Wim Quint

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.

Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study

BACKGROUND Knowledge about the distribution of human papillomavirus (HPV) genotypes in invasive cervical cancer is crucial to guide the introduction of prophylactic vaccines. We aimed to provide novel and comprehensive data about the worldwide genotype distribution in patients with invasive cervical cancer. METHODS Paraffin-embedded samples of histologically confirmed cases of invasive cervical cancer were collected from 38 countries in Europe, North America, central South America, Africa, Asia, and Oceania. Inclusion criteria were a pathological confirmation of a primary invasive cervical cancer of epithelial origin in the tissue sample selected for analysis of HPV DNA, and information about the year of diagnosis. HPV detection was done by use of PCR with SPF-10 broad-spectrum primers followed by DNA enzyme immunoassay and genotyping with a reverse hybridisation line probe assay. Sequence analysis was done to characterise HPV-positive samples with unknown HPV types. Data analyses included algorithms of multiple infections to estimate type-specific relative contributions. FINDINGS 22,661 paraffin-embedded samples were obtained from 14,249 women. 10,575 cases of invasive cervical cancer were included in the study, and 8977 (85%) of these were positive for HPV DNA. The most common HPV types were 16, 18, 31, 33, 35, 45, 52, and 58 with a combined worldwide relative contribution of 8196 of 8977 (91%, 95% CI 90-92). HPV types 16 and 18 were detected in 6357 of 8977 of cases (71%, 70-72) of invasive cervical cancer. HPV types 16, 18, and 45 were detected in 443 of 470 cases (94%, 92-96) of cervical adenocarcinomas. Unknown HPV types that were identified with sequence analysis were 26, 30, 61, 67, 69, 82, and 91 in 103 (1%) of 8977 cases of invasive cervical cancer. Women with invasive cervical cancers related to HPV types 16, 18, or 45 presented at a younger mean age than did those with other HPV types (50·0 years [49·6-50·4], 48·2 years [47·3-49·2], 46·8 years [46·6-48·1], and 55·5 years [54·9-56·1], respectively). INTERPRETATION To our knowledge, this study is the largest assessment of HPV genotypes to date. HPV types 16, 18, 31, 33, 35, 45, 52, and 58 should be given priority when the cross-protective effects of current vaccines are assessed, and for formulation of recommendations for the use of second-generation polyvalent HPV vaccines. Our results also suggest that type-specific high-risk HPV-DNA-based screening tests and protocols should focus on HPV types 16, 18, and 45.

Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial

BACKGROUND The aim of this interim analysis of a large, international phase III study was to assess the efficacy of an AS04 adjuvanted L1 virus-like-particle prophylactic candidate vaccine against infection with human papillomavirus (HPV) types 16 and 18 in young women. METHODS 18,644 women aged 15-25 years were randomly assigned to receive either HPV16/18 vaccine (n=9319) or hepatitis A vaccine (n=9325) at 0, 1, and 6 months. Of these women, 88 were excluded because of high-grade cytology and 31 for missing cytology results. Thus, 9258 women received the HPV16/18 vaccine and 9267 received the control vaccine in the total vaccinated cohort for efficacy, which included women who had prevalent oncogenic HPV infections, often with several HPV types, as well as low-grade cytological abnormalities at study entry and who received at least one vaccine dose. We assessed cervical cytology and subsequent biopsy for 14 oncogenic HPV types by PCR. The primary endpoint--vaccine efficacy against cervical intraepithelial neoplasia (CIN) 2+ associated with HPV16 or HPV18--was assessed in women who were seronegative and DNA negative for the corresponding vaccine type at baseline (month 0) and allowed inclusion of lesions with several oncogenic HPV types. This interim event-defined analysis was triggered when at least 23 cases of CIN2+ with HPV16 or HPV18 DNA in the lesion were detected in the total vaccinated cohort for efficacy. Analyses were done on a modified intention-to-treat basis. This trial is registered with the US National Institutes of Health clinical trial registry, number NCT00122681. FINDINGS Mean length of follow-up for women in the primary analysis for efficacy at the time of the interim analysis was 14.8 (SD 4.9) months. Two cases of CIN2+ associated with HPV16 or HPV18 DNA were seen in the HPV16/18 vaccine group; 21 were recorded in the control group. Of the 23 cases, 14 (two in the HPV16/18 vaccine group, 12 in the control group) contained several oncogenic HPV types. Vaccine efficacy against CIN2+ containing HPV16/18 DNA was 90.4% (97.9% CI 53.4-99.3; p<0.0001). No clinically meaningful differences were noted in safety outcomes between the study groups. INTERPRETATION The adjuvanted HPV16/18 vaccine showed prophylactic efficacy against CIN2+ associated with HPV16 or HPV18 and thus could be used for cervical cancer prevention.

