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Traditional vaccine efficacy trials usually use fixed designs and often require large sample sizes. Recruiting a large number of subjects can make the trial expensive, long, and difficult to conduct. A possible approach to reduce the sample size and speed up the development is to use historical controls. In this paper, we extend the robust mixture prior (RMP) approach (a well established approach for Bayesian dynamic borrowing of historical controls) to adjust for covariates. The adjustment is done using classical methods from causal inference: inverse probability of treatment weighting, G-computation and double-robust estimation. We evaluate these covariate-adjusted RMP approaches using a comprehensive simulation study and demonstrate their use by performing a retrospective analysis of a prophylactic human papillomavirus vaccine efficacy trial. Adjusting for covariates reduces the drift between current and historical controls, with a beneficial effect on bias, control of type I error and power.
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Traditional vaccine efficacy trials usually use fixed designs with fairly large sample sizes. Recruiting a large number of subjects requires longer time and higher costs. Furthermore, vaccine developers are more than ever facing the need to accelerate vaccine development to fulfill the public's medical needs. A possible approach to accelerate development is to use the method of dynamic borrowing of historical controls in clinical trials. In this paper, we evaluate the feasibility and the performance of this approach in vaccine development by retrospectively analyzing two real vaccine studies: a relatively small immunological trial (typical early phase study) and a large vaccine efficacy trial (typical Phase 3 study) assessing prophylactic human papillomavirus vaccine. Results are promising, particularly for early development immunological studies, where the adaptive design is feasible, and control of type I error is less relevant.
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Proyectos de Investigación , Vacunas , Humanos , Estudios Retrospectivos , Teorema de Bayes , Tamaño de la MuestraRESUMEN
Clinical trial data and real-world evidence suggest that the AS04-adjuvanted vaccine targeting human papillomavirus types 16 and 18 (AS04-HPV-16/18) vaccine provides nearly 90% protection against cervical intraepithelial neoplasia grade 3 or higher irrespective of type, among women vaccinated before sexual debut. This high efficacy is not fully explained by cross-protection. Although AS04-HPV-16/18 vaccination does not affect clearance of prevalent infections, it may accelerate clearance of newly acquired infections. We pooled data from 2 large-scale randomized controlled trials to evaluate efficacy of the AS04-HPV-16/18 vaccine against clearance of nontargeted incident infections. Results of our analysis do not suggest an effect in expediting clearance of incident infections.
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Infecciones por Papillomavirus , Vacunas contra Papillomavirus/inmunología , Neoplasias del Cuello Uterino , Adyuvantes Inmunológicos , Costa Rica/epidemiología , Método Doble Ciego , Femenino , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Humanos , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/prevención & control , Resultado del Tratamiento , Neoplasias del Cuello Uterino/prevención & control , Neoplasias del Cuello Uterino/virologíaRESUMEN
INTRODUCTION: The pivotal efficacy study assessed efficacy and safety of GSK's AS04-HPV-16/18 vaccine in Chinese women aged 18-25 years up to 6 years. The present extension study, performed 4 years later, offered AS04-HPV-16/18 vaccination to placebo recipients. Vaccine safety and its long-term protective effect were assessed at Year 10. METHODS: All 6051 women who received AS04-HPV-16/18 or the placebo during the initial study (NCT00779766) were invited to phase III/IV, open-label, partially controlled extension Year 10 study (NCT03629886). Placebo recipients were offered three-dose AS04-HPV-16/18 vaccination and followed up over 12 months to assess the safety. Cervical samples from all women were examined. Vaccine efficacy (VE) against incident infections and cytological lesions associated with HPV-16/18 and other oncogenic types was assessed as exploratory objective. RESULTS: Among 3537 women (out of 6051) enrolled in the extension study, 1791 women (mean age 32.7 years; standard deviation 1.8 years) received AS04-HPV-16/18 and reported no serious adverse events, potential immune-mediated diseases, or adverse pregnancy outcomes related to vaccination. Among 6051 women, VE against incident HPV-16, -18, and -16/18 infections up to Year 10 was 82.8% (95% confidence interval: 72.5-89.7), 79.8% (64.5-89.2), and 80.8% (72.4-87.0), respectively. VE against HPV-16/18 ASC-US+, CIN1+, and CIN2+ was 92.7% (82.2-97.7), 94.8% (67.4-99.9), and 90.5% (34.6-99.8), respectively. CONCLUSION: AS04-HPV-16/18 vaccine showed an acceptable safety profile in Chinese women vaccinated at age 26 years or above, and a long-term protection similar to other efficacy trials worldwide.
