lipid-a and Papillomavirus-Infections

Development of non-infectious subunit vaccines is hampered by a slow pipeline of new adjuvants to replace or enhance alum in part because expectations of safety are high. Transient vaccine side effects are not clinical priorities because they cause no lasting harm and vaccine development has appropriately been focused on avoidance of serious adverse events. As a result, surprisingly little is known about the extent to which side effects caused by a vaccine's reactogencicity are predictive of successful immunization outcomes. Recent clinical studies of pertussis and human papillomavirus vaccines adjuvanted with alum or the TLR4 agonist monophosphoryl lipid A can be used to advance understanding of the relationship between vaccine side effects and immunization outcomes.

Topics: Adjuvants, Immunologic; Alum Compounds; Antibodies, Viral; Diphtheria-Tetanus-acellular Pertussis Vaccines; Drug-Related Side Effects and Adverse Reactions; Humans; Lipid A; Pain; Papillomavirus Infections; Papillomavirus Vaccines; Toll-Like Receptor 4; Treatment Outcome; Vaccination; Whooping Cough

Vaccines are available against human papillomavirus (HPV), the causal agent of cervical and other cancers. Efficacy data from the HPV-16/18 AS04-adjuvanted vaccine clinical trial program were reviewed. Six randomized, controlled phase II/III trials evaluating cervical endpoints enrolled women from diverse populations and geographical locations. The program analyzed extensively the cohorts most relevant from a public health perspective: the total vaccinated cohort (TVC), approximating a general population including those with existing or previous HPV infection, and TVC-naïve, approximating a population of young women before sexual debut. Results show that the vaccine reduces HPV-16/18 infection and associated cervical endpoints in women regardless of age, location, or sexual experience. It provides cross-protection against some non-vaccine oncogenic HPV types and types causing genital warts, and may be effective against vulvar, oral, and anal HPV infection. Early epidemiology data following its introduction suggest a decline in the prevalence of vaccine and some non-vaccine HPV types.

Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Anus Neoplasms; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Condylomata Acuminata; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Mouth Neoplasms; Papillomavirus Infections; Papillomavirus Vaccines; Randomized Controlled Trials as Topic; Uterine Cervical Neoplasms

The AS04-adjuvanted human papillomavirus (HPV) 16/18 vaccine (Cervarix®) is a noninfectious recombinant vaccine produced using purified virus-like particles (VLPs) that induce a strong immunogenic response eliciting high levels of anti-L1 VLP antibodies that persist at levels markedly greater than those observed with natural infection. The vaccine adjuvant (AS04) is composed of monophosphoryl-lipid A, which enhances cellular and humoral immune response, adsorbed to aluminium hydroxide. The vaccine is indicated for the prevention of premalignant cervical lesions and cervical cancer causally related to certain oncogenic HPV types in females aged ≥10 years. The AS04-adjuvanted HPV 16/18 vaccine administered in a three-dose schedule over 6 months elicits a high immunogenic response and is highly protective against cervical intraepithelial neoplasia and infection causally related to high-risk oncogenic HPV types. In well designed clinical trials in young women aged 15-25 years who were HPV 16/18 seronegative and DNA negative to 14 HPV high-risk types, high levels of immunogenicity and protection were sustained for follow-up periods of up to 8.4 years. High and persistent immunogenicity against infection with HPV 16/18 has also been demonstrated in older and younger females (aged 10-55 years) who were seronegative for vaccine HPV types. The AS04-adjuvanted HPV 16/18 vaccine elicited a greater immunogenic response than the quadrivalent HPV vaccine in women aged 18-45 years who were seronegative and DNA negative for HPV 16/18. The AS04-adjuvanted HPV 16/18 vaccine confers cross protection against certain non-vaccine, high-risk HPV types. A rapid and strong anamnestic humoral immune response was elicited following a fourth dose of the vaccine. The AS04-adjuvanted HPV 16/18 vaccine is generally well tolerated, and pharmacoeconomic analyses have demonstrated the potential for public health benefits and cost effectiveness when vaccination programmes are run in conjunction with screening programmes. Thus, the AS04-adjuvanted HPV 16/18 vaccine prevents cervical disease associated with certain oncogenic HPV types, thereby reducing the burden of premalignant cervical lesions and, very likely, cervical cancer.

Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Clinical Trials, Phase II as Topic; Female; Humans; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Uterine Cervical Diseases; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vaccines, Synthetic

Persistent infection with human papillomavirus (HPV) is a necessary cause of cervical cancer, resulting annually in 274,000 deaths worldwide. Two prophylactic HPV vaccines are licensed in >100 countries, and immunization programs in young, adolescent girls have been widely implemented. HPV-16/18 AS04-adjuvanted vaccine (Cervarix; GlaxoSmithKline Biologicals, Rixensart, Belgium) has demonstrated type-specific protection against the five most frequent cancer-causing types (16, 18, 31, 33, and 45) that are responsible for 82% of invasive cervical cancers globally. Cervarix has demonstrated efficacy against HPV-45, which is the third most common HPV type in cervical cancer and adenocarcinoma. Final results of a large phase 3 trial recently showed Cervarix substantially reduced the overall burden of cervical precancerous lesions (cervical intraepithelial neoplasia 2+) by 70.2% in an HPV-naïve population approximating young girls prior to sexual debut, the target of most current vaccination programs. Protection offered by Cervarix against nonvaccine types (mainly 31, 33, and 45) might potentially allow for 11%-16% additional protection against cervical cancers, compared to a vaccine only offering protection against HPV-16/18. Another recent study directly compared the antibody response of Cervarix to that of quadrivalent HPV-6/11/16/18 vaccine (Gardasil; Merck, Whitehouse Station, NJ, USA). Cervarix induced significantly superior neutralizing antibody levels as compared with Gardasil for HPV-16 and HPV-18 in all age groups studied. This may translate into more women having detectable (neutralizing) antibodies in cervicovaginal secretions for HPV-16 and HPV-18 after vaccination with Cervarix when compared with Gardasil. Cervarix induced significantly higher frequencies of antigen-specific memory B-cells and T-cells in responders for HPV-16 and HPV-18 as compared with Gardasil. Cervarix continues to show sustained high levels of total and neutralizing antibodies for HPV-16 and HPV-18, 7.3 years after vaccination. This is associated with high efficacy and no breakthrough cases in the HPV-naïve population, and is the longest duration follow-up for safety, immunogenicity, and efficacy for any licensed HPV vaccine to date.

Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Female; Humans; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Precancerous Conditions; Randomized Controlled Trials as Topic; Uterine Cervical Neoplasms

Persistent infection with oncogenic human papillomavirus (HPV)-16 and -18 accounts for over 70% of all cases of cervical cancer. Vaccination against these HPV types has become a reality. This article discusses the latest data available for Cervarix (GlaxoSmithKline Biologicals), an AS04-adjuvanted HPV-16/18 vaccine, and considers immunological factors important in vaccine effectiveness. High and sustained HPV-16 and -18 antibody levels have now been observed together with 100% vaccine efficacy in preventing HPV-16/18-related persistent infections and cervical intraepithelial neoplasia grade 2 and above, up to 6.4 years after first vaccination. Significant crossprotection against incident and persistent infection has been observed, notably against HPV-45, the third most prevalent HPV type in cervical cancer. An integrated safety summary of Phase II/III trials has shown that GlaxoSmithKline's HPV-16/18 AS04-adjuvanted vaccine is generally safe. Further studies will reveal the full duration and extent of the immune response and protection induced by Cervarix in broad populations and age ranges of women.

Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Uterine Cervical Neoplasms

Vaccination is proven to significantly reduce the risk of human papillomavirus (HPV)-related complications, especially cervical cancer. This study aimed to assess the immunogenicity and safety of the investigational bivalent HPV vaccine (16/18), named Papilloguard (Noyan Pajouhan Biopharma, Tehran, Iran), in comparison with the reference product (Cervarix, bivalent HPV vaccine (16/18) manufactured by GlaxoSmithKline, Rixensart, Belgium) in a three-dose regimen.. This trial was a randomized, controlled, double-blind, phase III study of two HPV vaccines in healthy female volunteers aged 15-25. The primary endpoint was to test the noninferiority of Papilloguard (Noyan Pajouhan Biopharma) to Cervarix (GlaxoSmithKline) as measured by the geometric mean titer (GMT) ratios of HPV-16 and HPV-18 7 months after the first vaccination. Secondary endpoints were the proportion of local and systemic solicited and unsolicited events, and the number of females with seroconversion against HPV-16 and HPV-18 7 months after the first vaccination.. Out of 504 screened women, 218 were enrolled. Seven months after the first vaccination, GMT ratios of HPV-16 and HPV-18 were 0.59 and 0.93, respectively. The seroconversion rates of both Papilloguard (Noyan Pajouhan Biopharma) and Cervarix (GlaxoSmithKline) were more than 96%. Both vaccinated groups had a generally good profile of solicited and unsolicited adverse events (AEs). The most common AE was discomfort at the injection site, which was well tolerated.. The result analysis of this study supports the noninferiority of Papilloguard (Noyan Pajouhan Biopharma) to Cervarix (GlaxoSmithKline) in terms of safety and immunogenicity based on the GMT ratio. However, long-term comparative studies to evaluate the sustainability of GMT response and risk of cervical intraepithelial neoplasia grades 2-3 are needed.

Topics: Aluminum Hydroxide; Antibodies, Viral; Female; Healthy Volunteers; Humans; Iran; Lipid A; Papillomaviridae; Papillomavirus Infections; Papillomavirus Vaccines

We studied effectiveness of the AS04-adjuvanted HPV-16/18 (AS04-HPV-16/18) vaccine against human papillomavirus (HPV) oropharyngeal infections associated with the increase of head/neck cancers in western countries. All 38,631 resident adolescents from 1994 to 1995 birth cohorts of 33 Finnish communities were invited in this community-randomized trial (NCT00534638). During 2008-2009, 11,275 girls and 6,129 boys were enrolled in three arms of 11 communities each. In Arm A, 90% of vaccinated girls/boys, and in Arm B, 90% of vaccinated girls received AS04-HPV-16/18 vaccine. Other Arm A/B and all Arm C vaccinated participants received control vaccine. All Arm A participants and Arm B female participants were blinded to vaccine allocation. Oropharyngeal samples were analyzed from 4,871 18.5-year-old females who attended follow-up visit 3-6 years postvaccination. HPV DNA prevalence was determined by SPF-10 LiPA and Multiplex type-specific PCR. Total vaccine effectiveness (VE) was defined as relative reduction of oropharyngeal HPV prevalence in pooled Arms A/B HPV-vaccinated females vs. all Arm C females. VE against oropharyngeal HPV-16/18, HPV-31/45 and HPV-31/33/45 infections were 82.4% (95% confidence intervals [CI]: 47.3-94.1), 75.3% (95%CI: 12.7-93.0) and 69.9% (95% CI: 29.6-87.1), respectively. In conclusion, the AS04-HPV-16/18 vaccine showed effectiveness against vaccine and nonvaccine HPV-types oropharyngeal infections in adolescent females up to 6 years postvaccination.

Topics: Adolescent; Adult; Aluminum Hydroxide; Female; Finland; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Oropharyngeal Neoplasms; Oropharynx; Papillomavirus Infections; Papillomavirus Vaccines; Pharyngeal Diseases; Seroepidemiologic Studies; Young Adult

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.. 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.. 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.. 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.

Topics: Aluminum Hydroxide; Antibodies, Viral; Child; Child, Preschool; Clinical Trials, Phase III as Topic; Colombia; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Mexico; Panama; Papillomavirus Infections; Papillomavirus Vaccines; Randomized Controlled Trials as Topic; Single-Blind Method

The burden of cervical cancer caused by human papillomavirus (HPV) is high in Latin America. The suboptimal HPV vaccination coverage in adolescents could be improved by pediatric immunization. HPV vaccination has not yet been reported in girls <9 years of age.. This ongoing phase III, controlled, randomized, single-blind, multicenter study conducted in Colombia, Mexico and Panama (NCT01627561) evaluated the safety and immunogenicity of AS04-HPV-16/18 vaccine in 4-6-year-old girls. Healthy girls (randomized 1:1) received either 2 doses of AS04-HPV-16/18 vaccine (HPV group, N=74) or 1 dose of each measles-mumps-rubella and diphtheria-tetanus-acellular-pertussis vaccines (control group, N=74) 6 months apart. We report the safety and serum anti-HPV-16 and anti-HPV-18 antibodies (measured by enzyme-linked immunosorbent assay) up to 6 months postvaccination, that is, month (M) 12.. Injection site pain was the most frequently reported solicited local symptom in HPV vaccinees. The incidence of other solicited and unsolicited symptoms after each vaccination was similar between the HPV and control group. Until M12, 1 girl in the HPV group and 2 in the control group reported serious adverse events; all serious adverse events were assessed as unrelated to study vaccines. No potential immune-mediated diseases were identified. All girls seroconverted for both antigens after 2 doses of AS04-HPV-16/18. In initially seronegative girls, anti-HPV-16 geometric mean concentrations were 20080.0 enzyme-linked immunosorbent assay units (EU)/mL at M7 and 3246.5 EU/mL at M12; anti-HPV-18 geometric mean concentrations were 10621.8 EU/mL at M7 and 1216.6 EU/mL at M12.. Two-dose vaccination with AS04-HPV-16/18 was well tolerated and induced adequate antibody responses in 4-6-year-old girls.