Clinical relevance of the cagA, vacA, and iceA status of Helicobacter pylori.

BACKGROUND & AIMS Clinical outcome of Helicobacter pylori infection may be associated with specific virulence-associated bacterial genotypes. The aim of this study was to assess the relationships between H. pylori cagA, vacA, and iceA status and severity of disease. METHODS Gastric biopsy specimens from 94 patients in The Netherlands were analyzed by polymerase chain reaction and reverse hybridization. RESULTS cagA was present in 63 (67%) of 94 cases and was associated with peptic ulcer disease (P = 0.0019). vacA geno-types s1a/m1, s1b/m2, s1b/m1, s1b/m2, and s2/m2 were found in 36.2%, 23.4%, 2.1%, 5.3%, and 20.2%, respectively. Ten isolates (10.6%) contained multiple vacA genotypes. The presence of peptic ulcers was associated with type s1 strains (P = 0.0006) but not with the m type (P = 0.2035). cagA and vacA s1 were strongly associated (P < 10(-5)). iceA1 was found in 53 (56.4%) and iceA2 in 25 (26.6%) of the 94 cases. In 14 isolates (14.9%), both iceA alleles were found, and 2 (2.1%) were negative for both iceA1 and iceA2. iceA1 was also associated with peptic ulcer disease (P = 0.0042). The iceA allelic type was independent of the cagA and vacA status. CONCLUSIONS vacA s1, cagA, and iceA1 are markers of H. pylori strains that are more likely to lead to ulcer disease.

Geographic Distribution of vacA Allelic Types of Helicobacter pylori

BACKGROUND & AIMS Distinct allelic types of Helicobacter pylori vacA have been defined. The geographic distribution of vacA alleles and cagA was assessed in this study. METHODS A total of 735 cultures from patients in 24 countries were analyzed by polymerase chain reaction and reverse hybridization on a line probe assay (LiPA). RESULTS In 124 (16.9%) of the 735 cultures, multiple vacA genotypes were detected, permitting analysis of 611 strains. In Europe, a distribution gradient of s1 subtypes was observed. In northern and eastern Europe, 89% were subtype s1a. s1a and s1b were equally present in France and Italy, whereas in Spain and Portugal 89% of strains were subtype s1b. s1a and s1b were approximately equally prevalent in North America. In Central and South America, virtually all s1 strains were subtype s1b. Subtype s1c was observed in 77% of the s1 isolates from East Asia. m1 and m2a have equal presence, except on the Iberian peninsula and in Central and South America, where m1 (86.2%) is more prevalent than m2 (13.8%). Subtype m2b was found exclusively among East Asian s1c strains. In all parts of the world, vacA s1/cagA-positive genotypes were associated with peptic ulcer disease (P < 0.001). CONCLUSIONS These data indicate a geographic distribution of H. pylori genotypes and aid in understanding the relationship of H. pylori with disease.

Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis.

