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Papillomaviruses as cancer-causing agents and how they can be fought off

Studies presented at the recent International Papillomavirus Conference in Berlin demonstrate that vaccination can prevent infection with the types of HPV that cause the majority of cervical cancers. New improved vaccines to prevent HPV infections as well as therapeutic vaccines that are effective in people that are already infected are currently being developed. In addition, research has shown that other cancers can also be caused by infective factors.

Prof. Dr. Harald zur Hausen © DKFZ

When Professor Dr. Harald zur Hausen participated in the first ever conference on human papillomaviruses in Paris in 1975, only around 20 scientists were present. Around 40 years later, more than 2000 scientists from more than 80 countries attended the 27th International Papillomavirus Conference in Berlin in September 2011 (according to the official figures, although the actual number was slightly higher). In 1973, Harald zur Hausen, honorary president of the Berlin conference, presented his hypothesis which stated that human papillomaviruses (HPV) were the causes of cervical cancer. Although zur Hausen’s hypothesis was refuted by many people at the time, it has long since been accepted by the international science community, well before he was awarded the Nobel Prize in Physiology or Medicine in 2008.

Current debate relates mainly to other tumours that can also be caused by infectious agents such as viruses and bacteria. Zur Hausen estimates that around 20 per cent of all tumours are caused by viral and bacterial infections: the Epstein-Barr virus (EBV) is best known as the cause of infectious lymphomas, but there is also evidence that it is the cause of around 10 per cent of gastric carcinomas; the human herpes virus 8 (HHV-8) causes Kaposi’s sarcoma; hepatitis B and C viruses lead to liver cancer; Helicobacter pylori is a bacterium that causes gastric cancer. It is not yet known whether infectious factors also play a role in the development of colorectal cancer, pancreatic cancer, lung cancer in non-smokers and breast cancers that develop in pre-menopausal women.

Papillomavirus and skin cancer

At the conference, Professor Dr. Lutz Gissmann, Head of the Department of “Genome Modifications and Carcinogenesis” at the German Cancer Research Center (DKFZ), presented the latest research results that suggest that certain papillomaviruses are also involved in the development of cancer that results from over-exposure to UV. Working in cooperation with a group of researchers led by Massimo Tommassino in Lyon, the researchers from Heidelberg discovered epidermal skin growth (papillomas) in mice transfected with the E6 and E7 genes of beta-HPV, which developed into precancerous lesions and eventually into malignant squamous cell carcinoma (“white skin cancer”) when the genetically modified animals were exposed to UV radiation. Control animals exposed to the same UV radiation dose did not develop any skin alterations. The genes E6 and E7 in HPV 16 and HPV 18 (two HPV types that cause around 70 per cent of all cervical cancers and are closely related to the beta-HPV group of viruses) lead to the reactivation of DNA synthesis that is normally switched off in infected cells, thereby enabling the virus to propagate and turn the infected cell into a cancer cell, explained Gissmann.

Prof. Dr. Lutz Gissmann © German Cancer Research Centre

However, the researchers also found that viruses involved in the development of skin cancers caused by over-exposure to UV play a different role in the development of cervical cancer. It is far more difficult to demonstrate that beta-HPV is the cause of skin cancer than it is to show that HPV 16 and 18 are the causes of cervical carcinoma (this was already proven around 25 years ago). The researchers assume that the development of cancer no longer depends on the activity of the viral E6 and E7 genes once a “point of no return” has been reached.

Back in the 1970s, Lutz Gissmann and Harald zur Hausen isolated human papillomaviruses that cause warts on the hands and genitals as well as cervical carcinoma. In the early 1990s, Lutz Gissmann and Matthias Dürst worked with scientists from the National Institutes of Health to successfully produce large amounts of the viral L1 capsid protein using genetic engineering methods. This protein is the basis for prophylactic papillomavirus vaccines used against cervical cancer.

Vaccination is effective

Two HPV vaccines, Gardasil (approved in 2006) and Cervarix (approved in 2007), are currently on the market. Both vaccines provide almost 100% protection against the two types of HPV, HPV-16 and HPV-18, that cause 70% of cervical cancers. However, Gardasil and Cervarix are preventive vaccines and must be applied well before any HPV infection. It is therefore recommended that young women are vaccinated prior to their first sexual contact, as HPV is primarily sexually transmitted. German health insurance companies also pay for the vaccination in 12- to 17-year-old girls.

From 2007, the Australian government has been giving the human papillomavirus vaccine Gardasil free to all women and girls aged between 12 and 26 through the National HPV Vaccination Programme. Results have now demonstrated that the vaccination is effective and that initial doubts were the result of misunderstandings. In fact, the appearance of high-grade cervical lesions (precancerous stages) decreased by around 60 per cent in girls under 18 shortly after the programme started. The vaccination was most effective in the youngest age group who were vaccinated prior to their first sexual contact.