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Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Neoplasias del Cuello Uterino , Adolescente , Adulto , Femenino , Humanos , Embarazo , Adulto Joven , Pueblos del Este de Asia , Estudios de Seguimiento , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/efectos adversos , Vacunas contra Papillomavirus/uso terapéutico , Neoplasias del Cuello Uterino/prevención & controlRESUMEN
In clinical trials, several covariate-adaptive designs have been proposed to balance treatment arms with respect to key covariates. Although some argue that conventional asymptotic tests are still appropriate when covariate-adaptive randomization is used, others think that re-randomization tests should be used. In this manuscript, we compare by simulation the performance of asymptotic and re-randomization tests under covariate-adaptive randomization. Our simulation study confirms results expected by the existing theory (e.g. asymptotic tests do not control type I error when the model is miss-specified). Furthermore, it shows that (i) re-randomization tests are as powerful as the asymptotic tests if the model is correct; (ii) re-randomization tests are more powerful when adjusting for covariates; (iii) minimization and permuted blocks provide similar results.
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Proyectos de Investigación , Simulación por Computador , Distribución AleatoriaRESUMEN
Human papillomavirus (HPV) vaccines are efficacious against HPV infections and associated lesions in women HPV-naïve at vaccination. However, vaccine efficacy (VE) against oncogenic, high-risk HPV (HR-HPV) types in women infected with any other HR-HPV type at first vaccination (baseline) remains unclear. This post-hoc analysis of a phase II/III study (NCT00779766) evaluated AS04-adjuvanted HPV-16/18 (AS04-HPV-16/18) VE against HR-HPV type infection in 871 Chinese women aged 18-25 years over a 72-month follow-up period. Study participants were DNA-negative at baseline to HR-HPV type(s) considered for VE and DNA-positive to any other HR-HPV type. Initial serostatus was not considered. Baseline DNA prevalence was 14.6% for any HR-HPV type and 10.6% excluding HPV-16/18. In the total vaccinated cohort for efficacy, VE against 6-month and 12-month HPV-16/18 persistent infections (PIs) in women DNA-negative to HPV-16/18 but DNA-positive to any other HR-HPV type at baseline was 100.0% (95% Confidence Interval [CI]: 79.8-100.0) and 100.0% (95%CI: 47.2-100.0), respectively. VE against HPV-16/18 incident infections in women DNA-positive to one vaccine type but DNA-negative to the other one at baseline was 66.8% (95%CI: -18.9-92.5). VE against HPV-31/33/45 incident infections, in women DNA-positive to HPV-16/18 and DNA-negative to the considered HPV type at baseline was 71.0% (95%CI: 27.3-89.8). No HPV-16/18 PIs were observed in vaccinated women with non-vaccine HPV A7/A9 species cervical infection at baseline. These findings indicated that women with existing HR-HPV infection at vaccination might still benefit from the AS04-HPV-16/18 vaccine. However, this potential benefit needs further demonstration in the future.
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Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Adyuvantes Inmunológicos , Adolescente , Adulto , China , Método Doble Ciego , Femenino , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Humanos , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: Hepatitis A virus infection is more severe in adults than children. Although vaccination can protect adults, current childhood programs cover a large population more successfully. Childhood vaccination is, therefore, a solution to protecting adults if it induces lasting immunity. Fifteen-year protection has been demonstrated in children, but longer-term data are only available for adults. We aimed to predict long term persistence of antibody in children beyond 15 years and assess if immunological mechanisms triggered by vaccination support longer-term protection. METHODS: Long-term clinical studies using hepatitis A (HAV) or A/B vaccines (HAB) containing 720 or 1440 Enzyme-linked immunosorbent assay Units (EU) of hepatitis A virus antigen were identified. Duration of persistence of antibodies and possible protection was determined by descriptively comparing antibody geometric mean concentration (GMC) kinetics, as well as GMC (95% confidence interval) at 15 years post-vaccination across studies. Immunological mechanism studies describing hepatitis A vaccination were identified. RESULTS: One study in children 12-15 years (2-dose HAB 720) and four in adults (2-dose HAV 1440 and 3-dose HAB 720) showed comparable GMC kinetics and per year rates of change up to 15 years. At 15 years, the GMC in children [414.7 mEU/ml (336.9; 510.5)] was in the same range as in adults [range 282.6 (217.6; 367.0) to 550.1 (416.0; 727.4)]. Based on these data, mathematical model predictions from adult studies (showing > 85% protected at 50 years) were deemed likely to also apply to children. Studies identified, both humoral and cell-mediated responses are induced following vaccination. CONCLUSION: Based on comparable antibody data in adults and children up to 15 years, similar longer-term antibody persistence is expected in children with 2-dose inactivated hepatitis A 720 containing vaccine at least up to 50 years. Accordingly, improving routine childhood hepatitis A vaccination coverage could protect against more severe disease in adulthood. Fig. 1 Plain language summary TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT00875485, NCT01000324, NCT01037114, NCT00289757, NCT00291876.
