibodies seroconverted after the second HPV-16/18 vaccine dose and remained seropositive up to 1 month after the third dose. Both vaccines were generally well tolerated, with no difference in reactogenicity between groups. In conclusion, coadministration of the HPV-16/18 AS04-adjuvanted vaccine did not affect the immunogenicity or safety of the hepatitis B vaccine administered in an accelerated schedule in young women.

Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted vaccine administered according to an alternative dosing schedule compared with the standard dosing schedule in healthy women aged 15 to 25 years: results from a randomized study.

BACKGROUND: The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine is immunogenic, has a clinically acceptable safety profile, and prevents incident and persistent HPV-16/18 infection and cervical precancerous lesions. This study (NCT00552279) evaluated the vaccine when administered according to an alternative dosing schedule (0-1-12 months) compared with the standard dosing schedule (0-1-6 months). METHODS: The study was of randomized open design and was conducted at multiple centers in Europe. Healthy women aged 15 to 25 years were randomized (1:1) to receive HPV-16/18 vaccine according to the standard schedule at months 0, 1, and 6 (n = 401) or an alternative schedule at months 0, 1, and 12 (n = 403). HPV-16 and -18 antibodies were measured by enzyme-linked immunosorbent assay at months 0, 2, and 7 or 13 (depending on group); noninferiority evaluation was performed sequentially for seroconversion rates and geometric mean antibody titers. Primary analysis of immunogenicity was based on the according-to-protocol cohort. Vaccine safety and reactogenicity were assessed on the total vaccinated cohort. RESULTS: Predefined noninferiority criteria were met 1 month after the third vaccine dose when the HPV-16/18 vaccine was administered according to the 0-1-12 month schedule compared with the 0-1-6 month schedule in terms of seroconversion rates for HPV-16 (100% and 100%) and HPV-18 (99.7% and 100%) and geometric mean antibody titers for HPV-16 (11884.7 and 10311.9 ELISA units/mL) and HPV-18 (4501.3 and 3963.6 ELISA units/mL), respectively. The HPV-16/18 vaccine had a clinically acceptable safety profile when administered according to either schedule. CONCLUSIONS: The third dose of the HPV-16/18 vaccine can be administered any time between 6 and 12 months after the first dose, with adequate immunogenicity and a clinically acceptable safety profile.

Co-administration of human papillomavirus-16/18 AS04-adjuvanted vaccine with hepatitis B vaccine: randomized study in healthy girls.

BACKGROUND: To evaluate co-administration of GlaxoSmithKline Biologicals' human papillomavirus-16/18 AS04-adjuvanted vaccine (HPV) and hepatitis B vaccine (HepB). METHODS: This was a randomized, controlled, open, multicenter study. Healthy girls, aged 9-15 years, were randomized to receive HPV (n=247), HepB (n=247) or HPV co-administered with HepB (HPV+HepB; n=247) at Months 0, 1 and 6. Antibodies against hepatitis B surface antigen (HBs), HPV-16 and HPV-18 were measured, and reactogenicity and safety monitored. Co-primary objectives were to demonstrate non-inferiority of hepatitis B and HPV-16/18 immune responses at Month 7 for co-administered vaccines, compared with vaccines administered alone, in the according-to-protocol cohort. RESULTS: The pre-defined criteria for non-inferiority were met for all co-primary immunogenicity endpoints at Month 7. Anti-HBs seroprotection rates ≥10mIU/mL were achieved by 97.9% and 100% of girls, respectively, following co-administration or HepB alone. Anti-HBs geometric mean titers (GMTs) (95% confidence interval) were 1280.9 (973.3-1685.7) and 3107.7 (2473.1-3905.1) milli-international units/mL, respectively. Anti-HPV-16 and -18 seroconversion rates were achieved by ≥99% of girls following co-administration or HPV alone. Anti-HPV-16 GMTs were 19819.8 (16856.9-23303.6) and 21712.6 (19460.2-24225.6) ELISA units (ELU)/mL, respectively. Anti-HPV-18 GMTs were 8835.1 (7636.3-10222.1) and 8838.6 (7948.5-9828.4) ELU/mL, respectively. Co-administration was generally well tolerated. CONCLUSIONS: The study results support the co-administration of HPV-16/18 AS04-adjuvanted vaccine with hepatitis B vaccine in adolescent girls aged 9-15 years. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov registration number NCT00652938.

Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted vaccine coadministered with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine and/or meningococcal conjugate vaccine to healthy girls 11 to 18 years of age: results from a randomized open trial.

BACKGROUND: A combined immunization strategy for administration of human papillomavirus (HPV) vaccine with other routine vaccines may lead to better compliance. Reactions and immunologic interference with concomitantly administered vaccines are unpredictable, necessitating clinical evaluation. METHODS: This was a randomized, open study conducted at 48 centers in the United States (NCT00369824). Healthy girls 11 to 18 years of age were randomized equally to 1 of 6 groups to receive 3 doses of HPV-16/18 AS04-adjuvanted vaccine administered at 0, 1, and 6 or 1, 2, and 7 months, with or without 1 dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) and/or 1 dose of meningococcal polysaccharide diphtheria toxoid conjugate vaccine (MCV4) in different coadministration regimens (1283 girls vaccinated). Coadministered vaccines were injected at separate sites. Antibodies were measured for all vaccine components. Reactogenicity and safety were monitored. RESULTS: The prespecified criteria for noninferiority were met for all primary and secondary immunogenicity end points, demonstrating similar immunogenicity of Tdap and MCV4 when given alone or coadministered with the HPV vaccine. Immunogenicity of the HPV vaccine (in terms of seroconversion rates and geometric mean antibody titers to HPV antigens) was similar, regardless of whether it was given alone or coadministered with Tdap and/or MCV4. No differences were observed in the reactogenicity profile of the HPV vaccine administered alone or coadministered with either Tdap and/or MCV4 in different regimens. CONCLUSIONS: Concomitant administration of HPV-16/18 AS04-adjuvanted vaccine with Tdap and/or MCV4 in different regimens did not interfere with the immune response to any of the vaccines and had an acceptable safety profile.