ArticlesSustained 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
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.
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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
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2022, Current Problems in CancerCitation Excerpt :However, antibodies developed during natural infection do not fully protect against reinfection, likely due to low or diminishing titers.31,32 On the other hand, HPV vaccines induce high concentrations of antibodies,33,34 and the vaccine is very effective in preventing cervical intraepithelial neoplasia (CIN) 2 or worse associated with HPV 16 and 18: there is documented 93% effectiveness for the bivalent vaccine and 98% for the quadrivalent vaccine.35–38 Established risk factors for HPV persistence and progression to dysplasia include the HPV genotype (particularly HPV 16 and 18), the viral load per cellular unit, the integration of the viral DNA into cellular DNA, concurrent human immunodeficiency virus (HIV) infection, immunosuppression, and tobacco use.39,40
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