Topics: Aluminum Hydroxide; Antibodies, Viral; Child; Child, Preschool; Colombia; Drug-Related Side Effects and Adverse Reactions; Enzyme-Linked Immunosorbent Assay; Female; Healthy Volunteers; Human papillomavirus 16; Human papillomavirus 18; Humans; Immunization Schedule; Incidence; Lipid A; Mexico; Panama; Papillomavirus Infections; Papillomavirus Vaccines; Single-Blind Method

In this randomized, partially-blind study ( clinicaltrials.gov ; NCT00541970), the licensed formulation of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (20 μg each of HPV-16/18 antigens) was found highly immunogenic up to 4 y after first vaccination, whether administered as a 2-dose (2D) schedule in girls 9-14 y or 3-dose (3D) schedule in women 15-25 y. This end-of-study analysis extends immunogenicity and safety data until Month (M) 60, and presents antibody persistence predictions estimated by piecewise and modified power law models. Healthy females (age stratified: 9-14, 15-19, 20-25 y) were randomized to receive 2D at M0,6 (N = 240 ) or 3D at M0,1,6 (N = 239). Here, results are reported for girls 9-14 y (2D) and women 15-25 y (3D). Seropositivity rates, geometric mean titers (by enzyme-linked immunosorbent assay) and geometric mean titer ratios (GMRs; 3D/2D; post-hoc exploratory analysis) were calculated. All subjects seronegative pre-vaccination in the according-to-protocol immunogenicity cohort were seropositive for anti-HPV-16 and -18 at M60. Antibody responses elicited by the 2D and 3D schedules were comparable at M60, with GMRs close to 1 (anti-HPV-16: 1.13 [95% confidence interval: 0.82-1.54]; anti-HPV-18: 1.06 [0.74-1.51]). Statistical modeling predicted that in 95% of subjects, antibodies induced by 2D and 3D schedules could persist above natural infection levels for ≥ 21 y post-vaccination. The vaccine had a clinically acceptable safety profile in both groups. In conclusion, a 2D M0,6 schedule of the HPV-16/18 AS04-adjuvanted vaccine was immunogenic for up to 5 y in 9-14 y-old girls. Statistical modeling predicted that 2D-induced antibodies could persist for longer than 20 y.

Topics: Adjuvants, Immunologic; Adolescent; Aluminum Hydroxide; Antibodies, Viral; Child; Drug-Related Side Effects and Adverse Reactions; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Immunization Schedule; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Time Factors; Treatment Outcome; Young Adult

This randomized, open trial compared regimens including 2 doses (2D) of human papillomavirus (HPV) 16/18 AS04-adjuvanted vaccine in girls aged 9-14 years with one including 3 doses (3D) in women aged 15-25 years.. Girls aged 9-14 years were randomized to receive 2D at months 0 and 6 (M0,6; (n = 550) or months 0 and 12 (M0,12; n = 415), and women aged 15-25 years received 3D at months 0, 1, and 6 (n = 482). End points included noninferiority of HPV-16/18 antibodies by enzyme-linked immunosorbent assay for 2D (M0,6) versus 3D (primary), 2D (M0,12) versus 3D, and 2D (M0,6) versus 2D (M0,12); neutralizing antibodies; cell-mediated immunity; reactogenicity; and safety. Limits of noninferiority were predefined as <5% difference in seroconversion rate and <2-fold difference in geometric mean antibody titer ratio.. One month after the last dose, both 2D regimens in girls aged 9-14 years were noninferior to 3D in women aged 15-25 years and 2D (M0,12) was noninferior to 2D (M0,6). Geometric mean antibody titer ratios (3D/2D) for HPV-16 and HPV-18 were 1.09 (95% confidence interval, .97-1.22) and 0.85 (.76-.95) for 2D (M0,6) versus 3D and 0.89 (.79-1.01) and 0.75 (.67-.85) for 2D (M0,12) versus 3D. The safety profile was clinically acceptable in all groups.. The 2D regimens for the HPV-16/18 AS04-adjuvanted vaccine in girls aged 9-14 years (M0,6 or M0,12) elicited HPV-16/18 immune responses that were noninferior to 3D in women aged 15-25 years.. NCT01381575.

Topics: Adjuvants, Immunologic; Adolescent; Age Factors; Aluminum Hydroxide; Antibodies, Neutralizing; Antibodies, Viral; Child; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Immunization Schedule; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Treatment Outcome; Young Adult

This community-randomized controlled trial was initiated to assess the overall and herd effects of 2 different human papillomavirus (HPV) immunization strategies in over 80,000 girls and boys aged 12-15 y in 33 communities in Finland (ClinicalTrials.gov NCT00534638). Overall, 14,838 adolescents received HPV-16/18 vaccine (2,440 boys and 12,398 girls) and 17,338 received hepatitis-B virus (HBV) vaccine (9,221 boys and 8,117 girls). In an interim analysis, vaccine safety was assessed by active monitoring and surveillance via health registry linkage. Active monitoring showed that the HPV-16/18 vaccine has acceptable safety and reactogenicity in boys. In all study participants, the observed incidences (per 100,000 person-years) of serious adverse events (SAEs) possibly related to vaccination were 54.3 (95% Confidence Interval [CI]: 34.0-82.1) in the HPV-16/18 group and 64.0 (95% CI: 43.2-91.3) in the HBV group. During the follow-up period for this interim analysis, the most common new-onset autoimmune diseases (NOADs; with incidence rate ≥15 per 100,000) in any group based on hospital discharge registry (HILMO) download were ulcerative colitis, juvenile arthritis, celiac disease, insulin-dependent diabetes mellitus (IDDM) and Crohn's disease. No increased NOAD incidences were observed in HPV-16/18 vaccine recipients compared to HBV vaccine recipients. In both the SAE possibly related- and HILMO-analyses, a lower incidence of IDDM was observed in HPV-16/18 vaccinees compared to HBV vaccinees (relative risks, 0.26 [95% CI: 0.03-1.24] and 0.16 [95% CI: 0.03-0.55], respectively).

Topics: Adolescent; Aluminum Hydroxide; Autoimmune Diseases; Child; Drug-Related Side Effects and Adverse Reactions; Female; Finland; Hepatitis B Vaccines; Humans; Lipid A; Male; Papillomavirus Infections; Papillomavirus Vaccines

The efficacy of the human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against cervical infections with HPV in the Papilloma Trial against Cancer in Young Adults (PATRICIA) was evaluated using a combination of the broad-spectrum L1-based SPF10 PCR-DNA enzyme immunoassay (DEIA)/line probe assay (LiPA25) system with type-specific PCRs for HPV-16 and -18. Broad-spectrum PCR assays may underestimate the presence of HPV genotypes present at relatively low concentrations in multiple infections, due to competition between genotypes. Therefore, samples were retrospectively reanalyzed using a testing algorithm incorporating the SPF10 PCR-DEIA/LiPA25 plus a novel E6-based multiplex type-specific PCR and reverse hybridization assay (MPTS12 RHA), which permits detection of a panel of nine oncogenic HPV genotypes (types 16, 18, 31, 33, 35, 45, 52, 58, and 59). For the vaccine against HPV types 16 and 18, there was no major impact on estimates of vaccine efficacy (VE) for incident or 6-month or 12-month persistent infections when the MPTS12 RHA was included in the testing algorithm versus estimates with the protocol-specified algorithm. However, the alternative testing algorithm showed greater sensitivity than the protocol-specified algorithm for detection of some nonvaccine oncogenic HPV types. More cases were gained in the control group than in the vaccine group, leading to higher point estimates of VE for 6-month and 12-month persistent infections for the nonvaccine oncogenic types included in the MPTS12 RHA assay (types 31, 33, 35, 45, 52, 58, and 59). This post hoc analysis indicates that the per-protocol testing algorithm used in PATRICIA underestimated the VE against some nonvaccine oncogenic HPV types and that the choice of the HPV DNA testing methodology is important for the evaluation of VE in clinical trials. (This study has been registered at ClinicalTrials.gov under registration no. NCT00122681.).

