Kevin A. Ault

Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial

BACKGROUND A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). METHODS 277 young women (mean age 20.2 years [SD 1.7]) were randomly assigned to quadrivalent HPV (20 microg type 6, 40 microg type 11, 40 microg type 16, and 20 microg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20.0 years [1.7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. FINDINGS Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71-97, p<0.0001) in those assigned vaccine compared with those assigned placebo. INTERPRETATION A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types.

Vaginal microbiome of reproductive-age women

The means by which vaginal microbiomes help prevent urogenital diseases in women and maintain health are poorly understood. To gain insight into this, the vaginal bacterial communities of 396 asymptomatic North American women who represented four ethnic groups (white, black, Hispanic, and Asian) were sampled and the species composition characterized by pyrosequencing of barcoded 16S rRNA genes. The communities clustered into five groups: four were dominated by Lactobacillus iners, L. crispatus, L. gasseri, or L. jensenii, whereas the fifth had lower proportions of lactic acid bacteria and higher proportions of strictly anaerobic organisms, indicating that a potential key ecological function, the production of lactic acid, seems to be conserved in all communities. The proportions of each community group varied among the four ethnic groups, and these differences were statistically significant [χ2(10) = 36.8, P < 0.0001]. Moreover, the vaginal pH of women in different ethnic groups also differed and was higher in Hispanic (pH 5.0 ± 0.59) and black (pH 4.7 ± 1.04) women as compared with Asian (pH 4.4 ± 0.59) and white (pH 4.2 ± 0.3) women. Phylotypes with correlated relative abundances were found in all communities, and these patterns were associated with either high or low Nugent scores, which are used as a factor for the diagnosis of bacterial vaginosis. The inherent differences within and between women in different ethnic groups strongly argues for a more refined definition of the kinds of bacterial communities normally found in healthy women and the need to appreciate differences between individuals so they can be taken into account in risk assessment and disease diagnosis.

Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials

BACKGROUND Cervical cancer and its obligate precursors, cervical intraepithelial neoplasia grades 2 and 3 (CIN2/3), and adenocarcinona in situ (AIS), are caused by oncogenic human papillomavirus (HPV). In this combined analysis of four clinical trials we assessed the effect of prophylactic HPV vaccination on these diseases. METHODS 20,583 women aged 16-26 years were randomised to receive quadrivalent HPV6/11/16/18 vaccine (n=9087), its HPV16 vaccine component (n=1204), or placebo (n=10 292). They underwent periodic Papanicolaou testing, with colposcopy or biopsy for detected abnormalities. The primary composite endpoint was the combined incidence of HPV16/18-related CIN2/3, AIS, or cervical cancer. These trials are registered at ClinicalTrials.gov, numbers NCT00365378, NCT00365716, NCT00092521, and NCT00092534. FINDINGS Mean follow-up was 3.0 years (SD 0.66) after first dose. In women negative for HPV16 or HPV18 infection during the vaccination regimen (n=17 129, per protocol), vaccine efficacy was 99% for the primary endpoint (95% CI 93-100), meeting the statistical criterion for success. In an intention-to-treat analysis of all randomised women (including those who were HPV16/18 naive or HPV16/18-infected at day 1), efficacy was 44% (95% CI 31-55); all but one case in vaccine recipients occurred in women infected with HPV16 or HPV18 before vaccination. In a second intention-to-treat analysis we noted an 18% reduction (95% CI 7-29) in the overall rate of CIN2/3 or AIS due to any HPV type. INTERPRETATION Administration of HPV vaccine to HPV-naive women, and women who are already sexually active, could substantially reduce the incidence of HPV16/18-related cervical precancers and cervical cancer.

Efficacy of Human Papillomavirus-16 Vaccine to Prevent Cervical Intraepithelial Neoplasia A Randomized Controlled Trial