To clarify the role of human papillomavirus (HPV) in penile cancer we evaluated the prevalence of HPV DNA in different histological subtypes of penile carcinoma, dysplasia, and condyloma using a novel, sensitive SPF10 HPV polymerase chain reaction assay and a novel genotyping line probe assay, allowing simultaneous identification of 25 different HPV types. Formalin-fixed, paraffin-embedded tissue samples were collected from the United States and Paraguay. HPV DNA was detected in 42% cases of penile carcinoma, 90% cases of dysplasia, and 100% cases of condyloma. There were significant differences in HPV prevalence in different histological cancer subtypes. Although keratinizing squamous cell carcinoma and verrucous carcinoma were positive for HPV DNA in only 34.9 and 33.3% of cases, respectively, HPV DNA was detected in 80% of basaloid and 100% of warty tumor subtypes. There was no significant difference in HPV prevalence between cases from Paraguay and the United States. In conclusion, the overall prevalence of HPV DNA in penile carcinoma (42%) is lower than that in cervical carcinoma (approximately 100%) and similar to vulvar carcinoma (approximately 50%). In addition, specific histological subtypes of penile cancer--basaloid and warty--are consistently associated with HPV, however, only a subset of keratinizing and verrucous penile carcinomas is positive for HPV DNA, and thus these two tumor groups seem to develop along different pathogenetic pathways.

Prevalence of Human Papillomavirus DNA in Different Histological Subtypes of Cervical Adenocarcinoma

The prevalence of human papilloma virus (HPV) DNA in different histological subtypes of cervical adenocarcinoma and related tumors was examined using formalin-fixed, paraffin-embedded tissue samples from 105 primary cervical adenocarcinomas and adenosquamous carcinomas. Broad-spectrum HPV DNA amplification and genotyping was performed with the SPF10 primer set and line probe assay (LiPA), respectively. HPV DNA was detected in 82 of 90 (91%) mucinous adenocarcinomas, encompassing endocervical, intestinal, and endometrioid histological subtypes, and in nine of nine adenosquamous tumors (100%). HPV DNA was not detected in any nonmucinous adenocarcinomas including clear cell, serous, and mesonephric carcinomas (0/6). The most common viral types detected in adenocarcinoma were HPV 16 (50%) and HPV 18 (40%), followed by HPV 45 (10%), HPV52 (2%), and HPV 35 (1%). Multiple HPV types were detected in 9.7% of the cases. In conclusion, mucinous adenocarcinomas and adenosquamous carcinomas of the cervix demonstrate a very high prevalence of HPV DNA, similar to that reported for cervical squamous cell carcinoma. Only rare histological variants of cervical adenocarcinoma seem unrelated to HPV infection.

Reduced Prevalence of Oral Human Papillomavirus (HPV) 4 Years after Bivalent HPV Vaccination in a Randomized Clinical Trial in Costa Rica

Background Human papillomavirus (HPV) infection, particularly with type 16, causes a growing fraction of oropharyngeal cancers, whose incidence is increasing, mainly in developed countries. In a double-blind controlled trial conducted to investigate vaccine efficacy (VE) of the bivalent HPV 16/18 vaccine against cervical infections and lesions, we estimated VE against prevalent oral HPV infections 4 years after vaccination. Methods and Findings A total of 7,466 women 18–25 years old were randomized (1∶1) to receive the HPV16/18 vaccine or hepatitis A vaccine as control. At the final blinded 4-year study visit, 5,840 participants provided oral specimens (91·9% of eligible women) to evaluate VE against oral infections. Our primary analysis evaluated prevalent oral HPV infection among all vaccinated women with oral and cervical HPV results. Corresponding VE against prevalent cervical HPV16/18 infection was calculated for comparison. Oral prevalence of identifiable mucosal HPV was relatively low (1·7%). Approximately four years after vaccination, there were 15 prevalent HPV16/18 infections in the control group and one in the vaccine group, for an estimated VE of 93·3% (95% CI = 63% to 100%). Corresponding efficacy against prevalent cervical HPV16/18 infection for the same cohort at the same visit was 72·0% (95% CI = 63% to 79%) (p versus oral VE = 0·04). There was no statistically significant protection against other oral HPV infections, though power was limited for these analyses. Conclusions HPV prevalence four years after vaccination with the ASO4-adjuvanted HPV16/18 vaccine was much lower among women in the vaccine arm compared to the control arm, suggesting that the vaccine affords strong protection against oral HPV16/18 infection, with potentially important implications for prevention of increasingly common HPV-associated oropharyngeal cancer. ClinicalTrials.gov, Registry number NCT00128661

