Vaccination and testing for HPV could eradicate CC

According to a cervical cancer (CC) screening expert, Professor Jack Cuzick, from Cancer Research UK, the disease could be eradicated within the next 50 years if countries implement national screening programmes based on the detection of the human papillomavirus (HPV). Cuzick told the recent joint 15th ECCO and 34th ESMO Congress that while the current HPV vaccines protect against two cancer-causing strains of the HPV virus, soon there would be vaccines available that protect against nine types. If vaccination were to be combined with HPV screening, which is much more sensitive than the currently used Pap smear test, then eventually the cancer would disappear in those countries that had successfully implemented national programmes. However, this would require political will and effort at both national and European levels.

The current vaccine holds the promise of eradicating approximately 70 to 75 per cent of CC (caused by HPV types 16 and 18), and there appears to be some additional cross protection amongst types that are closely related to 16 or 18, in particular 31, 45 and a part of 33. There are new vaccines being planned that will vaccinate against nine types; if they are successful, there should be no need to screen women that have been vaccinated at all.

The Pap test relies on subjective assessments by people examining the cells in the smear with a microscope and therefore is open to human error. Cuzick believes that such errors will increase as the proportions of smears with affected cells decline due to increasing numbers of women having been vaccinated. In contrast, the HPV test is almost completely automated, is designed to detect the virus in the smear rather than relying on visual examination and therefore is much less likely to be affected by human error. Cuzick commented: "there's overwhelming evidence that HPV screening is more effective than the Pap smear test, which misses about a third to a half of all high-grade lesions". However, Cuzick warned that the EU and national governments should take the initiative in discussions on implementing screening and vaccination programmes, rather than leaving it to pharmaceutical companies to lead the debate.

During the last fortnight, much data have been reported in relation to CC drug and vaccine trials. Of particular note, results from the PATRICIA (PApilloma TRIal Cervical cancer In young Adults or HPV 008) study showed that GlaxoSmithKline's Cervarix is highly effective at protecting against the two most common CC-causing HPV types, 16 and 18. Furthermore, Cervarix demonstrated efficacy against cervical intraepithelial neoplasia 2+ lesions associated with 12 additional HPV types beyond 16 and 18, including HPV 31, 33 and 45.

In addition, Phase I trial results of ADXS11-001 have shown 36-month survival in three of the 13 evaluable patients treated with Advaxis' therapeutic cancer vaccine, which treats women who have already developed CC as a result of HPV infection, indicating the possibility of persistent immune protection. Further, interim safety and immunogenicity data from a Phase I trial of Inovio Biomedical's VGX-3100 showed that the therapeutic CC vaccine was generally safe and well tolerated, plus it achieved significant cellular and humoral immune responses at the lowest dose administered. VGX-3100 is a DNA vaccine targeting the E6 and E7 proteins of HPV types 16 and 18.

Alice Rossiter - Cancer Drug News Editor

New study reinforces Gardasil's safety

An analysis of the adverse events (AEs) reported following distribution of Merck & Co's quadrivalent human papillomavirus (qHPV) recombinant vaccine, Gardasil, since 2006, has indicated that AE rates were consistent with prelicensing data and expected background rates of other vaccines, with the exception of a higher proportion of reports of fainting and blood clots.

Gardasil is the world's first cervical cancer vaccine, which can also help to prevent vulvar and vaginal cancers and genital warts caused by HPV types 6, 11, 16 and 18. In June 2006, the FDA licensed Gardasil for females aged nine to 26 years to prevent infection with genital HPV. Shortly after that, the Advisory Committee on Immunization Practices recommended routine vaccination of females aged 11 to 12 years with three doses of qHPV and catch-up vaccination for females aged 13 to 26 years.

In the new study, published in the 19th August issue of JAMA (2009;302:750-757), the researchers analysed reports of AEs following qHPV immunisation received by the Vaccine Adverse Event Reporting System (VAERS) from 1st June 2006 until 31st December 2008. Additional analyses were performed for some AEs following immunisations (AEFIs) in prelicensure trials, those of unusual severity or those that had received public attention.

During the study period, VAERS received 12,424 reports of AEFIs following receipt of qHPV, an overall reporting rate of 53.9 reports per 100,000 vaccine doses distributed. Of the 8,247 reports that included onset interval, 4,393 (40 per cent) occurred on the day of vaccination. Among 9,396 reports (77 per cent) with dose information, 5,772 (61 per cent) followed the first dose, 2,380 (25 per cent) followed the second dose and 1,183 (13 per cent) followed the third dose of qHPV.

Among the 12,424 AEFI reports, 772 (6.2 per cent) were serious, including 32 reports of death. The reporting rates per 100,000 qHPV doses distributed were: 8.2 for syncope; 7.5 for local site reactions; 6.8 for dizziness; 5.0 for nausea; 4.1 for headache; 3.1 for hypersensitivity reactions; 2.6 for urticaria; 0.2 for venous thromboembolic events, autoimmune disorders and Guillain-Barré syndrome; and 0.1 for anaphylaxis and death. Analysis indicated a disproportional reporting of fainting and blood clot events.

The VAERS database that was the primary source for the study is one of the many mechanisms used to assess the safety of vaccines. Merck also monitors vaccine safety by conducting comprehensive analyses of AEs reported to the company and shares these analyses with the Centers for Disease Control and Prevention (CDC), the FDA, and regulatory and medical authorities around the world to support their efforts. After carefully reviewing all of the information available to Merck about reported AEs, including the findings in the discussed study, the company continues to be confident in the safety profile of Gardasil. While no vaccine or medicine is completely without risk, leading health organisations throughout the world, including the CDC and EMEA, have reviewed the available safety and efficacy information about Gardasil and continue to recommend its use.