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BACKGROUND: The AS04-adjuvanted HPV16/18 (AS04-HPV16/18) vaccine provides excellent protection against targeted human papillomavirus (HPV) types and a variable degree of cross-protection against others, including types 6/11/31/33/45. High efficacy against any cervical intraepithelial neoplasia grade 3 or greater (CIN3+; >90%) suggests that lower levels of protection may exist for a wide range of oncogenic HPV types, which is difficult to quantify in individual trials. Pooling individual-level data from two randomized controlled trials, we aimed to evaluate AS04-HPV16/18 vaccine efficacy against incident HPV infections and cervical abnormalities . METHODS: Data were available from the Costa Rica Vaccine Trial (NCT00128661) and Papilloma Trial Against Cancer in Young Adults trial (NCT00122681), two large-scale, double-blind randomized controlled trials of the AS04-HPV16/18 vaccine. Primary analyses focused on disease-free women with no detectable cervicovaginal HPV at baseline. RESULTS: A total of 12 550 women were included in our primary analyses (HPV arm = 6271, control arm = 6279). Incidence of 6-month persistent oncogenic and nononcogenic infections, excluding known and accepted protected types 6/11/16/18/31/33/45 (focusing on 34/35/39/40/42/43/44/51/52/53/54/56/58/59/66/68/73/70/74), was statistically significantly lower in the HPV arm than in the control arm (efficacy = 9.9%, 95% confidence interval [CI] = 1.7% to 17.4%). Statistically significant efficacy (P < .05) was observed for individual oncogenic types 16/18/31/33/45/52 and nononcogenic types 6/11/53/74. Efficacy against cervical abnormalities (all types) increased with severity, ranging from 27.7% (95% CI = 21.7% to 33.3%) to 58.7% (95% CI = 34.1% to 74.7%) for cytologic outcomes (low-grade squamous intraepithelial neoplasia lesion or greater, and high-grade squamous intraepithelial neoplasia lesion or greater, respectively) and 66.0% (95% CI = 54.4% to 74.9%) to 87.8% (95% CI = 71.1% to 95.7%) for histologic outcomes (CIN2+ and CIN3+, respectively). Comparing Costa Rica Vaccine Trial and Papilloma Trial Against Cancer in Young Adults results, there was no evidence of heterogeneity, except for type 51 (efficacy = -28.6% and 20.7%, respectively; two-sided P = .03). CONCLUSIONS: The AS04-HPV16/18 vaccine provides some additional cross-protection beyond established protected types, which partially explains the high efficacy against CIN3+.
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Adyuvantes Inmunológicos/administración & dosificación , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/administración & dosificación , Adolescente , Adulto , Costa Rica/epidemiología , Femenino , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/aislamiento & purificación , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/aislamiento & purificación , Humanos , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/epidemiología , Vacunas contra Papillomavirus/química , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Estudios Retrospectivos , Resultado del Tratamiento , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/prevención & control , Neoplasias del Cuello Uterino/virología , Adulto Joven , Displasia del Cuello del Útero/epidemiología , Displasia del Cuello del Útero/prevención & control , Displasia del Cuello del Útero/virologíaRESUMEN
AIM: In 9-17-year-old Chinese girls, the AS04-adjuvanted HPV-16/18 vaccine (AS04-HPV-16/18) given as three-dose schedule induced high antibody levels, which were noninferior 1 month after the third dose to those observed in 18-25-year-old Chinese women in a large efficacy study. We assessed the persistence of antibodies 8-9 years after vaccination in the same subjects. METHODS: This follow-up phase III, open-label study (NCT03355820) included subjects who had received three doses of AS04-HPV-16/18 in the initial trial (NCT00996125). Serum antibody concentrations were assessed by ELISA and compared to antibody persistence observed in 18-25-year-old Chinese women 6 years after first vaccination in the efficacy study (NCT00779766). RESULTS: Out of the 227 enrolled subjects, 223 were included in the per-protocol immunogenicity analysis. Mean interval from first AS04-HPV-16/18 dose to blood sampling was 101.4 months (8.5 years). For antibodies against HPV-16 and -18, 8.5 years after first vaccine dose all subjects remained seropositive and antibody. Geometric mean concentrations (GMCs) were 1236.3 (95% confidence interval [CI]: 1121.8; 1362.4) and 535.6 (95% CI: 478.6; 599.4) ELISA Units/mL, respectively. These seropositivity rates and antibody GMCs were higher than those observed 6 years after first vaccination of 18-25-year-old women. CONCLUSION: Sustained anti-HPV-16 and -18 immune responses were observed 8-9 years after AS04-HPV-16/18 vaccination of 9-17 year-old Chinese girls that were higher than the ones observed 6 years after first vaccination in Chinese adult women in whom AS04-HPV-16/18 efficacy against cervical intraepithelial neoplasia of grade ≥2 was demonstrated.
