Immunogenicity and safety of the AS04-HPV-16/18 and HPV-6/11/16/18 human papillomavirus vaccines in asymptomatic young women living with HIV aged 15-25 years: A phase IV randomized comparative study.

BACKGROUND: Women living with HIV (WLWH) are at higher risk of acquisition and progression of human papillomavirus (HPV) infection. Evidence on effect of HPV vaccination in this population is limited. METHODS: This phase IV randomized controlled observer-blind study assessed immunogenicity and safety of two HPV vaccines (AS04-HPV-16/18 vs. 4vHPV) given in WLWH (stage 1) and HIV- females aged 15-25 years. Co-primary endpoints were to demonstrate, in WLWH subjects, non-inferiority (and if demonstrated, superiority) of AS04-HPV-16/18 vs. 4vHPV for HPV-16 and HPV-18 by pseudovirion-based neutralization assay (PBNA) at month 7 and safety. Non-inferiority criteria was lower limit (LL) of the 95% confidence interval (CI) of the GMT ratio AS04-HPV-16/18/4vHPV above 0.5, in the according to protocol population. NCT01031069. FINDINGS: Among 873 subjects recruited between 26-Oct-2010 and 14-May-2015, 546 were randomized (1:1) and received at least one vaccine dose (total vaccinated cohort, TVC): 257 were WLWH (129 AS04-HPV-16/18; 128 4vHPV) and 289 were subjects without HIV (144 AS04-HPV-16/18; 145 4vHPV). Baseline CD4 cell count in WLWH was at least 350 cells/mm3.At month 7, AS04-HPV-16/18 showed immunological superiority to 4vHPV in WLWH. Neutralizing anti-HPV-16 and HPV-18 antibody GMTs were 2·74 (95% CI: 1·83; 4·11) and 7·44 (95% CI: 4·79; 11·54) fold higher in AS04-HPV-16/18 vs. 4vHPV (LL of the GMT ratio >1 in TVC, p<0·0001), respectively. Similar results were observed by ELISA up to month 24.Solicited local and general symptoms were in line with product labels. The number of reported serious adverse events (SAEs) was balanced throughout the study. INTERPRETATION: Both vaccines showed an acceptable safety profile in all subjects. Despite the absence of an immunological correlate of protection for HPV, differences in immune responses elicited by the vaccines especially for HPV-18 may translate into longer lasting or more robust protection against cervical cancer with the AS04-HPV-16/18 vaccine in WLWH.

Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese girls and women aged 9 to 45 years.

Immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine were evaluated in healthy Chinese females aged 9-45 years in 2 phase IIIB, randomized, controlled trials. Girls aged 9-17 years (ClinicalTrials.gov, NCT00996125) received vaccine (n = 374) or control (n = 376) and women aged 26-45 years (NCT01277042) received vaccine (n = 606) or control (n = 606) at months 0, 1, and 6. The primary objective was to show non-inferiority of anti-HPV-16 and -18 immune responses in initially seronegative subjects at month 7, compared with Chinese women aged 18-25 years enrolled in a separate phase II/III trial (NCT00779766). Secondary objectives were to describe the anti-HPV-16 and -18 immune response, reactogenicity and safety. At month 7, immune responses were non-inferior for girls (9-17 years) vs. young women (18-25 years): the upper limit of the 95% confidence interval (CI) for the geometric mean titer (GMT) ratio (women/girls) was below the limit of 2 for both anti-HPV-16 (0.37 [95% CI: 0.32, 0.43]) and anti-HPV-18 (0.42 [0.36, 0.49]). Immune responses at month 7 were also non-inferior for 26-45 year-old women vs. 18-25 year-old women: the upper limit of the 95% CI for the difference in seroconversion (18-25 minus 26-45) was below the limit of 5% for both anti-HPV-16 (0.00% [-1.53, 1.10]) and anti-HPV-18 (0.21% [-1.36, 1.68]). GMTs were 2- to 3-fold higher in girls (9-17 years) as compared with young women (18-25 years). The HPV-16/18 AS04-adjuvanted vaccine had an acceptable safety profile when administered to healthy Chinese females aged 9-45 years.

