Say no to cervical cancer The vaccine no woman should be without By Aida Uy Sze The most important manifestation of genital human papillomavirus (HPV) infection is cervical cancer. It is estimated that the global disease burden of cervical cancer is at 470,000 new cases and 230,000 deaths every year. Almost 80% of these cases occur in developing countries, where it is often the most common cancer among women.   The two most prevalent HPV types associated with cervical cancer are HPV 16 and HPV 18.  HPV16 accounts for more than 60% of cervical cancers and HPV 18 for about 10%. Vaccination against them could prevent the development of up to 70% of cervical cancers worldwide.    A new follow-up study on a bi-valent vaccine candidate for cervical cancer prevention extends earlier findings of vaccine efficacy and protection against most prevalent cancer-causing types of the human papillomavirus (HPV). The candidate vaccine is formulated with a proprietary adjuvant system called AS04, selected to ensure the vaccine confers strong and sustained antibody levels in women.    The efficacy trial A randomised, double-blind, controlled trial (an earlier study published in 2004) was conducted by Dr Diane Harper (of Norris Cotton Cancer Center, Dartmouth Medical School in the US) and her team to asses the efficacy, safety and immunogenicity of a bivalent HPV 16/18 L1 virus-like particle vaccine for the prevention of incident and persistent infection with the two virus types, associated cervical cytological abnormalities and pre-cancerous lesions.   A total of 1,113 women aged between 15 and 25 were randomised to receive three doses of either the vaccine formulated with AS04 adjuvant or placebo on a 0-month, 1-month, and 6-month schedule in North America and Brazil. The study vaccine was administered to 560 women and the placebo to 553 women. The women were assessed for HPV infection by cervical cytology and self-obtained cervicovaginal samples for up to 27 months, and were also assessed for vaccine safety and immunogenicity.   The team finds: “In the according-to-protocol analyses, vaccine efficacy was 91.6% (95% CI 64.5-98.0) against incident infection and 100% against persistent infection (47.0-100) with HPV-16/18. In the intention-to-treat analyses, vaccine efficacy was 95.1% (63.5 to 99.3) against persistent cervical infection with HPV 16/18 and 92.9% (70.0 to 98.3) against cytological abnormalities associated with HPV 16/18 infection.”   The study showed that the HPV 16/18 virus-like particle vaccine formulated with the proprietary adjuvant system AS04 induces a level of antibody production against HPV 16/18 that is much higher than that induced by natural infection.   The bivalent HPV 16/18 vaccine was found to be safe and well tolerated. There were no serious vaccine-related adverse events reported. Dr Harper’s team found that neither local nor general vaccine-related symptoms affected overall subject compliance. It was observed that there were greater local reaction rates in the vaccine group, but general symptom rates were equivalent to placebo.     Dr Harper states: “The bivalent HPV vaccine was efficacious in the prevention of incident and persistent cervical infections with HPV 16 and HPV 18, and associated cytological abnormalities and lesions. Vaccination against such infections could substantially reduce incidence of cervical cancer.”   The extended follow-up trial A high level of sustained protection against infection and pre-cancerous lesions is required for effective vaccination against HPV 16 and HPV 18 to prevent cervical cancer. The duration of protection provided by prophylactic HPV vaccination will be important in overall vaccine effectiveness, as predicted by mathematical modelling. Dr Dianne Harper’s team followed up the earlier study to assess the long-term efficacy, immunogenicity and safety of a bivalent HPV-16/18 L1 virus-like particle AS04 vaccine against incident and persistent infection with HPV 16 and HPV 18 and their associated cytological and histological outcomes.   Women were enrolled in the follow-up of the double-blind, multicentre, randomised, placebo-controlled clinical trial, assessing the safety, immunogenicity and efficacy of the vaccine. The eligible women included in this extended study were those who had participated in the initial efficacy study and received all three doses of bivalent HPV-16/18 virus-like particle AS04 vaccine  (0.5 ml; n=393) or placebo (n=383). The treatment allocation remained double-blinded. The HPV DNA was assessed using cervical samples and yearly cervical assessments were conducted. The long-term immunogenicity and safety of the vaccine was also studied.   