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Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/uso terapéutico , Pueblo Asiatico , Femenino , Estudios de Seguimiento , Humanos , Vacunas contra Papillomavirus/farmacología , MujeresRESUMEN
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-16/18â¯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-16/18â¯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-16/18â¯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.
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BACKGROUND: Substantial heterogeneity has been reported in efficacy against high-grade cervical intraepithelial neoplasia (CIN) irrespective of HPV type in phase III results for bivalent and quadrivalent human papillomavirus virus (HPV) vaccines (AS04-HPV and qHPV). Real-world data recently confirmed a very high overall impact of AS04-HPV, supporting the validity of the observed heterogeneity. To explore the reasons for heterogeneous efficacy, we assessed vaccine impact on high-grade lesions not caused by vaccine types. RESEARCH METHODS: We extracted case counts of CIN lesions containing (1) at least one vaccine HPV type, (2) at least one vaccine HPV type and a high-risk non-vaccine type (co-infections) and (3) no vaccine types (non-vaccine or no high-risk HPV types). Based on these, Phase III cross-protective efficacies were estimated with exclusion (3) and with inclusion (2 and 3) of co-infections. RESULTS: Cross-protective efficacy of AS04-HPV against CIN3 lesions ranges from 81.3% (95%CI: 34.7;96.5) (excluding co-infections) to 88.5% (95%CI:62.4;97.8) (including co-infections). For qHPV the efficacy ranges from -58.7% (95%CI: -180.5;8.5) (excluding co-infections) to 13.1% (95%CI: -39.0;45.9) (including co-infections). CONCLUSIONS: Heterogenous overall efficacy against CIN3 between AS04-HPV and qHPV is driven by differential efficacy against lesions that do not contain vaccine types, which may be related to the impact of different adjuvants on the immune response.
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Papillomaviridae/inmunología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/administración & dosificación , Adyuvantes Inmunológicos/administración & dosificación , Ensayos Clínicos Fase III como Asunto , Femenino , Estudios de Seguimiento , Humanos , Infecciones por Papillomavirus/inmunología , Vacunas contra Papillomavirus/inmunología , Adulto Joven , Displasia del Cuello del Útero/prevención & controlRESUMEN
BACKGROUND: The burden of human papillomavirus (HPV) diseases is high in Latin America. HPV vaccines licensed from 2006 onwards offer protection against most HPV-related cancers, especially when introduced into national immunization programs. Barriers to optimal vaccine uptake are, however, lowering the impact of adolescent HPV vaccination programs. Immunization of children might overcome these barriers and be a strategy of choice for some countries. METHODS: This multicenter phase III randomized, controlled, single-blind study (NCT01627561) was conducted in Colombia, Mexico and Panama to assess safety and immunogenicity of 2-dose vaccination with AS04-adjuvanted HPV-16/18 vaccine in girls 4-6 years of age. We report safety outcomes and anti-HPV-16/18 antibody titers measured by enzyme-linked immunosorbent assay in HPV-vaccinated girls that were followed over a 36-month period. RESULTS: Over 36 months (ie, 30 months after the second vaccine dose), among 74 girls included in the HPV group, 1 serious adverse event unrelated to vaccination has been reported. No withdrawal because of (serious) adverse events has been reported. At month 36, all girls in the per-protocol-cohort were still seropositive for anti-HPV-16 and anti-HPV-18 with geometric mean concentrations of 1680.6 and 536.4 enzyme-linked immunosorbent assay units/mL, respectively. CONCLUSIONS: The AS04-adjuvanted HPV-16/18 vaccine administered according to a 2-dose schedule to girls 4-6 years of age induced a high and sustained immunologic response with an acceptable safety profile during the 30 months following vaccination.