Baseline prevalence and type distribution of human papillomavirus in healthy Chinese women aged 18-25 years enrolled in a clinical trial.

Baseline human papillomavirus (HPV) prevalence and type distribution were evaluated in young Chinese women enrolled in a clinical trial of an HPV vaccine (ClinicalTrials.gov registration NCT00779766). Cervical specimens and blood samples were collected at baseline from women aged 18-25 years (n = 6,051) from four sites across Jiangsu province. Cervical specimens were tested for HPV DNA by SPF10 PCR-DEIA-LiPA25 version 1, and HPV-16/18 type-specific polymerase chain reaction. Anti-HPV-16 and anti-HPV-18 antibody titres were quantified by enzyme-linked immunosorbent assay. At baseline, 15.3% of women were DNA positive for any of 14 HPV high-risk (hr) types (HPV-16/18/31/33/35/39/45/51/52/56/58/59/66/68). The most commonly detected hrHPV types in cervical specimens were HPV-52 (4.0%) and HPV-16 (3.7%). High-risk HPV DNA-positivity increased with severity of cytological abnormalities: 39.3% in atypical squamous cells of undetermined significance, 85.0% in low-grade squamous intraepithelial lesions and 97.8% in high-grade squamous intraepithelial lesions (HSIL). The hrHPV types most frequently detected in HSIL were HPV-16 (63.0%), HPV-18 (17.4%), HPV-52 (17.4%), HPV-58 (15.2%) and HPV-33 (15.2%). The hrHPV types most frequently detected in cervical intraepithelial neoplasia 2+ were HPV-16 (66.1%), HPV-33 (16.1%), HPV-52 (16.1%), HPV-58 (14.5%) and HPV-51 (11.3%). Multiple hrHPV infections were reported for 24.4% of hrHPV DNA positive women. Regardless of baseline HPV DNA status, 30.5% and 16.0% of subjects were initially seropositive for anti-HPV-16 and anti-HPV-18, respectively. In conclusion, the high baseline seropositivity rate and intermediate prevalence of cervical hrHPV types in Chinese women aged 18-25 years underlines the importance of early HPV vaccination in this population.

Efficacy, immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese women aged 18-25 years: results from a randomized controlled trial.

This phase II/III, double-blind, randomized trial assessed the efficacy, immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in young Chinese women (ClinicalTrials.gov registration NCT00779766). Women aged 18-25 years from Jiangsu province were randomized (1:1) to receive HPV vaccine (n = 3,026) or Al(OH)3 control (n = 3,025) at months 0, 1 and 6. The primary objective was vaccine efficacy (VE) against HPV-16/18 associated 6-month persistent infection (PI) and/or cervical intraepithelial neoplasia (CIN) 1+. Secondary objectives were VE against virological and clinical endpoints associated with HPV-16/18 and with high-risk HPV types, immunogenicity and safety. Mean follow-up for the according-to-protocol cohort for efficacy (ATP-E) was ∼15 months after the third dose. In the ATP-E (vaccine = 2,889; control = 2,894), for initially HPV DNA negative and seronegative subjects, HPV-16/18 related VE (95% CI) was 94.2% (62.7, 99.9) against 6-month PI and/or CIN1+ and 93.8% (60.2, 99.9) against cytological abnormalities. VE against HPV-16/18 associated CIN1+ and CIN2+ was 100% (-50.4, 100) and 100% (-140.2, 100), respectively (no cases in the vaccine group and 4 CIN1+ and 3 CIN2+ cases in the control group). At Month 7, at least 99.7% of initially seronegative vaccine recipients had seroconverted for HPV-16/18; geometric mean antibody titres (95% CI) were 6,996 (6,212 to 7,880) EU/mL for anti-HPV-16 and 3,309 (2,942 to 3,723) EU/mL for anti-HPV-18. Safety outcomes between groups were generally similar. The HPV-16/18 AS04-adjuvanted vaccine is effective, immunogenic and has a clinically acceptable safety profile in young Chinese women. Prophylactic HPV vaccination has the potential to substantially reduce the burden of cervical cancer in China.