Richard M Haupt, head of the Gardasil clinical programme commented: "we will continue our practice of effectively communicating the safety profile of Gardasil, it's a responsibility Merck takes very seriously...Parents should understand the extensive data supporting the safety profile of this vaccine, and we encourage them to look to CDC and FDA, and to the advice of their own physicians, to make an informed choice about something as important as a vaccine to help prevent cervical cancer".

Alice Rossiter Cancer Drug News Editor

Price may prohibit HPV vaccination in developing world

As vaccinations against human papillomavirus (HPV) begin for girls in another western country, this time in Scotland, questions remain about how best to utilise this technology in other world regions. As discussed at the World Cancer Congress, which was held from 27th to 31st August, in Geneva, Switzerland, the development of highly-effective vaccines against HPV and promising new screening tests provide an unprecedented opportunity to tackle the disease in poor countries, where pap smear screening has largely failed because it is too expensive and too complicated to implement.

At present, approximately 80 per cent of cervical cancer (CC) deaths occur in developing countries, and estimates predict that if current trends continue, these regions will face a 75 per cent increase in the number of cases in the next two decades. Presented at the Congress was the first broad analysis of the cost-effectiveness of introducing HPV vaccination and new screening methods into the hardest hit regions of the world, which include Asia-Pacific, Latin America and the Caribbean. The benefits varied, depending on the size and make-up of the population and the burden of CC in each country.

It was determined that in the Asia-Pacific region, which accounts for more than half of the world's CC cases, vaccination would be cost-effective, even in the poorest countries, if the cost per vaccinated girl was between US$10 and US$25. For Latin America and the Caribbean, the cost per vaccinated girl, including delivery and logistics costs, would have to be less than US$25 to be cost-effective for all countries. In the most developed populations in the region, vaccination would be cost-saving if the cost per vaccinated girl is between US$25 and US$60, and cost-effective at higher prices.

According to Professor Francesc Xavier Bosch of the Catalan Institute of Oncology: "Efforts are needed now to adapt the current price of the vaccines so they meet what individual countries can afford; the solution may be tiered pricing according to gross national income per capita and according to the scale of country effort. Currently the vaccine's price in the private sector is approximately US$120 per dose, or US$360 per vaccinated girl. Many countries will need subsidies for some time."

The price of the vaccine and the support for massive vaccination campaigns is one of the biggest barriers for the moment, but several other challenges lay ahead. Those include generating the political support for an intervention whose pay-off is two or more decades away, cultural acceptability of the vaccine and monitoring the circulating virus. Uncertainties that may affect the success of vaccination programmes include the duration of protection and whether booster shots might be needed, and whether the vaccines will be as effective in girls whose immune systems are suppressed by either malnutrition or other chronic infections, such as HIV or malaria.

For the near future, in developing countries, both vaccination and screening will be needed. However, in the beginning, many countries may have to continue to focus on screening alone until the vaccine becomes more affordable.

Matthew Dennis - Editor, Cancer Drug News

UK chooses Cervarix over Gardasil

The Department of Health (DoH), UK, has awarded the contract to provide the vaccine against human papillomavirus (HPV) to GlaxoSmithKline for its product, Cervarix. The contract is to supply the vaccine that protects against cervical cancer (CC) and precancerous cell changes in the cervix caused by HPV. The vaccine will guard against the two HPV strains that cause 70 per cent of cases of CC, types 16 and 18. The vaccine will be made available to girls aged 12 to 13 years from September, while a year later it will also be administered to girls up to 18 years of age in a two-year, catch-up programme.

GSK's CC vaccine is approved in 64 countries worldwide, but this was the first major national tender for which the company had bid. According to Eddie Gray, President of Pharmaceuticals Europe for GSK: "This is great news for girls and women across the UK and reflects the growing confidence in Cervarix, which provides cervical cancer protection with a strong and sustained immune response."

The UK's Joint Committee on Vaccination and Immunisation, which provides independent expert advice to ministers on vaccination, examined a wide range of evidence before recommending in June 2007 that an HPV vaccination programme be routinely introduced for 12 to 13 year old girls. However, this left the DoH to choose between Cervarix and its competitor, sanofi pasteur MSD's (sanofi-aventis and Merck & Co joint venture) Gardasil (quadrivalent HPV types 6, 11, 16, 18, recombinant vaccine), which are both licensed in the EU.

An adjudication was carried out to examine the vaccines offered against a wide range of criteria, such as their scientific qualities and cost effectiveness. The criteria used for the adjudication had been shared in advance with the companies which tendered. Following this process, the DoH selected Cervarix, going against the decision of many EU countries who have opted for Gardasil and the wider protection it offers. Commenting on this, Dr Nicholas Kitchin, UK Medical Director, sanofi pasteur MSD, stated: "We regret that school girls in the UK, unlike most of their peers in Western Europe, the USA, Australia, New Zealand and Canada, will not benefit from the unmatched cervical cancer protection and additional benefits provided by the world's leading HPV vaccine, Gardasil."

Cervarix uses GSK's proprietary AS04 adjuvant as its main differentiating point, which may enhance the immunogenicity of the vaccine, therefore potentially reducing the need for booster shots. However, the long-term efficacy of the two vaccines is believed to be similar.

The key reason for the DoH choosing Cervarix is likely to be price. With a list price for a full course of Gardasil as high as US$375 per person in the US, HPV vaccine costs are a key issue. Although the cost of Cervarix is commercially confidential, it can presently be administered through private clinics at a cost of £130.00 per injection (the immunisation course consists of three injections). GSK may have offered a heavily discounted price, relative to Gardasil, making the DoH’s decision easier. Another factor that must not be forgotten is the fact that GSK is, after all, a British company.

Matthew Dennis - Editor, Cancer Drug News