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aluminum Hydroxide; DNA, Viral; Female; Genotype; Humans; Lipid A; Papillomaviridae; Papillomavirus Infections; Papillomavirus Vaccines; Polymerase Chain Reaction; Treatment Outcome; Young Adult

We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ((HPV-16/18) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA). The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine, n = 9,319; control, n = 9,325) at months 0, 1, and/or 6. The TVC-naive (vaccine, n = 5,822; control, n = 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1+), CIN2+, and CIN3+ associated with HPV-16/18 was 55.5% (96.1% confidence interval [CI], 43.2, 65.3), 52.8% (37.5, 64.7), and 33.6% (-1.1, 56.9). VE against CIN1+, CIN2+, and CIN3+ irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1), and 33.4% (9.1, 51.5) and was consistently significant only in 15- to 17-year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7], and 55.8% [19.2, 76.9]). In the TVC-naive, VE against CIN1+, CIN2+, and CIN3+ associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100), and 100% (64.7, 100), and irrespective of HPV DNA it was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9), and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0), and that against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. (This study has been registered at ClinicalTrials.gov under registration no. NCT001226810.).

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aluminum Hydroxide; Animals; Antibodies, Viral; DNA, Viral; Double-Blind Method; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Precancerous Conditions; Treatment Outcome; Uterine Cervical Neoplasms; Young Adult

Endemic malaria and helminth infections in sub-Saharan Africa can act as immunological modulators and impact responses to standard immunizations. We conducted a cohort study to measure the influence of malaria and helminth infections on the immunogenicity of the bivalent HPV-16/18 vaccine.. We evaluated the association between malaria and helminth infections, and HPV-16/18 antibody responses among 298 Tanzanian females aged 10-25 years enrolled in a randomized controlled trial of the HPV-16/18 vaccine. Malaria parasitaemia was diagnosed by examination of blood smears, and helminth infections were diagnosed by examination of urine and stool samples, respectively. Geometric mean antibody titres (GMT) against HPV-16/18 antibodies were measured by enzyme-linked immunosorbent assay.. Parasitic infections were common; one-third (30.4%) of participants had a helminth infection and 10.2% had malaria parasitaemia. Overall, the vaccine induced high HPV-16/18 GMTs, and there was no evidence of a reduction in HPV-16 or HPV-18 GMT at Month 7 or Month 12 follow-up visits among participants with helminths or malaria. There was some evidence that participants with malaria had increased GMTs compared to those without malaria.. The data show high HPV immunogenicity regardless of the presence of malaria and helminth infections. The mechanism and significance for the increase in GMT in those with malaria is unknown.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aluminum Hydroxide; Antibodies, Viral; Antibody Formation; Child; Double-Blind Method; Female; Helminthiasis; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Malaria; Papillomavirus Infections; Papillomavirus Vaccines; Tanzania; Young Adult

Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine were evaluated up to 6 years postvaccination (month 72) in preteen/adolescent girls.. Participants, who had received 3 HPV-16/18 AS04-adjuvanted vaccine doses at 10-14 years of age in an initial controlled, observer-blinded, randomized study (NCT00196924) and participated in the open 3-year follow-up (NCT00316706), were invited to continue the follow-up for up to 10 years postvaccination (NCT00877877). Anti-HPV-16 and -18 antibody titers were measured by enzyme-linked immunosorbent assays at yearly visits and were used to fit the modified power-law and piecewise models, predicting long-term immunogenicity. Serious adverse events (SAEs) and pregnancy information were recorded.. In the according-to-protocol immunogenicity cohort, all participants (N = 505) with data available remained seropositive for anti-HPV-16 and -18 antibodies at month 72. In initially seronegative participants, anti-HPV-16 and -18 antibody geometric mean titers were 65.8- and 33.0-fold higher than those associated with natural infection (NCT00122681) and 5.0- and 2.5-fold higher than those measured at month 69-74 in a study demonstrating vaccine efficacy in women aged 15-25 years (NCT00120848). Exploratory antibody modeling, based on the 6-year data, predicted that vaccine-induced population anti-HPV-16 and -18 antibody geometric mean titers would remain above those associated with natural infection for at least 20 years postvaccination. The HPV-16/18 AS04-adjuvanted vaccine safety profile was clinically acceptable.. In preteen/adolescent girls, the HPV-16/18 AS04-adjuvanted vaccine induced high anti-HPV-16 and -18 antibody levels up to 6 years postvaccination, which were predicted to remain above those induced by natural infection for at least 20 years.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aluminum Hydroxide; Antibodies, Viral; Child; Drug-Related Side Effects and Adverse Reactions; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Infant, Newborn; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Pregnancy; Single-Blind Method; Treatment Outcome; Uterine Cervical Neoplasms; Young Adult

In this open, extended follow-up study (NCT00929526, Clinicaltrials.gov), we evaluated the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine efficacy, immunogenicity and safety up to 4 years after first vaccination in Japanese women aged 20-25 years. In the initial randomized, double-blind study (NCT00316693), 1040 women received the study vaccine or hepatitis A control vaccine; 752 women were included in the follow-up study. In women from the according-to-protocol efficacy cohort (ATP-E), who were initially seronegative for the HPV type analyzed, no cervical intraepithelial neoplasia (CIN) grade 1 or greater (CIN1+) cases associated with HPV-16/18 were reported in the HPV group, while in the control group, 5 cases were identified in extended follow-up analyses (vaccine efficacy [VE] 100% [95% CI: -3.7-100]) and 8 cases in combined initial and follow-up studies analyses (VE 100% [42.2-100]). In the ATP-E, VE against CIN1+ and CIN2+ associated with high-risk HPV types reached 66.4% (21.6-87.1) and 83.0% (22.1-98.2) in extended follow-up analyses, and 63.4% (28.8-82.3) and 77.3% (30.4-94.4) in analyses of combined studies, respectively. During the 4-year period, protection against CIN1+ and CIN2+, irrespective of the HPV type, was 56.7% (32.8-72.6) and 54.9% (20.5-75.3) in women receiving ≥1 vaccine dose, regardless of baseline serostatus (total vaccinated cohort [TVC]) and 61.0% (11.8-84.2) and 73.9% (1.1-95.3) in women naïve to HPV infection at baseline (TVC-naïve), respectively. The high VE observed in Japanese women, accompanied by a sustained immune response and a clinically acceptable safety profile, support findings of large, international trials.

