Anne Schuind

Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial.

BACKGROUND Vaccination against the most common oncogenic human papillomavirus (HPV) types, HPV-16 and HPV-18, could prevent development of up to 70% of cervical cancers worldwide. We did a randomised, double-blind, controlled trial to assess the efficacy, safety, and immunogenicity of a bivalent HPV-16/18 L1 virus-like particle vaccine for the prevention of incident and persistent infection with these two virus types, associated cervical cytological abnormalities, and precancerous lesions. METHODS We randomised 1113 women between 15-25 years of age to receive three doses of either the vaccine formulated with AS04 adjuvant or placebo on a 0 month, 1 month, and 6 month schedule in North America and Brazil. Women were assessed for HPV infection by cervical cytology and self-obtained cervicovaginal samples for up to 27 months, and for vaccine safety and immunogenicity. FINDINGS In the according-to-protocol analyses, vaccine efficacy was 91.6% (95% CI 64.5-98.0) against incident infection and 100% against persistent infection (47.0-100) with HPV-16/18. In the intention-to-treat analyses, vaccine efficacy was 95.1% (63.5-99.3) against persistent cervical infection with HPV-16/18 and 92.9% (70.0-98.3) against cytological abnormalities associated with HPV-16/18 infection. The vaccine was generally safe, well tolerated, and highly immunogenic. INTERPRETATION The bivalent HPV vaccine was efficacious in prevention of incident and persistent cervical infections with HPV-16 and HPV-18, and associated cytological abnormalities and lesions. Vaccination against such infections could substantially reduce incidence of cervical cancer.

Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial.

BACKGROUND Effective vaccination against HPV 16 and HPV 18 to prevent cervical cancer will require a high level of sustained protection against infection and precancerous lesions. Our aim was to assess the long-term efficacy, immunogenicity, and safety of a bivalent HPV-16/18 L1 virus-like particle AS04 vaccine against incident and persistent infection with HPV 16 and HPV 18 and their associated cytological and histological outcomes. METHODS We did a follow-up study of our multicentre, double-blind, randomised, placebo-controlled trial reported in 2004. We included women who originally received all three doses of bivalent HPV-16/18 virus-like particle AS04 vaccine (0.5 mL; n=393) or placebo (n=383). We assessed HPV DNA, using cervical samples, and did yearly cervical cytology assessments. We also studied the long-term immunogenicity and safety of the vaccine. FINDINGS More than 98% seropositivity was maintained for HPV-16/18 antibodies during the extended follow-up phase. We noted significant vaccine efficacy against HPV-16 and HPV-18 endpoints: incident infection, 96.9% (95% CI 81.3-99.9); persistent infection: 6 month definition, 94.3 (63.2-99.9); 12 month definition, 100% (33.6-100). In a combined analysis of the initial efficacy and extended follow-up studies, vaccine efficacy of 100% (42.4-100) against cervical intraepithelial neoplasia (CIN) lesions associated with vaccine types. We noted broad protection against cytohistological outcomes beyond that anticipated for HPV 16/18 and protection against incident infection with HPV 45 and HPV 31. The vaccine has a good long-term safety profile. INTERPRETATION Up to 4.5 years, the HPV-16/18 L1 virus-like particle AS04 vaccine is highly immunogenic and safe, and induces a high degree of protection against HPV-16/18 infection and associated cervical lesions. There is also evidence of cross protection.

Comparison of the immunogenicity and safety of Cervarix™ and Gardasil® human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18–45 years

