Elsevier

The Lancet

Volume 374, Issue 9706, 12–18 December 2009, Pages 1975-1985
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(09)61567-1Get rights and content

Summary

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).

Introduction

Cervical cancer is the second most common malignant disease in women worldwide, with the largest burden in developing countries.1 In 2002, there were nearly 500 000 new cases of cervical cancer and 270 000 deaths from the disease.1 Cervical cancer has substantial societal effects, since it affects women at a younger age than do most other cancers.2

Infection with oncogenic human papillomavirus (HPV) is the necessary cause of cervical cancer.3 15 oncogenic HPV types have been identified,4 most belonging to two important families: types related to HPV 16 and those related to HPV 18.5 Studies of HPV distribution in invasive cervical cancer have shown a prevalence of about 70% for HPV 16 and HPV 18 combined, with other common types being HPV 31, 33, 45, 52, and 58.6, 7 This distribution seems to be similar across continents. There is a larger contribution of HPV 18 and HPV 45 in adenocarcinoma than in squamous-cell carcinoma.7

Prophylactic vaccines against HPV infection are expected to provide a major advance in the prevention of cervical cancer. Such vaccines have to provide long-term protection, since the risk of acquiring an infection starts at sexual debut and women remain vulnerable to development of HPV-related lesions throughout their life. Serum neutralising antibodies are believed to be a major basis of protection offered by HPV vaccines.8, 9 Antibody concentrations after natural infection are low.10 Women with a naturally acquired HPV infection remain at risk for a new infection with the same HPV type, possibly because antibody concentrations after natural infection are insufficient to confer protection.11, 12 Alternatively, these results could be due to inadequate antibody assay specificity. In one study, a sustained high concentration of IgG antibody to HPV 16 after natural infection was associated with a reduced risk of subsequent infection with HPV 16 and related types, whereas individuals with a low concentration of IgG antibody were not protected.13 Therefore, in the absence of a serological correlate of protection, which has yet to be identified, vaccination should induce higher neutralising antibody concentrations than should natural infection.14, 15

The HPV-16/18 vaccine is adjuvanted with AS04—an adjuvant system comprising aluminium salt and the immunostimulatory molecule, 3-O-desacyl-4L'monophosphoryl lipid A (MPL).16 Studies of AS04-adjuvanted vaccines have shown that they produce consistently higher antibody titres that are sustained over a longer period, together with a higher frequency of memory B cells, than do the same antigens adjuvanted with aluminium salts alone.17, 18

Findings from several clinical studies19, 20, 21, 22, 23 have shown that the HPV-16/18 AS04-adjuvanted vaccine has a strong and sustained antibody response and a favourable safety profile. The initial efficacy study started in 2001 and the long-term follow-up study in 2003. Results of the initial study and of two interim analyses of the follow-up study have been reported previously.21, 22, 24 Here, we report the analysis of the follow-up study, with a total follow-up of up to 6·4 years after vaccination.

Section snippets

Study setting, design, and participants

The method of the initial study21 and the follow-up study22 has been described previously. In brief, the follow-up study took place in 27 sites (five in Brazil, five in Canada, and 17 in the USA) between Nov 10, 2003, and Aug 9, 2007.21, 22 The study protocol, which described the length of follow-up and all prespecified timepoints for analysis, and written informed consent, which was obtained at the screening visit from all participants or from a legally acceptable representative for those

Results

Of the 1113 women included in the initial study, 776 continued in the follow-up study, which 700 (90%) completed. Figure 1 shows the disposition of the participants in the follow-up study. For the combined analysis of the initial and follow-up studies, the TVC included 560 women in the vaccine group and 553 in the placebo group, whereas the ATP efficacy cohort included 465 in the vaccine group and 454 in the placebo group.

The mean follow-up period from the start of the initial study to the end

Discussion

Findings from this study have shown that the HPV-16/18 AS04-adjuvanted vaccine in healthy women aged 15–25 years provides high, sustained efficacy up to 6·4 years against HPV-16/18 infection and cytohistological endpoints, associated with high and persistent concentrations of total and neutralising antibodies against HPV 16 and HPV 18. We also recorded cross-protection against HPV-31 and HPV-45 incident infection, and a favourable safety profile.

With consideration of all data from the follow-up

References (37)

Cited by (333)

  • Systematic literature review of cross-protective effect of HPV vaccines based on data from randomized clinical trials and real-world evidence

    2021, Vaccine
    Citation Excerpt :

    None of the cohorts of the two phase II extended follow-up studies showed statistically significant efficacy for the individual HPV types [19,20]. Among three RCTs measuring cross-protective efficacy against any histologically confirmed CIN1+ with individual HPV types 31, 33, 45, 52, or 58 (two phase II extended follow-up studies [19,20] and the follow-up study of the Chinese RCT [16]), only the Chinese study reported a statistically significant cross-protective effect, and only for HPV 31 [100% (95% CI: 14.9 to 100)] in the ATP cohort (Appendix 4). Four publications reporting on RCTs with the quadrivalent vaccine met the inclusion criteria (Table 2).

View all citing articles on Scopus

Members listed at end of paper

View full text