Topics: Adolescent; Adult; Aluminum Hydroxide; Antibodies, Viral; Female; Follow-Up Studies; Human papillomavirus 16; Human papillomavirus 18; Humans; Japan; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Uterine Cervical Dysplasia; Young Adult

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.

Topics: Adolescent; Adult; Aluminum Hydroxide; Antibodies, Viral; Asian People; Child; China; Drug-Related Side Effects and Adverse Reactions; Female; Healthy Volunteers; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Middle Aged; Papillomavirus Infections; Papillomavirus Vaccines; Treatment Outcome; Uterine Cervical Dysplasia; Young Adult

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.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aluminum Hydroxide; Antibodies, Viral; CD4-Positive T-Lymphocytes; Drug-Related Side Effects and Adverse Reactions; Female; HIV; HIV Infections; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Single-Blind Method; South Africa; Vaccination; Viral Load; Young Adult

Cervical cancer is a major public health problem for women in sub-Saharan Africa. Availability of a human papillomavirus (HPV) vaccine could have an important public health impact.. In this phase IIIb, double-blind, randomized, placebo-controlled, multicenter trial (NCT00481767), healthy African girls and young women seronegative for human immunodeficiency virus (HIV) were stratified by age (10-14 or 15-25 years) and randomized (2:1) to receive either HPV-16/18 AS04-adjuvanted vaccine (n = 450) or placebo (n = 226) at 0, 1, and 6 months. The primary objective was to evaluate HPV-16/18 antibody responses at month 7. Seropositivity rates and corresponding geometric mean titers (GMTs) were measured by enzyme-linked immunosorbent assay.. In the according-to-protocol analysis at month 7, 100% of initially seronegative participants in the vaccine group were seropositive for both anti-HPV-16 and anti-HPV-18 antibodies (n = 130 and n = 128 for 10-14-year-olds, respectively; n = 190 and n = 212 for 15-25-year-olds). GMTs for HPV-16 and HPV-18 were higher in 10-14-year-olds (18 423 [95% confidence interval, 16 185-20 970] and 6487 [5590-7529] enzyme-linked immunosorbent assay units (EU)/mL, respectively) than in 15-25-year-olds (10 683 [9567-11 930] and 3743 [3400-4120] EU/mL, respectively). Seropositivity was maintained at month 12. No participant withdrew owing to adverse events. No vaccine-related serious adverse events were reported.. The HPV-16/18 AS04-adjuvanted vaccine was highly immunogenic and had a clinically acceptable safety profile when administered to healthy HIV-seronegative African girls and young women.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Africa South of the Sahara; Aluminum Hydroxide; Antibodies, Viral; Child; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Enzyme-Linked Immunosorbent Assay; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Placebos; Uterine Cervical Neoplasms; Young Adult

Cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the surrogate endpoint used in licensure trials of human papillomavirus (HPV) vaccines. Vaccine efficacy against CIN3+, the immediate precursor to invasive cervical cancer, is more difficult to measure because of its lower incidence, but provides the most stringent evidence of potential cancer prevention. We report vaccine efficacy against CIN3+ and adenocarcinoma in situ (AIS) in the end-of-study analysis of PATRICIA (PApilloma TRIal against Cancer In young Adults).. Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA, irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to receive an HPV-16/18 AS04-adjuvanted vaccine or a control hepatitis A vaccine via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The patients and study investigators were masked to allocated vaccine. The primary endpoint of PATRICIA has been reported previously. In the present end-of-study analysis, we focus on CIN3+ and AIS in the populations of most clinical interest, the total vaccinated cohort (TVC) and the TVC-naive. The TVC comprised all women who received at least one vaccine dose, approximating catch-up populations and including sexually active women (vaccine n=9319; control=9325). The TVC-naive comprised women with no evidence of oncogenic HPV infection at baseline, approximating early adolescent HPV exposure (vaccine n=5824; control=5820). This study is registered with ClinicalTrials.gov, number NCT00122681.. Vaccine efficacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 85·5-100) in the TVC-naive and 45·7% (22·9-62·2) in the TVC. Vaccine efficacy against all CIN3+ (irrespective of HPV type in the lesion and including lesions with no HPV DNA detected) was 93·2% (78·9-98·7) in the TVC-naive and 45·6% (28·8-58·7) in the TVC. In the TVC-naive, vaccine efficacy against all CIN3+ was higher than 90% in all age groups. In the TVC, vaccine efficacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 15-17 year age group and progressively decreased in the 18-20 year and 21-25 year age groups. Vaccine efficacy against all AIS was 100% (31·0-100) and 76·9% (16·0-95·8) in the TVC-naive and TVC, respectively. Serious adverse events occurred in 835 (9·0%) and 829 (8·9%) women in the vaccine and control groups, respectively; only ten events (0·1%) and five events (0·1%), respectively, were considered to be related to vaccination.. PATRICIA end-of-study results show excellent vaccine efficacy against CIN3+ and AIS irrespective of HPV DNA in the lesion. Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverage of early adolescents might have the potential to substantially reduce the incidence of cervical cancer.. GlaxoSmithKline Biologicals.

Topics: Adenocarcinoma; Adjuvants, Immunologic; Adolescent; Adult; Age Factors; Aluminum Hydroxide; Asia; Australia; DNA, Viral; Double-Blind Method; Europe; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Neoplasm Grading; North America; Papillomavirus Infections; Papillomavirus Vaccines; South America; Time Factors; Treatment Outcome; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Young Adult

