The 'Cervarix' human papilloma virus (HPV) vaccine from GlaxoSmithKline offers sustained 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 published in an Article Online First (www.thelancet.com) and in an upcoming edition of The Lancet. The study is by Dr Cosette Wheeler, University of New Mexico, Health Sciences Center, Albuquerque, NM, USA, and colleagues from the GlaxoSmithKline Vaccine HPV-007 study group.
Cervical cancer is the second most common malignant disease in women worldwide, with 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 substantial 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 favourable safety profile. The present study consisted of an initial efficacy study started in 2001 and a long-term follow-up study in 2003. Results of the initial study and two interim analyses of the follow-up study have been reported previously. Here, the authors report the final analysis of the follow-up study, with a total follow-up of up to 6.4 years after vaccination.
The original study analysed 1,113 women aged 15 years, with a normal cervical profile, who had no evidence of infection with HPV-16 or 18 or any of 12 other cancer-causing HPV types. 27 sites in three countries participated in the follow-up study of the original randomised controlled trial; the study included 393 women in the vaccine group and 383 in the placebo group. Cervical samples were tested every 6 months for HPV DNA. 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. The authors performed a combined analysis of efficacy data from the initial and follow-up study up to 6.4 years after first vaccination, in order to give a good estimation of the overall vaccine efficacy, both short-term and long-term.
Vaccine efficacy* against incident infection with HPV-16/18 was 95% and against 12-month persistent infection was 100%. Vaccine efficacy against CIN2+** was 100% for lesions associated with HPV-16/18 and 72% 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. 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.
The authors say: "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%."
Furthermore the authors point out 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 say: "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."
In terms of public health benefit, the authors say that adolescents before sexual debut are the main target for immunisation because they are most likely to benefit from population-based HPV vaccination programmes. They say a strength of their study is that it was done in women who were naive to cancer-causing HPV infection at the time of vaccination, and thus it attempts to represent the target population. Because the incidence of cervical cancer peaks on average more than 30 years after adolescence, the vaccine has to confer protection for many years. So far, 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*** has (so far) been shown for up to 5 years after vaccination.
The authors conclude: "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 accompanying Comment, Dr Gary M Clifford, International Agency for Research on Cancer, Lyon, France, says that HPV vaccination is being considered by the GAVI Alliance for sustainable funding.
He concludes: "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."
Dr Cosette Wheeler, University of New Mexico, Health Sciences Center, Albuquerque, NM, USA. T) +1 505 272-5785 / + 1 505 269-5817 E) CWheeler@salud.unm.edu
For Dr Gary Dubin (who is part of study group), Vice President and Director, Global Clinical Development Center Philadelphia and North American Clinical Affairs GlaxoSmithKline Biologicals, please contact Donatella Latocca T) +32 10 85 29 51 E) donatella.m.latocca@gskbio.com
Dr Gary M Clifford, International Agency for Research on Cancer, Lyon, France. T) +33 472738425 E) clifford@iarc.fr
For full Article and Comment, see: http://press.thelancet.com/hpv6year.pdf
Note to editors: * 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 phase III 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.
**CIN= Cervical intraepithelial neoplasia. These are precancerous lesions that can develop into cervical cancer.
***This alternative vaccine is manufactured by Merck
Journal
The Lancet