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Hidróxido de Aluminio/efectos adversos , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Lípido A/análogos & derivados , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/efectos adversos , Vacunas contra Papillomavirus/inmunología , Hidróxido de Aluminio/administración & dosificación , Anticuerpos Antivirales/sangre , Niño , Preescolar , Ensayos Clínicos Fase III como Asunto , Colombia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Estudios de Seguimiento , Humanos , Lípido A/administración & dosificación , Lípido A/efectos adversos , México , Panamá , Vacunas contra Papillomavirus/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Método Simple CiegoRESUMEN
This study assessed long-term immunogenicity and safety following 3 doses of AS04-adjuvanted human papillomavirus (HPV)-16/18 L1 virus-like particle (VLP) vaccine in females 10-14 years old. Girls included in the immunogenicity subset in the primary controlled, observer-blinded, randomized study (NCT00196924) who received 3 doses were invited for a 10-year follow-up (NCT00316706 and NCT00877877). Serum antibody responses against HPV-16/18 (vaccine types) and HPV-31/45 (non-vaccine types) were measured by enzyme-linked immunosorbent assay (ELISA) using type-specific VLP as coating antigens. Serious adverse events (SAEs) and pregnancy information were recorded. At Month (M) 120, all subjects (N = 418, according-to-protocol immunogenicity cohort) were seropositive for anti-HPV-16/18 antibodies. Geometric mean titers (GMTs) were 1589.9 ELISA Units [EU]/mL (95% confidence interval [CI]: 1459.8-1731.6) for anti-HPV-16 and 597.2 EU/mL (95% CI: 541.7-658.5) for anti-HPV-18 in subjects seronegative at baseline for the type analyzed. Post hoc mathematical modeling predicted a durability ≥50 years for anti-HPV-16 and anti-HPV-18. For the non-vaccine humoral type response, all initially seronegative subjects had seroconverted at M7, with anti-HPV-31 GMT of 2030.5 EU/mL (95% CI: 1766.2-2334.4) and anti-HPV-45 GMT of 2300.8 EU/mL (95% CI: 2036.8-2599.0). At M120, 87.7% and 85.1% remained seropositive for anti-HPV-31 with GMT of 242.9 EU/mL (95% CI: 201.4-293.0) and anti-HPV-45 with GMT of 204.7 EU/mL (95% CI: 170.0-246.6). During the 10-year follow-up, no SAEs or abnormal pregnancy outcomes were causally related to vaccination. Three doses of the AS04-HPV-16/18 vaccine induced high and sustained antibody response against HPV-16,18,31 and 45 in girls aged 10-14 years during the 10-year follow-up, with an acceptable long-term safety profile.
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Anticuerpos Antivirales/sangre , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Inmunogenicidad Vacunal , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adolescente , Niño , Femenino , Estudios de Seguimiento , Humanos , Vacunas contra Papillomavirus/administración & dosificación , Vacunas contra Papillomavirus/efectos adversos , Factores de Tiempo , Neoplasias del Cuello Uterino/prevención & control , VacunaciónRESUMEN
We assessed the immunogenicity and safety of a three-dose primary vaccination schedule with the combined diphtheria-tetanus-acellular pertussis-inactivated poliovirus/Haemophilus influenzae type b vaccine (DTPa-IPV/Hib) in Korean infants. In this phase III open-label, multicenter study (NCT01309646), healthy infants aged 42-69 days (randomized 1:1) received three doses of either pentavalent DTPa-IPV/Hib (DTPa-IPV/Hib group) or DTPa-IPV and Hib vaccines administered separately (DTPa-IPV+Hib group) at 2, 4, 6 months of age. The primary objective was to demonstrate non-inferiority of DTPa-IPV/Hib compared to DTPa-IPV+Hib vaccines in terms of immune responses to all vaccine antigens, 1 month post-dose 3. Solicited symptoms (local and general) were recorded during 4 days, and unsolicited adverse events (AEs) during 31 days, after each vaccination. Serious AEs (SAEs) were recorded throughout the study duration. The immunogenicity of the pentavalent DTPa-IPV/Hib vaccine was non-inferior compared to concomitant administration of DTPa-IPV+Hib vaccines. One month post-dose 3, nearly all infants had antibody levels above the seroprotective thresholds for anti-diphtheria toxoid, anti-tetanus toxoid, anti-polyribosyl-ribitol phosphate, and anti-poliovirus type 1, 2 and 3, and had antibody levels above the seropositive thresholds for anti-pertussis toxoid (PT), anti-filamentous hemagglutinin (FHA) and anti-pertactin (PRN) antibodies. A vaccine response for PT, FHA and PRN was observed in at least 96.7% of study participants. Anti-PRP geometric mean concentrations appeared lower for the DTPa-IPV/Hib group (8.456 µg/mL) than for the DTPa-IPV+Hib group (18.700 µg/mL). In both groups, the most common solicited symptoms were injection site redness and irritability. Fifty-seven SAEs were reported throughout the study; none were considered to be vaccination related.
