Elsevier

The Lancet

Volume 390, Issue 10108, 11–17 November 2017, Pages 2143-2159
The Lancet

Articles
Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16–26 years: a randomised, double-blind trial

https://doi.org/10.1016/S0140-6736(17)31821-4Get rights and content

Summary

Background

Primary analyses of a study in young women aged 16–26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years.

Methods

We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16–26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor's study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543.

Findings

Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10 000 person-years in the 9vHPV and 19·0 cases per 10 000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0–99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related.

Interpretation

The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide.

Funding

Merck & Co, Inc.

Introduction

Human papillomavirus (HPV) infection causes benign, precancerous, and malignant disease, localised primarily in the anogenital area and upper airway, including cancers and precancers of the cervix, vulva, vagina, anus, penis, tonsil, and base of the tongue.1 HPV infection can also cause anogenital warts and recurrent respiratory papillomatosis.1 Available HPV vaccines, including the bivalent HPV 16 and 18 L1 virus-like particle vaccine and the quadrivalent HPV 6, 11, 16, and 18 L1 virus-like particle (qHPV) vaccine, prevent infection and disease related to oncogenic HPV 16 and 18.2 HPV 16 and 18 are responsible for approximately 70% of cervical cancer cases worldwide.3 The qHPV vaccine was also shown to prevent anogenital warts related to HPV 6 and 11.2, 4 Although partial cross-protection has been observed against HPV 31 for the qHPV vaccine and HPV 31 and 45 for the bivalent HPV vaccine in clinical studies and in real-world public health programmes where high coverage has occurred, its extent, duration, and public health significance remain uncertain.2, 5, 6

Research in context

Evidence before this study

The quadrivalent human papillomavirus (qHPV; 6, 11, 16, and 18) and bivalent HPV (16 and 18) prophylactic vaccines were first licensed in 2006 and 2007, respectively. We searched PubMed with no language restrictions for articles published between Jan 1, 2000, and Sept 1, 2016, with the terms “HPV type detection” AND “cervical cancer” AND “worldwide”, and found several epidemiology studies showing that the HPV types most commonly associated with cervical cancer are HPV 16 and HPV 18, and the next five most common types are HPV 31, 33, 45, 52, and 58. Another PubMed search between Jan 1, 2007, and Sept 1, 2016 based on the terms “HPV vaccine” AND “cross-protection” AND (“clinical trial” OR “epidemiology”) found that partial cross-protection against oncogenic HPV types other than HPV 16 and HPV 18 has been reported for both licensed vaccines in clinical trials and real-world public health programmes, although its extent, duration, and public health significance remain uncertain. Finally, we searched PubMed with the search terms “HPV vaccine” AND “clinical trial” to identify studies published between Jan 1, 2007, and Sept 1, 2016, that assessed broader spectrum prophylactic HPV vaccines other than the nine-valent (HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine (9vHPV). We found one phase 2 study of two tetravalent vaccine candidates targeting HPV 16, 18, 31, and 45 and HPV 16, 18, 33, and 58, respectively; however, vaccine development was unsuccessful because of immune interference.

Added value of this study

This is the first phase 3 efficacy clinical trial of a 9vHPV vaccine. Primary analyses previously showed efficacy against infection and disease due to HPV 31, 33, 45, 52, and 58 and non-inferior HPV 6, 11, 16, and 18 antibody responses at 1 month after vaccination compared with the qHPV vaccine. Here we document persistence of efficacy against infection and disease for up to 6 years, a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18 over the entire study, and substantial reductions in abnormal cervical cytology and related clinical procedures. Taken together, these results suggest substantial protection against disease caused by HPV 31, 33, 45, 52, and 58 that augments protection against HPV 6, 11, 16, and 18 with the qHPV vaccine.

Implications of all the available evidence

The 9vHPV vaccine is licensed in more than 60 countries for the prevention of HPV-related anogenital cancers and pre-cancers, and genital warts. The results of this study support comprehensive vaccination programmes and inform public health decisions related to implementation. Additionally, these findings inform further refinement of cervical cancer screening algorithms for vaccinated populations. Previously developed HPV vaccines cover oncogenic HPV 16 and 18, which cause approximately 70% of cervical cancer cases worldwide; the 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide. It could also prevent nearly 90% of HPV-related vulvar and vaginal cancers, 70–85% of high-grade cervical disease in females, as well as 90% of anal cancers and of genital warts in both males and females.

A nine-valent HPV (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine (Gardasil 9; Merck & Co, Inc, Kenilworth, NJ, USA) was developed to provide direct protection against the HPV types already covered by the qHPV vaccine and the next five HPV types most commonly associated with cervical cancer worldwide: HPV 31, 33, 45, 52, and 58.3 On the basis of epidemiological studies, the 9vHPV vaccine could prevent around 90% of cervical cancers, 90% of HPV-related vulvar and vaginal cancers, and 70–85% of high-grade cervical disease in women7, 8 and around 90% of HPV-related anal cancers and genital warts in both men and women worldwide.1, 9, 10

A phase 3 efficacy, immunogenicity, and safety study of the 9vHPV vaccine was undertaken in women aged 16–26 years.11 The results of this study were published after sufficient numbers of prespecified endpoints were met for the endpoint-driven efficacy assessment.12 This primary analysis established nearly 97% efficacy of the 9vHPV vaccine against high-grade cervical, vulvar, and vaginal disease associated with HPV 31, 33, 45, 52, and 58 while showing non-inferior HPV 6, 11, 16, and 18 antibody responses 1 month after vaccination compared with the qHPV vaccine. The protocol (appendix) prespecified that the study would continue after the primary analyses were done for additional efficacy and safety follow-up, and that the study could be terminated after participants completed visits at least until month 42. With continued follow-up of the study participants, we extended the efficacy analyses to a follow-up period of up to 6 years following initial vaccination and evaluated antibody response kinetics over the entire study period. We aimed to report the effect of vaccination on cervical cytological abnormalities; cervical, vulvar, and vaginal high-grade disease (histology); and the number of related clinical procedures (cervical biopsy and cervical definitive therapy) avoided due to protection against disease caused by HPV 31, 33, 45, 52, and 58.

Section snippets

Study design and participants

This randomised, double-blind, controlled, dose-ranging, efficacy, immunogenicity, and safety study of the 9vHPV vaccine (protocol V503-001) was carried out at 105 study sites located in 18 countries (Austria, Brazil, Canada, Chile, Colombia, Denmark, Germany, Hong Kong, Japan, South Korea, Mexico, New Zealand, Norway, Peru, Sweden, Taiwan, Thailand, and the USA [including Puerto Rico]). Women aged 16–26 years old who were generally healthy, had no history of abnormal cervical cytology, no more

Results

We enrolled participants for part A from Sept 26, 2007, to Dec 13, 2007, and for part B from Sept 15, 2008, for sites that also participated in part A, and from Feb 23, 2009, at sites that only participated in part B; enrolment for part B ended on Dec 18, 2009. We randomly assigned 14 215 participants to participate in the efficacy portion of the study and to receive either the 9vHPV vaccine or the qHPV vaccine (figure 1). At the time the study was terminated, more than 82% of participants were

Discussion

The 9vHPV vaccine shows high and sustained efficacy for prevention of persistent infection and disease related to HPV 31, 33, 45, 52, and 58 up to 6 years following the first vaccination visit. Results of the data analysis indicated that vaccine efficacy through study completion remained unchanged compared with earlier analyses,12 thereby showing that vaccine efficacy persisted through the end of the study. Furthermore, robust efficacy to prevent cervical intraepithelial neoplasia grade 3 or

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