Comparison of the immunogenicity of the human papillomavirus (HPV)-16/18 vaccine and the HPV-6/11/16/18 vaccine for oncogenic non-vaccine types HPV-31 and HPV-45 in healthy women aged 18-45 years.

Protection against oncogenic non-vaccine types (cross-protection) offered by human papillomavirus (HPV) vaccines may provide a significant medical benefit. Available clinical efficacy data suggest the two licensed vaccines (HPV-16/18 vaccine, GlaxoSmithKline Biologicals (GSK), and HPV-6/11/16/18 vaccine, Merck & Co., Inc.) differ in terms of protection against oncogenic non-vaccine HPV types -31/45. The immune responses induced by the two vaccines against these two non-vaccine HPV types (cross-reactivity) was compared in an observer-blind study up to Month 24 (18 mo post-vaccination), in women HPV DNA-negative and seronegative prior to vaccination for the HPV type analyzed (HPV-010 [NCT00423046]). Geometric mean antibody titers (GMTs) measured by pseudovirion-based neutralization assay (PBNA) and enzyme-linked immunosorbent assay (ELISA) were similar between vaccines for HPV-31/45. Seropositivity rates for HPV-31 were also similar between vaccines; however, there was a trend for higher seropositivity with the HPV-16/18 vaccine (13.0-16.7%) versus the HPV-6/11/16/18 vaccine (0.0-5.0%) for HPV-45 with PBNA, but not ELISA. HPV-31/45 cross-reactive memory B-cell responses were comparable between vaccines. Circulating antigen-specific CD4+ T-cell frequencies were higher for the HPV-16/18 vaccine than the HPV-6/11/16/18 vaccine (HPV-31 [geometric mean ratio [GMR] =2.0; p=0.0002] and HPV-45 [GMR=2.6; p=0.0092]), as were the proportion of T-cell responders (HPV-31, p=0.0009; HPV-45, p=0.0793). In conclusion, immune response to oncogenic non-vaccine HPV types -31/45 was generally similar for both vaccines with the exception of T-cell response which was higher with the HPV-16/18 vaccine. Considering the differences in cross-protective efficacy between the two vaccines, the results might provide insights into the underlying mechanism(s) of protection.

Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 vaccine and HPV-6/11/16/18 vaccine: follow-up from months 12-24 in a Phase III randomized study of healthy women aged 18-45 years.

In this observer-blind study (NCT00423046), women (N=1,106), stratified by age (18-26, 27-35, 36-45 y), were randomized (1:1) to receive the HPV-16/18 vaccine (Cervarix®, GlaxoSmithKline Biologicals, Months 0, 1, 6) or the HPV-6/11/16/18 vaccine (Gardasil® Merck & Co., Inc., Months 0, 2, 6). Month 7 results were previously reported; we now report Month 24 results. In the according-to-protocol cohort for immunogenicity (seronegative and DNA-negative at baseline for HPV type analyzed), seropositivity rates of neutralizing antibodies (nAbs) [pseudovirion-based neutralization assay] were, across all age strata, 100% (HPV-16/18 vaccine) and 97.5-100% (HPV-6/11/16/18 vaccine) for HPV-16, and 99.0-100% (HPV-16/18 vaccine) and 72.3-84.4% (HPV-6/11/16/18 vaccine) for HPV-18. Corresponding geometric mean titers (GMTs) were 2.4-5.8-fold higher for HPV-16 and 7.7-9.4-fold higher for HPV-18 with the HPV-16/18 vaccine versus the HPV-6/11/16/18 vaccine; HPV-16 and HPV-18 GMTs were significantly higher with the HPV-16/18 vaccine than the HPV-6/11/16/18 vaccine (p< 0.0001) in the total vaccinated cohort (received ≥1 vaccine dose, irrespective of baseline sero/DNA-status). Similar results were obtained using enzyme-linked immunosorbent assay (ELISA). Positivity rates and GMTs of antigen-specific IgG antibodies in cervicovaginal secretions (ELISA) were not significantly different between vaccines. At Month 24, CD4⁺ T-cell responses for HPV-16 and HPV-18 were higher with the HPV-16/18 vaccine; memory B-cell response was higher for HPV-18 with the HPV-16/18 vaccine and similar between vaccines for HPV-16. Both vaccines were generally well tolerated. Although an immunological correlate of protection has not been defined, differences in the magnitude of immune response between vaccines may represent determinants of duration of protection.