OBJECTIVE: Human papillomavirus (HPV) virus-like particle (VLP) vaccines have demonstrated effectiveness in preventing persistent HPV infections. Whether protection lasts longer than 18 months and, thus, impacts rates of cervical intraepithelial neoplasia (CIN) 2–3 has not yet been established. We present results from an HPV16 L1 VLP vaccine trial through 48 months. METHODS: A total of 2,391 women, aged 16–23 years, participated in a randomized, double-blind, placebo-controlled trial. Either 40 &mgr;g HPV16 L1 VLP vaccine or placebo was given intramuscularly at day 1, month 2, and month 6. Genital samples for HPV16 DNA and Pap tests were obtained at day 1, month 7, and then 6-monthly through month 48. Colposcopy and cervical biopsies were performed if clinically indicated and at study exit. Serum HPV16 antibody titer was measured by radioimmunoassay. RESULTS: Among 750 placebo recipients in the per protocol population, 12 women developed HPV16-related CIN2–3 (6 CIN2 and 6 CIN3). Among 755 vaccine recipients, there were no cases (vaccine efficacy 100%, 95% confidence interval [CI] 65–100%). There were 111 cases of persistent HPV16 infection in placebo recipients and 7 cases in vaccine recipients (vaccine efficacy 94%, 95% CI 88–98%). After immunization, HPV16 serum antibody geometric mean titers peaked at month 7 (1,519 milli-Merck units [mMU]/mL), declined through month 18 (202 mMU/mL), and remained relatively stable between month 30 and month 48 (128–150 mMU/mL). CONCLUSION: The vaccine HPV16 L1 VLP provides high-level protection against persistent HPV16 infection and HPV16-related CIN2–3 for at least 3.5 years after immunization. Administration of L1 VLP vaccines targeting HPV16 is likely to reduce risk for cervical cancer. LEVEL OF EVIDENCE: I

Safety of influenza vaccination during pregnancy

The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommends routine influenza vaccination for all women who are or will be pregnant during the influenza season. During seasonal influenza epidemics, during previous pandemics, and with the current influenza A (H1N1) pandemic, pregnancy places otherwise healthy women at increased risk for serious complications from influenza, including death. Inactivated influenza vaccine can be safely and effectively administered during any trimester of pregnancy. No study to date has demonstrated an increased risk of either maternal complications or adverse fetal outcomes associated with inactivated influenza vaccination. Moreover, no scientific evidence exists that thimerosal-containing vaccines are a cause of adverse events among children born to women who received influenza vaccine during pregnancy. In this article, we review the evidentiary basis for the recommendation of vaccination of all women who will be pregnant during the influenza season and safety data of influenza vaccination during pregnancy.

Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial.

Objectives To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital warts (condyloma acuminata). Design Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months’ follow-up. Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world. Participants 17 622 women aged 16-26 years enrolled between December 2001 and May 2003. Major exclusion criteria were lifetime number of sexual partners (>4), history of abnormal cervical smear test results, and pregnancy. Intervention Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6. Main outcome measures Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative through month 7, and had no major protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied. Results In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma. Conclusions Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccine HPV types (6, 11, 16, and 18) and a substantial reduction in the burden of these diseases through 42 months of follow-up. Trial registrations NCT00092521 and NCT00092534.

A Pooled Analysis of Continued Prophylactic Efficacy of Quadrivalent Human Papillomavirus (Types 6/11/16/18) Vaccine against High-grade Cervical and External Genital Lesions

Quadrivalent human papillomavirus (HPV) vaccine has been shown to provide protection from HPV 6/11/16/18–related cervical, vaginal, and vulvar disease through 3 years. We provide an update on the efficacy of the quadrivalent HPV vaccine against high-grade cervical, vaginal, and vulvar lesions based on end-of-study data from three clinical trials. Additionally, we stratify vaccine efficacy by several baseline characteristics, including age, smoking status, and Papanicolaou (Pap) test results. A total of 18,174 females ages 16 to 26 years were randomized and allocated into one of three clinical trials (protocols 007, 013, and 015). Vaccine or placebo was given at baseline, month 2, and month 6. Pap testing was conducted at regular intervals. Cervical and anogenital swabs were collected for HPV DNA testing. Examination for the presence of vulvar and vaginal lesions was also done. Endpoints included high-grade cervical, vulvar, or vaginal lesions (CIN 2/3, VIN 2/3, or VaIN 2/3). Mean follow-up time was 42 months post dose 1. Vaccine efficacy against HPV 6/11/16/18–related high-grade cervical lesions in the per-protocol and intention-to-treat populations was 98.2% [95% confidence interval (95% CI), 93.3-99.8] and 51.5% (95% CI, 40.6-60.6), respectively. Vaccine efficacy against HPV 6/11/16/18–related high-grade vulvar and vaginal lesions in the per-protocol and intention-to-treat populations was 100.0% (95% CI, 82.6-100.0) and 79.0% (95% CI, 56.4-91.0), respectively. Efficacy in the intention-to-treat population tended to be lower in older women, women with more partners, and women with abnormal Pap test results. The efficacy of quadrivalent HPV vaccine against high-grade cervical and external anogenital neoplasia remains high through 42 months post vaccination.