Human Papillomavirus Genotype Distributions: Implications for Vaccination and Cancer Screening in the United States

Background Limited data are available describing human papillomavirus (HPV) genotype distributions in cervical cancer in the United States. Such studies are needed to predict how HPV vaccination and HPV-based screening will influence cervical cancer prevention. Methods We used the New Mexico Surveillance, Epidemiology, and End Results Registry to ascertain cases of in situ (n = 1213) and invasive (n = 808) cervical cancer diagnosed during 1985–1999 and 1980–1999, respectively, in the state of New Mexico. HPV genotyping was performed using two polymerase chain reaction–based methods on paraffin-embedded tissues from in situ and invasive cancers and on cervical Papanicolaou test specimen from control subjects (ie, women aged 18–40 years attending clinics for routine cervical screening [n = 4007]). Relative risks for cervical cancer were estimated, and factors associated with age at cancer diagnosis and the prevalence of HPV genotypes in cancers were examined. Results The most common HPV genotypes detected in invasive cancers were HPV type 16 (HPV16, 53.2%), HPV18 (13.1%), and HPV45 (6.1%) and those in in situ cancers were HPV16 (56.3%), HPV31 (12.6%), and HPV33 (8.0%). Invasive cancer case subjects who were positive for HPV16 or 18 were diagnosed at younger ages than those who were positive for other carcinogenic HPV genotypes (mean age at diagnosis: 48.1 [95% confidence interval {CI} = 46.6 to 49.6 years], 45.9 [95% CI = 42.9 to 49.0 years], and 52.3 years [95% CI = 50.0 to 54.6 years], respectively). The proportion of HPV16-positive in situ and invasive cancers, but not of HPV18-positive cancers, declined with more recent calendar year of diagnosis, whereas the proportion positive for carcinogenic HPV genotypes other than HPV18 increased. Conclusions HPV16 and 18 caused the majority of invasive cervical cancer in this population sample of US women, but the proportion attributable to HPV16 declined over the last 20 years. The age at diagnosis of HPV16- and HPV18-related cancers was 5 years earlier than that of cancers caused by carcinogenic HPV genotypes other than HPV16 and 18, suggesting that the age at initiation of cervical screening could be delayed in HPV-vaccinated populations.

Prevalence and Determinants of Genital Infection with Papillomavirus, in Female and Male University Students in Busan, South Korea

BACKGROUND Little is known about the prevalence of human papillomavirus (HPV) infection in young adults in Asia. METHODS We invited female and male students in Busan, South Korea, to participate in a survey that included, for females, self-collection of vaginal cells and, for males, physician-performed collection of exfoliated genital cells. The prevalences of 25 HPV types were evaluated, by a polymerase chain reaction-based assay, in 672 female students (median age, 19 years) and in 381 male students (median age, 22 years). RESULTS HPV DNA was detected more frequently in female students (15.2%) than in male students (8.7%); in both sexes, high-risk HPV types were predominant. Among sexually active students, HPV prevalence was 38.8% in females and 10.6% in males. In female students, currently smoking cigarettes and having multiple lifetime sex partners were the strongest risk factors for HPV infection; in male students, associations between HPV prevalence and sexual habits were similar to those in female students but never attained statistical significance. CONCLUSIONS Young women in South Korea start having penetrative sexual intercourse relatively late (median age, 18 years), but, once they begin, HPV prevalence quickly rises to levels comparable with those found in university students in the United States and in northern Europe. The high rate of participation in our study suggests that trials of new vaccines against HPV may be feasible among university students in South Korea.