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Anticuerpos Antibacterianos/sangre , Anticuerpos Antivirales/sangre , Vacuna contra Difteria, Tétanos y Tos Ferina/inmunología , Vacunas contra Haemophilus/inmunología , Esquemas de Inmunización , Inmunogenicidad Vacunal , Vacuna Antipolio de Virus Inactivados/inmunología , Vacuna contra Difteria, Tétanos y Tos Ferina/administración & dosificación , Relación Dosis-Respuesta Inmunológica , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Vacunas contra Haemophilus/administración & dosificación , Humanos , Lactante , Masculino , Vacuna Antipolio de Virus Inactivados/administración & dosificación , República de Corea , Vacunas Combinadas/administración & dosificación , Vacunas Combinadas/inmunologíaRESUMEN
BACKGROUND: Cervical cancer is a major public health concern in China. We report the end-of-study results of a phase II/III trial to assess the efficacy, immunogenicity, and safety of the AS04-human papillomavirus (HPV)-16/18 vaccine in Chinese women aged 18-25 years followed for up to 72 months after first vaccination. Results of approximately 57 months following first vaccination have been previously reported. METHODS: Healthy 18-25-year-old women (N = 6051) were randomized (1:1) to receive three doses of AS04-HPV-16/18 vaccine or Al(OH)3 (control) at Months 0-1-6. Vaccine efficacy against HPV-16/18 infection and cervical intraepithelial neoplasia (CIN), cross-protective vaccine efficacy against infections and lesions associated with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. Efficacy was assessed in the according-to-protocol efficacy (ATP-E) cohort (vaccine N = 2888; control N = 2892), total vaccinated cohort for efficacy (TVC-E; vaccine N = 2987; control N = 2985) and TVC-naïve (vaccine N = 1660; control N = 1587). RESULTS: In initially HPV-16/18 seronegative/DNA-negative women, vaccine efficacy against HPV-16/18-associated CIN grade 2 or worse was 87.3% (95% CI: 5.5, 99.7) in the ATP-E, 88.7% (95% CI: 18.5, 99.7) in the TVC-E, and 100% (95% CI: 17.9, 100) in the TVC-naïve. Cross-protective efficacy against incident infection with HPV-31, HPV-33 and HPV-45 was 59.6% (95% CI: 39.4, 73.5), 42.7% (95% CI: 15.6, 61.6), and 54.8% (95% CI: 19.3, 75.6), respectively (ATP-E). At Month 72, >95% of initially seronegative women who received HPV vaccine in the ATP cohort for immunogenicity (N = 664) remained seropositive for anti-HPV-16/18 antibodies; anti-HPV-16 and anti-HPV-18 geometric mean titers were 678.1 EU/mL (95% CI: 552.9, 831.5) and 343.7 EU/mL (95% CI: 291.9, 404.8), respectively. Serious adverse events were infrequent (1.9% vaccine group [N = 3026]; 2.7% control group [N = 3025]). Three and zero women died in the control group and the vaccine group respectively. New onset autoimmune disease was reported in two women in the vaccine group and two in the control group. CONCLUSIONS: This is the first large-scale randomized clinical trial of HPV vaccination in China. High and sustained vaccine efficacy against HPV-16/18-associated infection and cervical lesions was demonstrated up to Month 72. The vaccine had an acceptable safety profile. Combined with screening, prophylactic HPV vaccination could potentially reduce the high burden of HPV infection and cervical cancer in China. TRIAL REGISTRATION: NCT00779766.
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Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Inmunogenicidad Vacunal , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/inmunología , Adolescente , Adulto , Factores de Edad , China/epidemiología , Femenino , Humanos , Evaluación de Resultado en la Atención de Salud , Infecciones por Papillomavirus/virología , Vacunas contra Papillomavirus/administración & dosificación , Vacunas contra Papillomavirus/efectos adversos , Vigilancia en Salud Pública , Factores de Tiempo , Vacunación , Adulto JovenRESUMEN
INTRODUCTION: Two vaccines against rotavirus gastroenteritis (RVGE) in young children, Rotarix and RotaTeq, have been available in Europe since 2006. Vaccination against rotaviruses significantly reduces the burden of RVGE, but it is also associated with a very small increased risk of intussusception. In a benefit-risk analysis, the prevented RVGE burden is weighed against the possible excess of intussusception. PURPOSE: The aim was to compare the estimated benefits and risks of Rotarix vaccination in France. METHODS: We estimated the benefits (vaccine-preventable RVGE hospitalizations and deaths) and risks (vaccine-caused intussusception hospitalizations and deaths) following two doses of Rotarix in a birth cohort of 791,183 followed for 3-5 years in France. We used data from peer-reviewed clinical and epidemiological studies or publications, and government statistics. RESULTS: Within the total number of French children below 5 years of age, we estimate vaccination could prevent a median 11,132 [95% credible interval (CI) 7842-14,408] RVGE hospitalizations and 7.43 (95% CI 3.27-14.68) RVGE deaths. At the same time, vaccination could cause an average of 6.86 (95% CI 2.25-38.37) intussusception hospitalizations and 0.0099 (95% CI 0.0024-0.060) intussusception deaths in the entire French birth cohort of infants below 1 year of age. Therefore, for every intussusception hospitalization and every intussusception death caused by vaccination, 1624 (95% CI 240-5243) RVGE hospitalizations and 743 (95% CI 93-3723) RVGE deaths are prevented, respectively, by vaccination. CONCLUSIONS: The vaccine-prevented RVGE hospitalizations and deaths (benefit) greatly outweigh the excess potentially vaccination-related cases of intussusception (risk), indicating a favorable benefit-risk balance for Rotarix in France.