This observer-blind study compared the prophylactic human papillomavirus (HPV) vaccines, Cervarix™ (GlaxoSmithKline) and Gardasil® (Merck), by assessing immunogenicity and safety through one month after completion of the three-dose vaccination course. Women (n=1106) were stratified by age (18–26, 27–35, 36–45 years) and randomized (1:1) to receive Cervarix™ (Months 0, 1, 6) or Gardasil® (Months 0, 2, 6). At Month 7 after first vaccination, all women in the according-to-protocol cohort who were seronegative/DNA negative before vaccination for the HPV type analyzed had seroconverted for HPV-16 and HPV-18 serum neutralizing antibodies, as measured by pseudovirion-based neutralization assay (PBNA), except for two women aged 27–35 years in the Gardasil® group who did not seroconvert for HPV-18 (98%). Geometric mean titers of serum neutralizing antibodies ranged from 2.3–4.8-fold higher for HPV-16 and 6.8–9.1-fold higher for HPV-18 after vaccination with Cervarix™ compared with Gardasil®, across all age strata. In the total vaccinated cohort (all women who received at least one vaccine dose, regardless of their serological and DNA status prior to vaccination), Cervarix™ induced significantly higher serum neutralizing antibody titers in all age strata (p

Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years.

BACKGROUND Prophylactic human papillomavirus (HPV) vaccines have to provide sustained protection. We assessed efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. METHODS Women aged 15-25 years, with normal cervical cytology, who were HPV-16/18 seronegative and oncogenic HPV DNA-negative (14 types) at screening participated in a double-blind, randomised, placebo-controlled initial study (n=1113; 560 vaccine group vs 553 placebo group) and follow-up study (n=776; 393 vs 383). 27 sites in three countries participated in the follow-up study. Cervical samples were tested every 6 months for HPV DNA. Management of abnormal cytologies was prespecified, and HPV-16/18 antibody titres were assessed. The primary objective was to assess long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18, or both. We report the analyses up to 6.4 years of this follow-up study and combined with the initial study. For the primary endpoint, the efficacy analysis was done in the according-to-protocol (ATP) cohort; the analysis of cervical intraepithelial neoplasia grade 2 and above (CIN2+) was done in the total vaccinated cohort (TVC). The study is registered with ClinicalTrials.gov, number NCT00120848. FINDINGS For the combined analysis of the initial and follow-up studies, the ATP efficacy cohort included 465 women in the vaccine group and 454 in the placebo group; the TVC included 560 women in the vaccine group and 553 in the placebo group. Vaccine efficacy against incident infection with HPV 16/18 was 95.3% (95% CI 87.4-98.7) and against 12-month persistent infection was 100% (81.8-100). Vaccine efficacy against CIN2+ was 100% (51.3-100) for lesions associated with HPV-16/18 and 71.9% (20.6-91.9) for lesions independent of HPV DNA. Antibody concentrations by ELISA remained 12-fold or more higher than after natural infection (both antigens). Safety outcomes were similar between groups: during the follow-up study, 30 (8%) participants reported a serious adverse event in the vaccine group versus 37 (10%) in the placebo group. None was judged related or possibly related to vaccination, and no deaths occurred. INTERPRETATION Our findings show excellent long-term efficacy, high and sustained immunogenicity, and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. FUNDING GlaxoSmithKline Biologicals (Belgium).

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

The immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix®, GlaxoSmithKline Biologicals) administered according to its licensed vaccination schedule (3-dose, 3D) and formulation (20 μg of each HPV antigen; 20/20F) has previously been demonstrated. This partially-blind, controlled, randomized trial (NCT00541970) evaluated 2-dose (2D) schedules using the licensed 20/20F or an alternative formulation containing 40 μg of each antigen (40/40F), compared with the licensed 3D schedule. Healthy females stratified by age (9-14, 15-19, 20-25 years) 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 years were immunologically non-inferior to the 3D schedule in women 15-25 years (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 years versus the 3D schedule in women 15-25 years. 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 years and that the 2D schedule is likely adequate for younger females.

Sustained efficacy and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine up to 7.3 years in young adult women.

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.

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

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

Comparative evaluation of safety and immunogenicity of two dosages of an oral live attenuated human rotavirus vaccine.