We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of-study analysis after 4 years of follow-up in PATRICIA (PApilloma TRIal against Cancer In young Adults).. Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to HPV-16/18 vaccine or a control hepatitis A vaccine, via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The study was double-blind. The primary endpoint of PATRICIA has been reported previously; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of-study analysis. Analyses were done for three cohorts: the according-to-protocol cohort for efficacy (ATP-E; vaccine n=8067, control n=8047), total vaccinated HPV-naive cohort (TVC-naive; no evidence of infection with 14 oncogenic HPV types at baseline, approximating young adolescents before sexual debut; vaccine n=5824, control n=5820), and the total vaccinated cohort (TVC; all women who received at least one vaccine dose, approximating catch-up populations that include sexually active women; vaccine n=9319, control=9325). Vaccine efficacy was evaluated against 6-month persistent infection, cervical intraepithelial neoplasia grade 2 or greater (CIN2+) associated with 12 non-vaccine HPV types (individually or as composite endpoints), and CIN3+ associated with the composite of 12 non-vaccine HPV types. This study is registered with ClinicalTrials.gov, number NCT00122681.. Consistent vaccine efficacy against persistent infection and CIN2+ (with or without HPV-16/18 co-infection) was seen across cohorts for HPV-33, HPV-31, HPV-45, and HPV-51. In the most conservative analysis of vaccine efficacy against CIN2+, where all cases co-infected with HPV-16/18 were removed, vaccine efficacy was noted for HPV-33 in all cohorts, and for HPV-31 in the ATP-E and TVC-naive. Vaccine efficacy against CIN2+ associated with the composite of 12 non-vaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), with or without HPV-16/18 co-infection, was 46·8% (95% CI 30·7-59·4) in the ATP-E, 56·2% (37·2-69·9) in the TVC-naive, and 34·2% (20·4-45·8) in the TVC. Corresponding values for CIN3+ were 73·8% (48·3-87·9), 91·4% (65·0-99·0), and 47·5% (22·8-64·8).. Data from the end-of-study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine against four oncogenic non-vaccine HPV types-HPV-33, HPV-31, HPV-45, and HPV-51-in different trial cohorts representing diverse groups of women.. GlaxoSmithKline Biologicals.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aluminum Hydroxide; Antigens, Viral; Asia; Australia; Cross Reactions; DNA, Viral; Double-Blind Method; Europe; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Neoplasm Grading; North America; Papillomavirus Infections; Papillomavirus Vaccines; Precancerous Conditions; South America; Time Factors; Treatment Outcome; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Young Adult

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.. 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.. 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.. 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.

Topics: Adjuvants, Immunologic; Adolescent; Aluminum Hydroxide; Child; Drug Therapy, Combination; Female; Hepatitis A Vaccines; Hepatitis B Vaccines; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Safety; Uterine Cervical Neoplasms

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.

Topics: Adjuvants, Immunologic; Adult; Aluminum Hydroxide; Antibodies, Viral; Cancer Vaccines; Female; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Vaccines; Hepatitis B virus; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Treatment Outcome; Uterine Cervical Neoplasms; Young Adult

Anal cancer remains rare (incidence of about 1·5 per 100,000 women yearly), but rates are increasing in many countries. Human papillomavirus (HPV) 16 and 18 infections cause most cases of anal cancer. We assessed efficacy of an AS04-adjuvanted HPV 16 and HPV 18 vaccine against anal infection with HPV 16, HPV 18, or both (HPV 16/18).. Women from Costa Rica were registered between June 28, 2004, and Dec 21, 2005, in a randomised double-blind controlled trial that was designed to assess vaccine efficacy against persistent cervical HPV 16/18 infections and associated precancerous lesions. Eligible women were residents of Guanacaste and selected areas of Puntarenas, Costa Rica, age 18-25 years, in good general health, willing to provide informed consent, and were not pregnant or breastfeeding. Participants were randomly assigned (1:1) to receive an HPV vaccine (Cervarix, GlaxoSmithKline, Rixensart, Belgium) or a control hepatitis A vaccine (modified preparation of Havrix, GlaxoSmithKline, Rixensart, Belgium). Vaccines were administered in three 0·5 mL doses at enrolment, 1 month, and 6 months. Women, selected at the final blinded study visit 4 years after vaccination, provided anal specimens for assessment of vaccine efficacy against anal HPV 16/18 infection. Prevalence of anal HPV 16/18 infections, reported as vaccine efficacy, was the primary endpoint of the study described here. Vaccine efficacy against cervical HPV 16/18 infection in the same women at the 4-year visit was used as a comparator. Analyses were done in a restricted cohort of women who were negative for both cervical HPV 16 and HPV 18 DNA and who were HPV 16 and HPV 18 seronegative before enrolment (HPV naive), and also in the full cohort of women who provided an anal specimen. Investigators were masked to group assignment. This study is registered at ClinicalTrials.gov, number NCT00128661.. All women who attended the final blinded study visit and consented to anal specimen collection were included in the analysis (4210 of 6352 eligible women). In the full cohort, vaccine efficacy against prevalent HPV 16/18 infection measured one-time, 4 years post vaccination was lower at the anus (62·0%, 95% CI 47·1-73·1) compared with the cervix (76·4%, 67·0-83·5; p for interaction by anatomical site 0·031). In the restricted cohort, vaccine efficacy against anal HPV 16/18 infection was 83·6% (66·7-92·8), which was similar to vaccine efficacy against cervical HPV 16/18 infection (87·9%, 77·4-94·0). Safety issues were not addressed in the current analysis. Additional safety data will be published later in a separate article.. The AS04-adjuvanted vaccine affords strong protection against anal HPV infection, particularly among women more likely to be HPV naive at enrolment.. National Cancer Institute with contributions from the National Institutes of Health Office of Research on Women's Health. Vaccine was provided by GlaxoSmithKline Biologicals.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aluminum Hydroxide; Anus Neoplasms; Chi-Square Distribution; Costa Rica; Double-Blind Method; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Immunization Schedule; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Precancerous Conditions; Prevalence; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Uterine Cervical Neoplasms; Young Adult

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.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aluminum Hydroxide; Antibodies, Viral; Child; Dose-Response Relationship, Immunologic; Drug Administration Schedule; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Licensure; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Treatment Outcome; Uterine Cervical Neoplasms; Young Adult

The human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine has been demonstrated to be highly efficacious and immunogenic with a favorable safety profile. This study assessed the immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Korean girls aged 10-14 yr. This multi-center, observer-blind trial randomly assigned 321 healthy girls to receive three doses (0, 1, 6-month schedule) of HPV-16/18 AS04-adjuvanted vaccine or hepatitis A vaccine. Immunogenicity against vaccine antigens was assessed one month post-Dose 3. Solicited and unsolicited adverse events (AEs) and serious AEs (SAEs) were recorded. In the according-to-protocol analysis, all initially seronegative subjects vaccinated with the HPV-16/18 AS04-adjuvanted vaccine had seroconverted at Month 7, with a peak geometric mean titer (GMT) that was 600-fold higher than the natural infection titer of 29.8 EU/mL for HPV-16 and a peak GMT that was 400-fold higher than the natural infection titer of 22.6 EU/mL for HPV-18. The vaccine was well tolerated with no increase in reactogenicity with subsequent doses and no reports of vaccine-related SAEs. In conclusion, the HPV-16/18 AS04-adjuvanted vaccine is shown to be highly immunogenic and generally well-tolerated in Korean girls aged 10-14 yr.