Sustained efficacy and broader protection The follow-up study shows that more than 98% seropositivity was maintained for HPV 16/18 antibodies during the extended follow-up phase of the study. The team noted significant vaccine efficacy against HPV 16 and HPV 18 endpoints: incident infection, 96.9% (95% CI 81.3-99.9); persistent infection: 6-month definition, 94.3 (63.2 to 99.9); 12-month definition, 100% (33.6 to 100).  In a combined analysis of the initial efficacy and extended follow-up studies, vaccine efficacy of 100% (42.4 to 100) against cervical intraepithelial neoplasia (CIN) lesions associated with vaccine types. Broad protection against cytohistological outcomes beyond that anticipated for HPV 16/18 and protection against incident infection with HPV 45 and HPV 31 were noted.    The findings indicate that the HPV 16/18 L1 virus-like particle AS04 vaccine has sustained long-term vaccine efficacy against incident and persistent infections associated with HPV 16 and HPV 18 as indicated by the findings. “The results show sustained immune response and long-term efficacy against HPV 16 and HPV 18 infection, including persistence up to 12 months, and against related cytohistological outcomes as well as providing evidence of broader protection against cytohistological outcomes and cross-protection against HPV 45 and HPV 31.” The team suggests the AS04 adjuvant system used to formulate the vaccine could be contributing to the maintenance of the sustained immune response.   It is noted in the study that there is a high degree of protection against both incident and persistent infections of at least 6 months’ and 12 months’ duration up to 4.5 years of follow-up in the combined assessment of the initial and extended follow-up studies. “The high degree of protection lends support to the notion that persistent HPV infection is a valid virological endpoint in the clinical assessment of HPV vaccines. Given that persistent HPV infection is a valid intermediate endpoint for the development of high-grade dysplasia and cervical cancer, the high level of efficacy seen here against persistent infection might ultimately lead to the long-term prevention of HPV 16 and HPV 18 associated pre-cancerous and cancerous lesions.”   When the vaccine efficacy was estimated against cytological or histological endpoints associated with all high-risk HPV types and independent of HPV status, it is noted that protection seems to extend beyond the degree of effect that might be explained simply by protection against HPV16/18 endpoints alone. Analyses of vaccine efficacy against incident infection with other important oncogenic HPV types indicate a high degree of protection against HPV 45 and protection against HPV 31. These are the third and fourth most common HPV types associated with cervical cancers. Analyses of lesions associated with high-risk types other than HPV 16 and HPV18 are confounded by a high frequency of multiple infections, however, including HPV 16 and HPV 18.   The investigators presented safety data for the bivalent HPV-16/18 L1 virus-like particle AS04 vaccine up to 53 months. The vaccine is found to have a good long-term safety profile.   Conclusion Immunisation with the bivalent HPV 16/18 L1 virus-like particle vaccine combined with AS04 induces sustained high levels of antibodies that provide protection against HPV 16 and HPV 18 associated endpoints for up to 4.5 years. Dr Harper states: “These findings set the stage for the wide-scale adoption of HPV vaccination for prevention of cervical cancer.”   Mathematical modelling predicts that a prophylactic vaccine programme, directed at young adolescent women, is likely to be cost-effective in both screened and unscreened populations. There are important long-term implications for cervical cancer prevention, especially in countries where screening is limited or unavailable. Furthermore, additional benefits could also come from the vaccination of older women. The high vaccine efficacy in preventing cytological abnormalities associated with HPV-16/18 shows the potential to reduce the number of women receiving additional cytology or colposcopy. In countries with opportunistic or organised screening programmes, this translates to reducing the cost of medical treatments associated with cervical screening programmes. These preventable costs are estimated at several billion dollars per year in the USA.