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Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/uso terapéutico , Preescolar , Francia/epidemiología , Hospitalización/estadística & datos numéricos , Humanos , Lactante , Modelos Teóricos , Medición de Riesgo/métodos , Infecciones por Rotavirus/epidemiología , Vacunas contra Rotavirus/administración & dosificación , Vacunación/estadística & datos numéricos , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/uso terapéuticoRESUMEN
In 2010, porcine circovirus type 1 (PCV1) material was unexpectedly detected in the oral live-attenuated human rotavirus (RV) vaccine, Rotarix™ (GSK Vaccines, Belgium). An initial study (NCT01511133) found no immunologic response against PCV1 in 40 vaccinated infants. As a follow-up, the current study (NCT02153333), searched for evidence of post-vaccination serologic response to PCV1 in a larger number of archived serum samples. Unlike the previous study, serum anti-PCV1 antibodies were assessed with an adapted Immuno Peroxidase Monolayer Assay (IPMA) using a Vero-adapted PCV1 strain. Samples from 596 infants who participated in clinical trials of the human RV vaccine were randomly selected and analyzed. The observed anti-PCV1 antibody seropositivity rate 1-2 months post-dose 2 was approximately 1% [90% Confidence Interval (CI): 0.3-2.6] (3/299 samples) in infants who received the human RV vaccine and 0.3% [90% CI: 0.0-1.6] (1/297 samples) in those who received placebo; the difference between the groups was -0.66 [90% CI: -2.16-0.60]. One subject in the vaccinated group was also seropositive before vaccination. Notably, the seropositivity rate observed in vaccinated subjects was below that observed during assay qualification in samples from unvaccinated subjects outside of this study (2.5%; 5/200 samples). No serious adverse events had been reported in any of the 4 subjects providing anti-PCV1 positive samples during the 31-day post-vaccination follow-up period in the original studies. In conclusion, the presence of PCV1 in the human RV vaccine is considered to be a manufacturing quality issue and does not appear to pose a safety risk to vaccinated infants.
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Circovirus/inmunología , Contaminación de Medicamentos , Vacunas contra Rotavirus/administración & dosificación , Vacunas contra Rotavirus/inmunología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Inmunoensayo/métodos , Lactante , Masculino , Placebos/administración & dosificación , Estudios Retrospectivos , Vacunas contra Rotavirus/efectos adversos , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/efectos adversos , Vacunas Atenuadas/inmunologíaRESUMEN
Multivalent combination vaccines have reduced the number of injections and therefore improved vaccine acceptance, timeliness of administration and global coverage. The hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenzae type b (DTPa-HBV-IPV/Hib; Infanrix hexa™) vaccine, administered according to various schedules, is widely used for the primary vaccination of infants worldwide. In the current publication, we are presenting the immunogenicity and safety of 3 doses of DTPa-HBV-IPV/Hib vaccine when administered to Indian infants. 224 healthy infants (mean age 6.8 weeks) were vaccinated at 6-10-14 weeks (W) of age (n = 112) or 2-4-6 months (M) of age (n = 112). One month after the third vaccine dose, the seroprotection/seropositivity status against diphtheria, pertussis, tetanus, polio, hepatitis B and Hib antigens ranged from 98.6% to 100% in both groups. The vaccine response rate to the pertussis antigens ranged from 97% to 100%. Pain (6-10-14W group: 25.2%; 2-4-6M group: 13.4%) and fever (15.3% and; 15.2%, respectively) were the most frequently reported solicited local and general symptoms. Unsolicited adverse events were reported for 35.7% (6-10-14W group) and 22.3% (2-4-6M group) of subjects. No vaccine related serious adverse events were reported. In conclusion, the hexavalent DTPa-HBV-IPV/Hib vaccine was immunogenic and well tolerated, irrespective of the dosing schedule.