Of course, not enough time has elapsed since the programme was started to be able to show whether the vaccination also reduces the number of cases of cervical cancer. Cervical cancer takes around 15 years to manifest itself. In their speeches, Gissmann and zur Hausen also responded to critics who have claimed that the efficacy studies performed prior to the introduction of the vaccination programmes “only” proved the efficacy of the vaccines against pre-cancer stages, not against cervical carcinoma, as the study period was not long enough for cervical cancer to develop. Gissmann and zur Hausen explained that a placebo-controlled clinical trial must not go beyond the stage of precancerous lesions; they considered it unethical not to treat women in the control group who had developed such precancerous signs.

Call for a vaccination for boys

In contrast to Australia and Great Britain, only around 30 per cent of 12- to 17-year-old girls in Germany have received preventive HPV vaccination; the number is even lower in Austria where only 5 per cent have been vaccinated. For Harald zur Hausen this situation is lamentable given the large number of non-vaccinated women who will develop cervical cancer. Zur Hausen is tireless in his efforts to convince others of the need to extend vaccinations to boys and young men, a move that would make protection against cervical cancer even more effective. Both men and women are carriers of HPV and the viruses can be transmitted to women by men. Unfortunately, health insurance companies do not reimburse the costs of vaccination for boys and young men.

Electron microscope image of human papillomaviruses © DKFZ

Gardasil is a tetravalent vaccine that provides protection against the two high-risk HPV types HPV-16 and HPV-18 and against HPV-6 and HPV-11 that cause 90 per cent of genital warts. The work being done by Dr. Anna Giuliano and her colleagues at the Lee Moffitt Cancer Center in Tampa, Florida, also attracted a great deal of interest. Speaking in Berlin, Giuliano reported that Gardasil is also effective in protecting boys and young men from genital warts and virus-related precancerous genital lesions. Dr. Giuliano talked about a major study in which she analysed the high rate of new HPV infections and the prevalence of HPV in men. “The vaccination of boys has a dual advantage,” explained zur Hausen. “Men who have been vaccinated cannot infect their female partners, and the vaccination also protects men against cancers of the genital and anal regions. Of course, the preventive vaccines only protect against HPV infection if they are administered before an HPV infection has occurred.”

Next-generation vaccines

Research institutions and companies are working hard to develop new, more effective vaccines. Merck & Co. are developing a successor to Gardasil, which is a nonavalent vaccine that targets the four HPV types 6, 11, 16 and 18 as well as five other HPV types. The developers of these vaccines are aiming to increase the rate of effective protection from 70 per cent to 87 per cent. GSK’s bivalent Cervarix vaccine is combined with an excellent adjuvant (to enhance the immune response) and has shown effective cross-reactions with other HPV types. PD Dr. Andreas Kaufmann, Head of the Department of Gynaecological Tumour Immunology at the Charité in Berlin, believes that the development of such adjuvants contributes to the promising future of vaccine development.

Kaufmann also talked about an interesting new development approach to vaccines, based on the L2 capsid protein, a smaller protein than the L1 protein, the major component of the viral capsid. L2 has been shown to play a key role after the initial binding of the virus to the cell. It can only be detected by the human immune system during the process of infection as it is otherwise completely obscured by the much larger L1 protein. The advantage of L2 is that it displays little antigenic variability in the different HPV types known, which is why the vaccine is able to provide protection against a broad range of different types of virus. In addition, an L2-based vaccine can be produced in bacterial cell cultures and its production therefore costs less than the production of L1-based vaccines. The new vaccine, which is already being tested in clinical studies, therefore has the potential to be used for vaccination campaigns in Africa where women with cervical cancer are in dire need of treatment.

All the HPV vaccines that are currently available only have a preventive effect. Many research groups around the world are working on the development of therapeutic vaccines for women who are already infected with HPV. Such a vaccine, which might for example induce the human immune system to recognize and destroy virus-infected malignant cells, is of utmost urgency in countries such as Germany where cervical cancer will continue to be a frequent cancer, particularly given the limited number of women and girls who are given preventive vaccinations. The Dutch Professor Cornelis Melief from the University of Leiden delivered a keynote lecture on a therapeutic vaccine that consists of 13 different protein fragments (peptides) of the E6 and E7 HPV-16 oncoproteins. Precancerous vulva lesions have already been successfully treated with this vaccine. The therapeutic vaccine is already undergoing clinical testing. PD Dr. Dr. Angelika Riemer from the German Cancer Research Center in Heidelberg is pursuing a different approach to therapeutic HPV vaccines for the treatment of precancerous lesions of the cervix for which she has received generous funding from the Manfred Lautenschläger Foundation. However, it will be many years before a vaccine of this kind will be available on the market.

All the experts who participated in the recent conference agreed that it makes no sense at all to wait until new HPV vaccines reach the market in a few years’ time. They were convinced that currently available vaccines provide effective protection against the majority of cancer-causing papillomaviruses when they are applied early and correctly and that they are tolerated as well as any other vaccine. Adverse side effects have only been reported in one out of 100,000 vaccinated women.

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