The immunogenicity and safety of a reduced PRP-content DTPw-HBV/Hib vaccine when administered according to the accelerated EPI schedule.

BACKGROUND: Combination vaccines improve coverage, compliance and effectively introduce new antigens to mass vaccination programmes. This was a phase III, observer-blind, randomized study of GSK Biologicals diphtheria-tetanus-whole cell pertussis vaccine combined with hepatitis B and Haemophilus influenzae type b vaccines, containing a reduced amount of polyribosyl-ribitol-phosphate (PRP) and a DTPw component manufactured at a different site (DTPw-HBV/Hib2.5 [Kft]). The primary aim of this study was to demonstrate that DTPw-HBV/Hib2.5 [Kft] was not inferior to the licensed DTPw-HBV/Hib (Tritanrix(tm)-HepB/Hiberix(tm)) vaccine or the DTPw-HBV/Hib2.5 vaccine, also containing a reduced amount of PRP, with respect to the immune response to the PRP antigen, when administered to healthy infants, according to the Expanded Programme for Immunization (EPI) schedule at 6, 10 and 14 weeks of age. METHODS: 299 healthy infants were randomised to receive either DTPw-HBV/Hib2.5 [Kft] DTPw-HBV/Hib2.5 or DTPw-HBV/Hib according to the 6-10-14 week EPI schedule. Blood samples were analysed prior to the first dose of study vaccine and one month after the third vaccine dose for the analysis of immune responses. Solicited local and general symptoms such as pain, redness and swelling at the injection site and drowsiness and fever, unsolicited symptoms (defined as any additional adverse event) and serious adverse events (SAEs) were recorded up to 20 weeks of age. RESULTS: One month after the third vaccine dose, 100% of subjects receiving DTPw-HBV/Hib2.5 [Kft] or DTPw-HBV/Hib and 98.8% of subjects receiving DTPw-HBV/Hib2.5 vaccine had seroprotective levels of anti-PRP antibodies (defined as anti-PRP antibody concentration ≥0.15 µg/ml). Seroprotective antibody concentrations were attained in over 98.9% of subjects for diphtheria, tetanus and hepatitis B. The vaccine response rate to pertussis antigen was at least 97.8% in each group. Overall, the DTPw-HBV/Hib2.5 [Kft] vaccine was well tolerated in healthy infants; no SAEs were reported in any group. CONCLUSIONS: The DTPw-HBV/Hib2.5 [Kft] vaccine was immunogenic and well-tolerated when administered according to the EPI schedule to Indian infants. TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT00473668.

Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Indian women.

