An article published Online First and in an upcoming edition of The Lancet reports that the ‘Cervarix’ human papilloma virus (HPV) vaccine from GlaxoSmithKline offers continued protection beyond six years from infection against the types of HPV most commonly associated with cervical cancer (HPV-16 and HPV-18).This latest analysis of the vaccine’s safety, efficacy and immunogenicity is the work of Dr Cosette Wheeler, University of New Mexico, Health Sciences Center, Albuquerque, NM, USA, and colleagues from the GlaxoSmithKline Vaccine HPV-007 study group.
Worldwide, cervical cancer is the second most common malignant disease in women. It has the largest burden in developing countries. In 2002, there were nearly 500,000 new cases of cervical cancer and 270,000 deaths from the disease. Cervical cancer has important societal effects, since it affects women at a younger age than do most other cancers. Findings from several clinical studies have shown that the HPV-16/18 AS04-adjuvanted vaccine (Cervarix) induces a strong and sustained antibody response and has a good safety profile. The present study included the findings of an initial efficacy study started in 2001 and those of a long-term follow-up study in 2003. The results of the first study and two provisional analyses of the follow-up study have been reported earlier. At this point, the authors report the concluding analysis of the follow-up study. There is a total follow-up of up to 6.4 years after vaccination.
A total of 1,113 women aged 15 to 25 years participated in the original study. They all had a normal cervical profile, with no evidence of infection with HPV-16 or 18 or any of twelve other cancer-causing HPV types. There were twenty-seven sites in three countries who participated in the follow-up study of the original randomized controlled trial. The study included 393 women in the vaccine group and 383 in the placebo group. Cervical samples were tested every six months for HPV DNA. The primary objective was to evaluate long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18, or both. The authors carried out a combined analysis of efficacy data from the initial and follow-up study up to 6.4 years after first vaccination. This provided a good estimation of the general vaccine efficacy, both short-term and long-term.
Vaccine efficacy is defined as the reduction in the incidence of a disease among people who have received a vaccine compared to the incidence in unvaccinated people. The efficacy of a new vaccine is measured in clinical trials by giving one group of people a vaccine and comparing the incidence of disease in that group to another group of people who do not receive the vaccine. Vaccine efficacy against incident infection with HPV-16/18 was 95 percent and against 12-month persistent infection was 100 percent. Cervical intraepithelial neoplasias (CIN) are precancerous lesions that can develop into cervical cancer. Vaccine efficacy against CIN2+ was 100 percent for lesions associated with HPV-16/18 and 72 percent for lesions independent of HPV type. Antibody concentrations (against HPV-16/18) remained at least several fold higher in vaccinated individuals than would be found after natural HPV infection. Between groups, safety outcomes were similar: during the follow-up study, 30 participants (8 percent) reported a serious adverse event in the vaccine group compared to 37 participants (10 percent) in the placebo group. None of these undesirable events were judged related or possibly related to vaccination, and no deaths occurred.
The authors remark: “The study population was continuously exposed to HPV infections, as indicated by the continuous accrual of CIN cases in the placebo group, showing that the vaccine confers sustained protection and that efficacy does not wane up to 6•4 years after first vaccination. Vaccine efficacy against persistent infection with HPV-16/18 remained 100%.”
In addition, the authors indicate that vaccine efficacy was achieved against incident infection with HPV-31 and HPV-45, two cancer-causing HPV types related to HPV-16 and HPV-18, respectively. They explain: “HPV-31 and HPV-45 are among the types most frequently associated with cervical cancer after HPV-16 and HPV-18, and are responsible for 10% of all cervical cancer cases.”
As a public health benefit, the researchers explain that teenagers before sexual activity are the main target for immunization. The reason is that they are most likely to benefit from population-based HPV vaccination programs. They comment that a strong point of their study is that it was carried out in women who were naive to cancer-causing HPV infection at the time of vaccination. As a result, it attempts to represent the target population. Because the incidence of cervical cancer peaks on average more than thirty years after adolescence, the vaccine has to give protection for many years. Up to now, this study shows the longest duration of protection against HPV-16 and HPV-18 infections for a licensed prophylactic HPV vaccine. Protection with the alternative HPV-6/11/16/18 vaccine (alternative vaccine manufactured by Merck) has been shown, up to now, for up to five years after vaccination.
The authors write in conclusion: “Although further assessment is necessary to confirm long-term vaccine effects, in view of the data from our study, we expect protection to continue for many more years.”
In an associated note, Dr Gary M Clifford, International Agency for Research on Cancer, Lyon, France, remarks that HPV vaccination is being considered by the GAVI Alliance for sustainable funding.
He says in closing: “If, as hoped, some resources can be raised, eligible countries will need to obtain the maximum health benefit for every dose of HPV vaccine that they administer. Therefore priority needs to be given to preadolescent girls before sexual activity. Immunisation of older boys or women (other than in a very restricted catch-up programme), will always be a less effective use of resources than will further improvement of coverage among preadolescent girls. The target age, thus, is a balance being early enough to catch girls before sexual debut, but late enough to provide an as yet unknown duration of immunity that protects during as many subsequent years of sexual activity as possible. The data in today’s study would suggest that this window of protection is at least 6 years, but also leads us to strongly suspect that, as these and other vaccinated women are followed up, the period of protection might be much longer.”
“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”
The GlaxoSmithKline Vaccine HPV-007 Study Group
DOI: 10.1016/S0140-6736(09)61567-1
The Lancet
Written by Stephanie Brunner (B.A.)