Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

EUROGIN 2007 7th International Multidisciplinary Congress

Monte Carlo, Monaco / October 4-6, 2007

As stated by Dr. Monika Hampl, University Hospital, Düsseldorf, Germany, “Cervical cancer is the second most common cause of cancer death among young women in Europe, and every year about 33,000 new cases are diagnosed.” Cervical cancer is at the top of a pyramid of human papillomavirus (HPV)-related lesions, thus around 160,000 cases of aggressive grade 2/3 cervical intraepithelial neoplasia (CIN) and 500,000 cases of less aggressive CIN 1 are diagnosed each year in Europe.

Types 16 and 18 are responsible for 59% and 12% of cervical cancers, respectively. But given that approximately 90% of cervical cancer can be attributed to HPV infection, a number of other types, which alone make a small contribution, account for a significant number of cancers when taken together. Cross-protection against such types would clearly be of additional benefit.

The link with HPV infection is evident, as types 6, 11, 16 and 18 account for most CIN, but it is not just the cervix that is affected. In Europe, approximately 2000 cases of vulvar/vaginal cancers are diagnosed each year and these cancers also develop from precancerous lesions. Genital warts are another lesion associated with HPV infection, in this case, with types 6 and 11.

Thanks to screening programs, many CIN are detected before they progress to invasive cancer, but confirmatory tests and treatment can be traumatic for patients and recurrence is a common problem. Dr. Hampl concluded, “There is a wider impact of HPV infection that includes lower grade vulvar and vaginal lesions and genital warts.” Clearly, a vaccine that protects against such lesions would be of great benefit.

HPV Vaccines: How They Work and Why They Are Effective

The two HPV vaccines currently available are based on virus-like particles (VLPs) that have demonstrated five years of clinical efficacy and immune memory. Interestingly, the protection afforded by such vaccines is greater than that provided by natural infection. According to Prof. Margaret Stanley, Department of Pathology, University of Cambridge, UK, this is because “VLPs are delivered intramuscularly, thereby eliciting a potent antibody response from stromal dendritic cells.” During natural infection, however, “the strategy of the virus is to avoid contact with the immune system limiting immune response.” The immunogenicity of VLPs can be increased still further with aluminum adjuvants, which are used in both the bivalent and quadrivalent vaccines. The bivalent vaccine uses aluminum hydroxide and monophosphoryl lipid A whereas the quadrivalent vaccine uses a proprietary aluminum hydroxyl phosphate sulfate. “In experiments done in mice, the level of antibody response with the [quadrivalent vaccine] is about twice that obtained with [the bivalent vaccine],” Prof. Stanley reported. She attributed this difference to the negative surface charge of the proprietary adjuvant thereby facilitating VLP binding and activation.

Another issue is why vaccination seems to afford some degree of cross-protection when natural infection provides none. On this point, Prof. Stanley explained, “Each virus type will be responsible for a predominant response but response is not homogeneous.” So although the predominant response is against the specific type, given that these vaccines are highly immunogenic, there is a certain degree of response to other related types. The quadrivalent vaccine has also demonstrated immune memory when patients were challenged with a fourth dose after five years. By extrapolation, protection is therefore thought to extend well beyond the five-year period of clinical efficacy and immune memory.

The Quadrivalent Vaccine in Clinical Trials

Currently, three randomized, controlled, pivotal efficacy trials with the quadrivalent vaccine have been conducted in nearly 21,000 women aged 16 to 26 years old in North America, Europe and Asia. Ongoing trials are also investigating vaccine efficacy in older women (up to 45 years of age) and the efficacy at preventing infection in 16- to 26-year-old men. In the opinion of Prof. Anna Giuliano, Department of Interdisciplinary Oncology, University of South Florida, “Vaccination of this [latter] group is the way forward in terms of reducing overall disease burden.”

The efficacy end points of the pivotal studies were incidence of 6-, 11-, 16- and 18-related high-grade lesions of the cervix, vulva and vagina (CIN 2/3 and adenocarcinomas in situ), which are surrogate measures for invasive cancers. Data were also collected on low-grade lesions, genital warts and persistent infection. The primary efficacy analyses were performed on the per-protocol population, that is, those who received three doses and did not have active HPV infection during the vaccination schedule. As Prof. Giuliano explained, “This per-protocol population is very similar to what we expect to achieve vaccinating adolescents prior to their sexual debut.”

In three years’ of follow-up, one cervical high-grade lesion was reported in the vaccinated cohort compared to 85 in the placebo cohort, representing a vaccine efficacy of 99% (95% confidence interval [CI], 93% to 100%). In the case of HPV 16- and 18-related vulvar and vaginal high-grade lesions, the vaccine efficacy was 100%. Subgroup analyses for Latin American and European women—reported in separate presentations—showed that vaccine efficacy for preventing high-grade lesions was also high, underlining the robustness of the overall analyses and its applicability in a wide range of settings.

Cross-protection and Implications for Clinical Practice

A subanalysis of two of the pivotal studies (n=9291) revealed that the vaccine efficacy of the quadrivalent vaccine against the 10 most oncogenic types, excluding 16 and 18, was 38% (CI, 6-60%). This protection was most significant for the so-called A9 species (which include type 16) and less so for A7 species (which include type 18). According to Dr. Luisa Villa, Ludwig Institute for Cancer Research, São Paulo, Brazil, “This is the first demonstration of cross-protection of any HPV vaccine against high-grade precursor lesions of cancer.”

Prof. Christine Clavel, CHU, Reims, France, cautioned, “Vaccination is not a replacement for Pap tests.” Vaccinated women will continue to be screened given that neither of the vaccines currently available can fully protect against all oncogenic types. While is it not clear exactly how screening programs will eventually be modified, they will be less intensive. Indeed, Dr. Eduardo Franco, Department of Oncology, MUHC-McGill University, Montreal, Quebec, suggested, “If we start thinking smartly, we may be able to offset some of the costs of the vaccination program.”

An important aspect of this meeting was a presentation in which the outlines of a consensus for clinical practice were unveiled. The panellists, all leading experts in the field, were at pains to point out that, given how new these vaccines are, this consensus is more of a roadmap than a set of guidelines, to be used to orient further research. The consensus will be published in full before the end of 2007. The most important point was that clinicians should make every effort to vaccinate against HPV. Monitoring is also an important aspect, in particular, to confirm the current evidence that coverage is long lasting.

Although there is still much work to be done, protection against HPV will have a substantial positive impact on women’s health in the coming years.