AIM: India has the highest number of annual incident cases and mortality rates for cervical cancer worldwide. This study was conducted to assess the immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Indian women aged 18-35 years old. METHODS: This double-blind, randomized (1:1), controlled and multicenter trial with two parallel groups, the Vaccine and Placebo groups, included 354 subjects in four centers across India. Subjects were given GlaxoSmithKline's HPV-16/18 AS04-adjuvanted cervical cancer vaccine or aluminum hydroxide placebo according to a 0, 1 and 6 month schedule and followed up until month 7. Serum samples were drawn at pre-vaccination and at month 7. Safety data were collected throughout the study. RESULTS: A total of 330 subjects completed the study. One month post-Dose 3, all initially seronegative subjects in the Vaccine group had seroconverted for HPV-16 and HPV-18 antibodies with anti-HPV-16 and anti-HPV-18 geometric mean titer levels of 10226.5 EL.U/ml (95% confidence interval: 8847.1-11821.0) and 3953.0 EL.U/ml (95% confidence interval: 3421.8-4566.8), respectively. Initially seropositive subjects also showed an increase to similar geometric mean titer levels. Six serious adverse events (two in the Vaccine group and four in the Placebo group), all unrelated to vaccination, were reported. Commonly reported solicited local (injection-site pain) and general (fatigue, headache and fever) symptoms were similar in both groups. Compliance to the three-dose vaccination course was >97%. CONCLUSIONS: The AS04-adjuvanted HPV-16/18 cervical cancer vaccine was highly immunogenic and generally well-tolerated making it a potential tool for prevention and control of cervical cancer in India.

Retrospective surveillance for intussusception in children aged less than five years in a South Indian tertiary-care hospital.

To facilitate the assessment of the safety profile of rotavirus vaccines effectively, baseline data on intussusception are important for comparison with intussusception rates following the introduction of vaccine. The aim of the study was to describe epidemiological and clinical features of intussusception in children aged less than five years in an Indian medical facility. Hospital data on intussusception for children discharged during 1 January 2001-30 June 2004 from the Christian Medical College Hospital, Vellore, India, were reviewed. Relevant information was extracted from medical records to classify cases according to the criteria of the Brighton Collaboration Intussusception Working Group. Complete review of medical records for clinical and demographic information was only performed for those cases fulfilling level 1 diagnostic certainty (definite intussusception) (Study ID 101245). During the surveillance period, 31 infants and children with definite intussusception were identified. The majority (61.2%) of the cases occurred in the first year of life. The male : female ratio was 3.4 : 1. Intussusception cases occurred round the year with no distinct seasonality. No intussusception-associated death was recorded. This study provides baseline data on intussusception in South India. Cases identified in the study were similar in presentation and demographics as those observed in other Asian settings. Prospective surveillance systems, using standardized case definitions will further increase the understanding of the aetiology and epidemiology of intussusception, especially as new rotavirus vaccines are made available.

Community-based cross-sectional seroprevalence study of hepatitis A in Bangladesh.

AIM: To elucidate the age-distribution of anti-hepatitis A virus (HAV) seroprevalence across different socioeconomic status (SES) categories in Bangladesh which, despite scarce data, is generally deemed to have high endemicity. METHODS: Blood samples of 818 subjects from a stratified sample of schools and hospitals, comprising different age categories and SES were collected. They were assayed for total anti-HAV antibodies. Social and medical history data were obtained using a questionnaire. RESULTS: Overall anti-HAV seroprevalence was 69.6%, increasing with age from 1-5 years (40.4%) to > 30 years (98.4%). Seroprevalence was lowest (49.8%) in the high SES group and highest (96.5%) in the rural lower-middle SES group. Among subjects aged 6-20 years, anti-HAV seroprevalence was lowest in urban private school children (43.0%), followed by urban government school children (76.2%) and rural school children (96.5%) (P < 0.01). Within the high SES group, anti-HAV seroprevalence was 32.3% in subjects < 10 years and 51.7% in those aged 11-20 years. Until now Bangladesh has been deemed to have high endemicity for HAV. CONCLUSION: The transition from high to intermediate HAV endemicity may be underway; high SES adolescents and adults remain particularly at risk of symptomatic illness. Preventive measures need consideration.