Topics: Adjuvants, Immunologic; Adolescent; Aluminum Hydroxide; Antibodies, Viral; Child; Female; Hepatitis A; Hepatitis A Vaccines; Humans; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Republic of Korea; Seroepidemiologic Studies; Uterine Cervical Neoplasms

Vaccines not requiring cold-chain storage/distribution and suitable for needle-free delivery are urgently needed. Pulmonary administration is one of the most promising non-parenteral routes for vaccine delivery. Through a multi-component excipient and spray-drying approach, we engineered highly respirable dry-powder vaccine particles containing a three-fold repeated peptide epitope derived from human papillomavirus (HPV16) minor capsid protein L2 displayed on Pyrococcus furious thioredoxin as antigen. A key feature of our engineering approach was the use of the amphiphilic endotoxin derivative glucopyranosyl lipid A (GLA) as both a coating agent enhancing particle de-aggregation and respirability as well as a built-in immune-adjuvant. Following an extensive characterization of the in vitro aerodynamic performance, lung deposition was verified in vivo by intratracheal administration in mice of a vaccine powder containing a fluorescently labeled derivative of the antigen. This was followed by a short-term immunization study that highlighted the ability of the GLA-adjuvanted vaccine powder to induce an anti-L2 systemic immune response comparable to (or even better than) that of the subcutaneously administered liquid-form vaccine. Despite the very short-term immunization conditions employed for this preliminary vaccination experiment, the intratracheally administered dry-powder, but not the subcutaneously injected liquid-state, vaccine induced consistent HPV neutralizing responses. Overall, the present data provide proof-of-concept validation of a new formulation design to produce a dry-powder vaccine that may be easily transferred to other antigens.

Topics: Animals; Excipients; Lipid A; Lubricants; Mice; Mice, Inbred BALB C; Papillomavirus Infections; Powders; Vaccines

Adjuvants are a crucial component of recombinant vaccines such as the human papillomavirus (HPV) vaccine. Monophosphoryl lipid A (MPL) extracted from Salmonella Minnesota lipopolysaccharide is used as an adjuvant for the HPV vaccine. Due to the limitations in accessibility and reproducibility of MPL, investigating synthetic analogues of MPL (synMPL) is urgently needed to overcome these limitations. In this study, female BALB/c mice were vaccinated by HPV vaccine formulated with synMPL and aluminum hydroxide gel in which the concentration of synMPL ranged from 0 to 100 μg/dose. Anti-HPV L1 VLP antibody was measured for each group through Indirect ELISA and compared with Cervarix and Gardasil vaccines as approved anti-HPV vaccines. SynMPL showed a concentration-dependent increase up to 50 μg/dose in the immunogenicity of the vaccine. Therefore, synMPL at concentration of 50 μg/dose was selected as optimum concentration. The GMT profiling of synMPL-formulated vaccine (named Papilloguard) and Cervarix was not statistically different (Mann-Whitney test). The Gardasil vaccine showed 10-fold lower GMT for anti-HPV 18 L1 VLP antibody but anti-HPV 16 L1 VLP antibody was similar to Cervarix and Papilloguard. The current findings suggest that the synMPL in combination with aluminum hydroxide could be used as a potential adjuvant candidate for human vaccine.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Viral; Enzyme-Linked Immunosorbent Assay; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Mice, Inbred BALB C; Papillomavirus Infections; Papillomavirus Vaccines; Vaccination; Vaccine Potency; Vaccines, Synthetic

The human papillomavirus (HPV)-16/18 vaccine (Cervarix®) is a prophylactic vaccine for the prevention of cervical cancer. The vaccine contains recombinant virus-like particles assembled from the L1 major capsid proteins of the cervical cancer-causing viral types HPV-16 and HPV-18, and Adjuvant System 04 (AS04), which contains the immunostimulant MPL and aluminium salt. To evaluate potential local and systemic toxic effects of the HPV-16/18 vaccine or AS04 alone, three repeated-dose studies were performed in rabbits and rats. One rabbit study also included a single-dose evaluation. In rabbits (~2.5 kg), the full human dose (HD) of the vaccine was evaluated (0.5 ml per injection site), and in rats (~250 g), 1/5 HD of vaccine was evaluated, corresponding to ≥ 12 times the dosage in humans relative to body weight. In both animal models, the treatment-related changes included a slight transient increase in the number of circulating neutrophils as well as a local inflammatory reaction at the injection site. These treatment-related changes were less pronounced after four doses of AS04 alone than after four doses of the HPV-16/18 vaccine. Additional treatment-related changes in the rat included lower albumin/globulin ratios and microscopic signs of inflammation in the popliteal lymph nodes. In both animal models, 13 weeks after the fourth dose, recovery was nearly complete, although at the injection site in some animals there were signs of discoloration, muscle-fibre regeneration and focal points of macrophage infiltration. Therefore, in these non-clinical models, the single and repeated dose administrations of the HPV-16/18 vaccine or AS04 alone were safe and well tolerated.

Topics: Aluminum Hydroxide; Animals; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Human papillomavirus 16; Human papillomavirus 18; Injections, Intramuscular; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Rabbits; Rats; Uterine Cervical Neoplasms

Topics: Adenocarcinoma; Adjuvants, Immunologic; Aluminum Hydroxide; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Precancerous Conditions; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Topics: Adenocarcinoma; Adjuvants, Immunologic; Aluminum Hydroxide; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Cervical cancer is the third most common cancer in women worldwide and often affects women under 40 years of age with young families. Vaccination against HPV is a major advancement, as it offers primary prevention against the infectious agent that is the main cause of the disease. The bivalent AS04-adjuvanted prophylactic HPV vaccine provides high efficacy against disease associated with HPV 16 and 18, as well as significant cross-protection against some HPV types not included in the vaccine. Protection against HPV 45 may be particularly important, as it is relatively more common in adenocarcinoma. The vaccine's antibody response profile suggests a long duration of immunity. Safety data have been reassuring, which is not unexpected, given that the vaccine is composed of virus-like particles, rather than being a live-virus vaccine.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aluminum Hydroxide; Antibodies, Viral; Child; Cross Protection; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Lipid A; Middle Aged; Papillomavirus Infections; Papillomavirus Vaccines; Uterine Cervical Neoplasms; Young Adult

New innovative therapies are urgently required in order to combat the high mortality and morbidity associated with advanced cancers. Antigen-specific cancer immunotherapy using peptide-based vaccination has emerged as an attractive approach for the control of cancers due to its simplicity and easy preparation. However, such an approach requires the employment of suitable adjuvants. In the current study, we explored the employment of a sulfated polysaccharide compound from red algae, carrageenan (CGN) as an adjuvant for their ability to generate antigen-specific immune responses and antitumor effects in mice vaccinated with human papillomavirus type 16 (HPV-16) E7 peptide vaccine. We found that carrageenan can significantly enhance the E7-specific immune responses generated by E7 peptide vaccination via the TLR4 activation pathway. In addition, carrageenan could enhance the protective and therapeutic antitumor effects generated by E7 peptide vaccination against E7-expressing tumors. Furthermore, the observed enhancement was not restricted to E7 antigen but was also applicable to other antigenic systems. We also found that other structurally similar compounds to CGN, such as dextran, also generated similar immune enhancement. Thus, our data suggest that CGN and its structurally related compounds may serve as innovative adjuvants for enhancing peptide-based vaccine potency.