Background: Rotavirus is a major cause of gastroenteritis in children worldwide and is estimated to be responsible for more than 500,000 physician visits, 50,000 hospitalizations and 20 deaths in the United States each year. Objective: To compare the safety and immunogenicity of 2 dosages of a live attenuated oral monovalent G1 human rotavirus (HRV) vaccine in healthy infants. Design/Methods: In this randomized, double blind trial conducted in the United States and Canada, 529 healthy infants 5–15 weeks of age received HRV vaccine containing either 105.2 or 106.4 focus-forming units or placebo. Two doses were administered orally at a 2-month interval concomitantly with routine childhood vaccines. Symptoms of fever, irritability/fussiness, diarrhea, vomiting, loss of appetite and cough/runny nose were solicited for 15 days postvaccination, nonserious adverse events for 43 days postvaccination and serious adverse events throughout the study. Vaccine take was defined as appearance of serum antirotavirus IgA in postimmunization sera at a titer of ≥20 units/mL or vaccine virus shedding in any stool sample collected between the first dose and 2 months after the second dose. Results: No serious adverse events considered related to vaccine were reported. The incidence of solicited symptoms was similar among treatment groups during the 15-day postvaccination surveillance periods. No significant difference in vaccine take after 2 doses (88.0% in high dose group and 81.5% in low dose group) was seen between vaccine groups (P = 0.153). Conclusions: Two doses of either dosage level of HRV vaccine administered concurrently with routine childhood vaccines to healthy infants 5–15 weeks of age were well-tolerated and were highly immunogenic.

A local reaction at or near injection site: Case definition and guidelines for collection, analysis, and presentation of immunization safety data

The need for developing a case definition and guidelines for a local reaction at or near the injection site, methods for the development of the case definition and guidelines as an adverse event following immunization as well as the rationale for selected decisions about the case definition for a local reaction at or near the injection site are explained in the Preamble section. The case definition is structured in 2 levels of diagnostic certainty: level 1 includes any description of morphological or physiological change at or near the injection site that is described or identified by a healthcare provider. Level 2 is any description of morphological or physiological change at or near injection site that is described by any other person. In Guidelines section, the working group recommends to enable meaningful and standardized data collection, analysis, and presentation of information about a local reaction at or near the injection site. However, implementation of all guidelines might not be possible in all settings. The availability of information may vary depending upon resources, geographic region, and whether the source of information is a prospectively designed clinical trial, a post-marketing surveillance or epidemiologic study, or an individual report of a local reaction at injection site.

Persistence of an Incident Human Papillomavirus Infection and Timing of Cervical Lesions in Previously Unexposed Young Women

Background: We analyzed data from a cohort of 553 women enrolled in the placebo arm of a randomized controlled trial of the human papillomavirus (HPV) 16/18 vaccine to study the timing of the occurrence of squamous intraepithelial lesions (SIL) or cervical intraepithelial neoplasia (CIN) following incident HPV infection and its relation to persistence of the infection. Methods: At entry, women were cytologically negative, HPV 16/18 seronegative, and high-risk HPV (HR-HPV) DNA negative. Cervicovaginal samples were initially collected at 3-month and cervical samples at 6-month intervals. We estimated the mean time to SIL/CIN, relative risks of SIL/CIN following incident HPV, and odds ratios between persistent HPV and SIL/CIN. Results: The mean time for SIL/CIN detection was 43.3 [95% confidence interval (95% CI), 36.4-50.1] and 46.4 (95% CI, 42.0-50.7) months from first infection with HPV 16/18 and other HR-HPVs, respectively. Relative risks of SIL/CIN following incident HPV infection were 66.2 (95% CI, 14.9-295.1) for HPV 16/18 and 50.9 (95% CI, 11.5-225.4) for other HR-HPVs. The odds ratios of SIL/CIN for persistent HPV 16/18 infection, defined as a minimum of two and three (6 monthly) visits, were, respectively, 169.0 (95% CI, 37.2-768.6) and 169.1 (95% CI, 31.5-907.4). The majority of women with cervical infection with HPV 16/18 lasting >6 months (33 of 51, 65%) developed SIL and/or CIN. Conclusions: These analyses provide the first actuarial estimate of mean time between incident HR-HPV infection in previously uninfected women and onset of cervical lesion development. Persistent HR-HPV infection, particularly HPV 16/18, is a strong predictor of cervical lesion risk and potentially a reliable end point for clinical HPV research. (Cancer Epidemiol Biomarkers Prev 2009;18(3):854–62)