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.

PRIORITY PRESS - XIX World Congress of the International Federation of Gynecology and Obstetrics

Cape Town, South Africa / October 4-9, 2009

If natural acquisition of human papillomavirus (HPV) through sexual activity conferred future protection against infection or re-infection of the virus, there would be no need for HPV vaccines. Yet as experts have consistently shown, following natural infection, about half of women develop no measurable immune response, a reflection of the virus’ ability to evade the body’s immune response to infection (Viscidi et al. Cancer Epidemiol Biomarkers Prev 2004;13(2):324-7). Of those women who do mount an immune response, most exhibit only low levels of anti-HPV antibodies, according to investigators, and low anti-HPV antibody levels may not protect women against re-infection or reactivation of a previous infection.

In contrast, vaccination with both HPV vaccines—the bivalent vaccine in particular-—induce high and sustained levels of neutralizing antibodies. This was demonstrated in a recent trial that compared the bivalent vaccine against HPV 16/18 vs. the quadrivalent vaccine against HPV types 6, 11, 16 and 18 in over 1100 healthy females between the ages of 18 and 45.

Stratifying the group by age ranges, investigators found that the bivalent vaccine, which uses a unique ASO4 adjuvant system to enhance immune response to the vaccine, induced consistently higher neutralizing antibody titres than the quadrivalent vaccine at month 7 for each antigen in each group. As presented by Dr. Philippe Morris, Rixensart, Belgium, even women between the ages of 36 and 45 achieved a superior immune response to the bivalent vaccine than females from 18 to 26 years of age who received the quadrivalent vaccine.

Induction of high antibody titres can be expected to translate into high levels of protection against HPV 16 and 18, which has been clearly demonstrated in the PATRICIA (Papilloma Trial Against Cancer in Young Adults) program. PATRICIA was a large international phase III study involving 18,644 women aged 15 to 25 years who received either three doses of the bivalent vaccine or a control hepatitis A vaccine. Cervical samples were taken every six months and tested for HPV DNA genotype.

At three years, the final analysis of PATRICIA indicated that the bivalent vaccine was 92.9% effective against cervical intraepithelial neoplasia grade 2 (CIN2+) in the primary analysis and 98.1% effective against the same end point in an additional analysis, in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types.

Cross-protection Expands Vaccine Value

Protection against HPV 16/18, CIN1+ and CIN2+ afforded by the bivalent vaccine is only a partial reflection of its true public health value. In Canada and elsewhere, the incidence of cervical squamous cell carcinoma (CSCC) has slowly declined and is currently plateauing while the incidence of cervical adenocarcinoma is steadily rising. In Manitoba, for example, the proportion of women with adenocarcinoma of the cervix increased from 7% in 1970 to 22% in 1999 (Gari et al. J Obstet Gynaecol Can 2008;30(9):788-95). The majority of adenocarcinomas worldwide are caused by HPV 16, 18 and 45—the three most aggressive oncogenic HPV types, according to de Sanjose et al. (IPC 2009, Abstract 30.13). In his analysis presented here, these three HPV types accounted for over 88% of all cervical adenocarcinomas identified in the ICO survey.

Furthermore, despite the undeniable contribution Pap screening has made to reduction of cervical cancer in developed countries, adenocarcinoma is often more difficult to detect on Pap smear because practitioners cannot easily access the endocervical canal with a cervical smear brush where the cancer often resides. Adenocarcinoma is also more likely to occur in younger women and because it is more difficult to detect, it is often detected at a more advanced stage and thus has a poorer prognosis than CSCC. This makes cross-protection against HPV 45 and other oncogenic non-vaccine types a very important attribute for any HPV vaccine.