End-of-study safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine in adult women 24–45 years of age

Background:Previous analyses from a randomised trial in women aged 24–45 years have shown the quadrivalent human papillomavirus (qHPV) vaccine to be efficacious in the prevention of infection, cervical intraepithelial neoplasia (CIN), and external genital lesions (EGLs) related to HPV 6/11/16/18. In this report, we present end-of-study efficacy, safety, and immunogenicity data with a median follow-up time of 4.0 years.Methods:We enrolled 3819 24–45-year-old women with no history of cervical disease or genital warts in the past 5 years. Women received quadrivalent vaccine or placebo at day 1, and at months 2 and 6. Ascertainment of CIN/EGL was accomplished through Pap testing, genital inspection, and cervicovaginal sampling (every 6 months). The main analysis was conducted in a per-protocol efficacy population (that received three doses, was naive to the relevant HPV types at day 1, and remained free of infection through month 7). Efficacy was also estimated in other naive and non-naive populations.Results:Vaccine efficacy against the combined incidence of persistent infection, CIN/EGL related to HPV6/11/16/18 in the per-protocol population was 88.7% (95% CI: 78.1, 94.8). Efficacy for women who were seropositive and DNA negative for the relevant vaccine HPV type at the time of enrolment who received at least 1 dose was 66.9% (95% CI: 4.3, 90.6). At month 48, 91.5, 92.0, 97.4, and 47.9% of vaccinated women were seropositive to HPV 6/11/16/18, respectively. No serious vaccine-related adverse experiences were reported.Conclusions:The qHPV vaccine demonstrated high efficacy, immunogenicity, and acceptable safety in women aged 24–45 years, regardless of previous exposure to HPV vaccine type.

Use of primary high-risk human papillomavirus testing for cervical cancer screening: Interim clinical guidance

In 2011, the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology updated screening guidelines for the early detection of cervical cancer and its precursors. Recommended screening strategies were cytology and cotesting (cytology in combination with hrHPV testing). These guidelines also addressed the use of hrHPV testing alone as a primary screening approach, which was not recommended for use at that time. There is now a growing body of evidence for screening with primary hrHPV testing, including a prospective US-based registration study. Thirteen experts including representatives from the Society of Gynecologic Oncology, American Society for Colposcopy and Cervical Pathology, American College of Obstetricians and Gynecologists, American Cancer Society, American Society of Cytopathology, College of American Pathologists, and the American Society for Clinical Pathology, convened to provide interim guidance for primary hrHPV screening. This guidance panel was specifically triggered by an application to the FDA for a currently marketed HPV test to be labeled for the additional indication of primary cervical cancer screening. Guidance was based on literature review and review of data from the FDA registration study, supplemented by expert opinion. This document aims to provide information for healthcare providers who are interested in primary hrHPV testing and an overview of the potential advantages and disadvantages of this strategy for screening as well as to highlight areas in need of further investigation.

Epidemiology and Natural History of Human Papillomavirus Infections in the Female Genital Tract

Human papillomavirus (HPV) is the most common newly diagnosed sexually transmitted infection in the United States. Although the majority of sexually active adults will be infected with HPV at least once in their lives, it is sexually active women less than 25 years of age who consistently have the highest rates of infection. Besides youth and gender, common risk factors for HPV infection and clinical sequelae of infection include high number of sexual partners and coinfection with Chlamydia trachomatis or herpes simplex virus. Most HPV infections are cleared by the immune system and do not result in clinical complications. Clinical sequelae in cases of low-risk HPV infection consist of genital warts, and clinical manifestations of high-risk HPV infection include abnormal Pap test results, low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), and cervical cancer. LSIL, HSIL, and cervical cancer carry significant morbidity and/or mortality; genital warts and abnormal Pap test results are often significant sources of psychosocial distress. Currently, there are neither effective means of preventing HPV transmission nor cures for clinical manifestations: infection can only be prevented via complete sexual abstinence, while treatment for clinical sequelae such as genital warts and cytologic abnormalities consists of removing the problematic cells and watching for recurrence; this method consumes significant health care resources and is costly. New prophylactic HPV vaccines promise to dramatically reduce the incidence of HPV infection, genital warts, and cytologic abnormalities.