Topics: Adjuvants, Immunologic; Animals; Cancer Vaccines; Carrageenan; CD8-Positive T-Lymphocytes; Dextrans; Female; Lipid A; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms, Experimental; Papillomavirus E7 Proteins; Papillomavirus Infections; Papillomavirus Vaccines; Toll-Like Receptor 4; Vaccines, Subunit

We report efficacy and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine up to 7.3 years post-vaccination. The study was conducted in a population (N=433) of women enrolled in Brazilian centres from an initial placebo-controlled study. Women were aged 15-25 years at first vaccination. During the most recent year of follow-up, approximately 7 years after initial vaccination, no cases of infection or cytohistological lesions associated with HPV-16/18 were observed in the vaccinees. Vaccine efficacy (95% confidence interval) up to 7.3 years was 94.5% (82.9, 98.9) for incident infection, 100% (55.7, 100) for 12-month persistent infection and 100% (-129.8, 100) for cervical intraepithelial neoplasia grade 2+. Antibody titres for total IgG and neutralising antibodies remained several folds above natural infection levels and >or=96% of women were seropositive. Vaccine safety was similar to placebo. This is the longest follow-up study for a licensed cervical cancer vaccine.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Antibodies, Neutralizing; Antibodies, Viral; Brazil; Cancer Vaccines; Female; Follow-Up Studies; Human papillomavirus 16; Human papillomavirus 18; Humans; Immunoglobulin G; Lipid A; Papillomavirus Infections; Papillomavirus Vaccines; Uterine Cervical Neoplasms; Young Adult

Human papillomavirus (HPV) vaccines based on L1 virus-like particle (VLP) can prevent genital HPV infection and associated lesions after three intramuscular injections. Needle-free administration might facilitate vaccine implementation, especially in developing countries. Here we have investigated rectal and vaginal administration of HPV16 L1 VLPs in mice and their ability to induce anti-VLP and HPV16-neutralizing antibodies in serum and in genital, rectal and oral secretions. Rectal and vaginal immunizations were not effective in the absence of adjuvant. Cholera toxin was able to enhance systemic and mucosal anti-VLPs responses after rectal immunization, but not after vaginal immunization. Rectal immunization with Resiquimod and to a lesser extent Imiquimod, but not monophosphoryl lipid A, induced anti-HPV16 VLP antibodies in serum and secretions. Vaginal immunization was immunogenic only if administered in mice treated with nonoxynol-9, a disrupter of the cervico-vaginal epithelium. Our findings show that rectal and vaginal administration of VLPs can induce significant HPV16-neutralizing antibody levels in secretions, despite the fact that low titers are induced in serum. Imidazoquinolines, largely used to treat genital and anal warts, and nonoxonol-9, used as genital microbicide/spermicide were identified as adjuvants that could be safely used by the rectal or vaginal route, respectively.

Topics: Adjuvants, Immunologic; Administration, Intravaginal; Administration, Rectal; Animals; Antibodies, Viral; Antibody Formation; Capsid Proteins; Cholera Toxin; Female; Human papillomavirus 16; Humans; Imidazoles; Lipid A; Mice; Mouth; Nonoxynol; Oncogene Proteins, Viral; Papillomavirus Infections; Papillomavirus Vaccines; Rectum; Vaccines, Synthetic; Vagina

Adjuvant System 04 (AS04) combines the TLR4 agonist MPL (3-O-desacyl-4'-monophosphoryl lipid A) and aluminum salt. It is a new generation TLR-based adjuvant licensed for use in human vaccines. One of these vaccines, the human papillomavirus (HPV) vaccine Cervarix, is used in this study to elucidate the mechanism of action of AS04 in human cells and in mice. The adjuvant activity of AS04 was found to be strictly dependent on AS04 and the HPV Ags being injected at the same i.m. site within 24 h of each other. During this period, AS04 transiently induced local NF-kappaB activity and cytokine production. This led to an increased number of activated Ag-loaded dendritic cells and monocytes in the lymph node draining the injection site, which further increased the activation of Ag-specific T cells. AS04 was also found to directly stimulate those APCs in vitro but not directly stimulate CD4(+) T or B lymphocytes. These AS04-induced innate responses were primarily due to MPL. Aluminum salt appeared not to synergize with or inhibit MPL, but rather it prolonged the cytokine responses to MPL at the injection site. Altogether these results support a model in which the addition of MPL to aluminum salt enhances the vaccine response by rapidly triggering a local cytokine response leading to an optimal activation of APCs. The transient and confined nature of these responses provides further supporting evidence for the favorable safety profile of AS04 adjuvanted vaccines.

Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; B7-2 Antigen; CD4-Positive T-Lymphocytes; CD40 Antigens; Cell Line; Cytokines; Dendritic Cells; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Immunity, Innate; Lipid A; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; NF-kappa B; Ovalbumin; Papillomavirus Infections; Papillomavirus Vaccines; Toll-Like Receptor 4; Transfection

Immunization against infectious diseases is one of the most effective prevention instruments. Ongoing research has shown that revaccination against viral hepatitis type A and B (VHA and VHB) in healthy immunocompetent individuals is not necessary and that basic VHA and VHB vaccination schedules provide lifelong immunity. In the USA, Prevnar, a 7-valent conjugated pneumococcal vaccine, demonstrated its substantial direct and indirect effects on the incidence of invasive pneumococcal diseases (IPD). As a matter of fact, its introduction led to a dramatic decrease in invasive pneumococcal diseases both in children and, indirectly, also in the senior age cohorts. In addition, lower pneumococci colonisation of the mucosa, constituting this indirect effect, leads to a lower incidence of acute otitis among children up to 2 years of age. The use of Prevenar also decreases the incidence in the population of Streptococcus pneumoniae strains that are resistant to penicillin or erythromycin. The Fendrix is the first vaccine that has received market authorisation in the EU and that contains MPL (Monophosphoryl lipid A) as an adjuvans. It serves for the purpose of immunisation of haemodialysed patients and, in contrast to Engerix B, it creates a faster, more massive and longer immune response. At present, at haemodialysis units, two doses of the Engerix B vaccine (a total of 2 ml and 40 mcg of the HBsAg antigen) are used for basic immunisation that are applied according to a particular schedule-in month 0, 1, 2, and 6. Fendrix is applied in accordance with the same schedule however, only one dose is used. The applied schedule allows maintaining higher antibody titres for longer periods of time than with Engerix B. Thus further revaccination doses are spared for later use, since, in haemodialysed patients, the anti-HBs levels cannot fall under 10 mIU/ml.

Topics: Adjuvants, Immunologic; Hepatitis B; Hepatitis B Vaccines; Heptavalent Pneumococcal Conjugate Vaccine; Humans; Lipid A; Meningococcal Vaccines; Papillomavirus Infections; Papillomavirus Vaccines; Pneumococcal Infections; Pneumococcal Vaccines; Renal Dialysis; Vaccines, Conjugate; Vaccines, Synthetic

Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; Antibodies, Viral; Antibody Formation; Emulsions; Humans; Lipid A; Male; Papillomaviridae; Papillomavirus Infections; Rabbits; Recombinant Fusion Proteins; Tumor Virus Infections; Vaccines, Synthetic; Viral Vaccines