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Anticuerpos Antibacterianos/sangre , Anticuerpos Antivirales/sangre , Vacuna contra Difteria, Tétanos y Tos Ferina/efectos adversos , Vacuna contra Difteria, Tétanos y Tos Ferina/inmunología , Vacunas contra Haemophilus/efectos adversos , Vacunas contra Haemophilus/inmunología , Vacunas contra Hepatitis B/efectos adversos , Vacunas contra Hepatitis B/inmunología , Esquemas de Inmunización , Vacuna Antipolio de Virus Inactivados/efectos adversos , Vacuna Antipolio de Virus Inactivados/inmunología , Vacuna contra Difteria, Tétanos y Tos Ferina/administración & dosificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Fiebre/epidemiología , Vacunas contra Haemophilus/administración & dosificación , Voluntarios Sanos , Vacunas contra Hepatitis B/administración & dosificación , Humanos , India , Lactante , Dolor/epidemiología , Vacuna Antipolio de Virus Inactivados/administración & dosificación , Vacunas Combinadas/administración & dosificación , Vacunas Combinadas/efectos adversos , Vacunas Combinadas/inmunologíaRESUMEN
We conducted 3 phase III, randomized, open-label, clinical trials assessing the safety, reactogenicity (all studies), immunogenicity (Primary vaccination study) and persistence of immune responses (Booster study) to the combined diphtheria, tetanus, pertussis, poliomyelitis, and Haemophilus influenzae type b vaccine (DTPa-IPV/Hib) in Chinese infants and toddlers. In the Pilot study (NCT00964028), 50 infants (randomized 1:1) received 3 doses of DTPa-IPV/Hib at 2-3-4 (Group A) or 3-4-5 months of age (Group B). In the Primary study (NCT01086423), 984 healthy infants (randomized 1:1:1) received 3 doses of DTPa-IPV/Hib at 2-3-4 (Group A) or 3-4-5 (Group B) months of age, or concomitant DTPa/Hib and poliomyelitis (IPV) vaccination at 2-3-4 months of age (Control group); 825 infants received a booster dose of DTPa/Hib and IPV at 18-24 months of age (Booster study; NCT01449812). In the Pilot study, unsolicited symptoms were more frequent in Group A (16 versus 1 infant; mostly upper respiratory tract infection and pyrexia); this observation was attributed to an epidemic outbreak of viral infections. Non-inferiority of 3-dose primary vaccination with DTPa-IPV/Hib over separately administered DTPa/Hib and IPV was demonstrated for Group A (primary objective). Similar antibody concentrations were observed in all groups, except for anti-polyribosyl-ribitol phosphate and anti-poliovirus types 1-3 which were higher in DTPa-IPV/Hib recipients. Protective antibody levels against all vaccine antigens remained high until booster vaccination. Three-dose vaccination with DTPa-IPV/Hib had a clinically acceptable safety profile.
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Anticuerpos Antibacterianos/sangre , Anticuerpos Antivirales/sangre , Vacuna contra Difteria, Tétanos y Tos Ferina/efectos adversos , Vacuna contra Difteria, Tétanos y Tos Ferina/inmunología , Vacunas contra Haemophilus/efectos adversos , Vacunas contra Haemophilus/inmunología , Vacuna Antipolio de Virus Inactivados/efectos adversos , Vacuna Antipolio de Virus Inactivados/inmunología , China , Vacuna contra Difteria, Tétanos y Tos Ferina/administración & dosificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Vacunas contra Haemophilus/administración & dosificación , Humanos , Lactante , Masculino , Vacuna Antipolio de Virus Inactivados/administración & dosificación , Factores de Tiempo , Vacunas Conjugadas/administración & dosificación , Vacunas Conjugadas/efectos adversos , Vacunas Conjugadas/inmunologíaRESUMEN
We previously reported the results of a phase II/III, double-blind, randomized controlled study in Chinese women (NCT00779766) showing a 94.2% (95% confidence interval: 62.7-99.9) HPV-16/18 AS04-adjuvanted vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or higher (CIN1+) and/or 6-month (M) persistent infection (PI) with a mean follow-up of <2 years, and immunogenicity until 7 months post-dose 1. Here, we report efficacy and safety results from an event-triggered analysis with ~3 years longer follow-up, and immunogenicity until M24. Healthy 18-25-year-old women (N = 6051) were randomized (1:1) to receive three doses of HPV-16/18 vaccine or Al(OH)3 (control) at M0, 1, 6. VE against HPV-16/18-associated CIN2+, and cross-protective VE against infections with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. In the according-to-protocol efficacy cohort, in initially seronegative/DNA-negative women (vaccine group: N = 2524; control group: N = 2535), VE against HPV-16/18-associated CIN2+ was 87.3% (5.3-99.7); VE against incident infection or against 6-month persistent infection associated with HPV-31/33/45 was 50.1% (34.3-62.3) or 52.6% (24.5-70.9), respectively. At least, 99.6% of HPV-16/18-vaccines remained seropositive for anti-HPV-16/18 antibodies; anti-HPV-16 and -18 geometric mean titers were 1271.1 EU/mL (1135.8-1422.6) and 710.0 EU/ml (628.6-801.9), respectively. Serious adverse events were infrequent (1.7% vaccine group [N = 3026]; 2.5% control group [N = 3026]). Of the 1595 reported pregnancies, nine had congenital anomalies (five live infants, three elective terminations, one stillbirth) that were unlikely vaccination-related (blinded data). VE against HPV-16/18-associated CIN2+ was demonstrated and evidence of cross-protective VE against oncogenic HPV types was shown. The vaccine was immunogenic and had an acceptable safety profile.