As presented here by Prof. Suzanne Garland, Head, Clinical Microbiology and Infectious Diseases, Royal Women’s Hospital, Melbourne, Australia, a pre-specified analysis of the PATRICIA cohort who were HPV 45 DNA-negative at baseline showed that in the Total Vaccinated Cohort for Efficacy (TVC-E), vaccine efficacy was 71.6% for six-month persistent infection and 55.8% effective for 12-month persistent infection for CIN1+ and 100% effective for CIN2+. In the cohort that included women with high-grade cytology at baseline, prophylactic vaccine efficacy against CIN2+ associated with HPV 45 was also 100%. “The observation of cross-protection against HPV 45-persistent infection and CIN2+ lesions was unique and had not been reported in any other HPV vaccine study,” Prof. Garland observed. She also noted that under a conservative assumption that 50% of the target population would receive vaccination against HPV, a vaccine with cross-protection against HPV 45 was likely to reduce cervical cancer by an additional 2.7% and adenocarcinoma by a further 5.3% compared to a vaccine without HPV 45 cross-protection.

Other Non-vaccine Oncogenic Types

Dr. Anne Szarewski, Cancer Research UK Epidemiology, Barts and The London School of Medicine and Dentistry, presented more evidence that the cross-protection seen with the bivalent vaccine extends to other non-vaccine oncogenic types, further expanding its public health impact. Investigators analyzed the according-to-protocol (ATP) cohort in PATRICIA who received all three doses of either vaccine or control. Dr. Szarewski and colleagues found the bivalent vaccine to be 61.9% effective against CIN2+ for any oncogenic HPV type. For the 12 oncogenic non-vaccine types, the vaccine was 54% protective against CIN2+ in the ATP cohort.

Investigators then excluded lesions co-infected with HPV 16/18. At a most conservative estimate of cross-protection against the 12 oncogenic non-vaccine types not co-infected by 16/18, the vaccine was still 37.4% effective against CIN2+. This is the first report for any HPV vaccine of statistically significant cross-protection against CIN2+ lesions associated exclusively with oncogenic HPV non-vaccine types, “and generalizing the study to a broad population, the cross-protection against CIN2+ associated exclusively with non-vaccine types might theoretically result in a 48% increase in CIN2+ lesions prevented,” investigators concluded.

Burden of Adenocarcinoma

In an evaluation of the impact of HPV vaccination on the global burden of cervical adenocarcinoma, Prof. F. Xavier Bosch, Chief, Cancer Epidemiology Research Programme, Catalan Institute of Oncology, Barcelona, Spain, and colleagues estimated the percentage of adenocarcinoma in invasive cervical cancer; the global number of cases and incidence rates per 100,000 of cervical adenocarcinomas in 2008, and the number of adenocarcinoma cases attributable to HPV 16/18. Data sources included Cancer Incidence in Five Continents Vol IX; GLOBOCAN 2002 and the female mid-year population estimates in 2008 from the United Nation’s database.

Analyses revealed that adenocarcinoma represented 9.5% of all invasive cervical cancer overall, although its contribution varied substantially by country and region. Investigators calculated that the global incidence rate of adenocarcinoma in 2008 was 1.51 or over 50,000 new cases. With published findings indicating that the relative contribution of HPV 16, 18 and 45 types approaches 80% of all cervical adenocarcinomas, “it is thus estimated that these [HPV] types could be responsible for approximately 40,000 adenocarcinoma cases in 2008,” investigators indicated.

They concluded that current HPV 16/18 vaccines might offer the most efficient prevention strategy against cervical adenocarcinoma overall, and extended protection against HPV 45 would obviously be relevant.

Global Impact

In 2008, Prof. Harald zur Hausen, German Cancer Research Centre, Heidelberg, Germany, was awarded the Nobel Prize for Medicine for discovering that HPV caused cervical cancer. That he should be singled out for the most prestigious award ever offered to scientists speaks to how important cervical cancer is as a global disease entity, from which half of some 493,000 women with newly diagnosed cervical cancer die each year.

Prof. zur Hausen predicted that a global vaccination program against HPV infection has the potential to all but eliminate cervical cancer. This vision can be realized if the campaign to eradicate HPV oncogenic types is allowed to continue to develop globally.