lipid-a and Precancerous-Conditions

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

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

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

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

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