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The first active immunisations against cancer

The first anti-cancer vaccines were developed to prevent women from becoming infected with papillomaviruses and to protect them against cervical cancer. The development of vaccines can be traced back to the work of Nobel Laureate Harald zur Hausen and his colleagues at the German Cancer Research Centre in Heidelberg. But more development is required in the field of anti-cancer vaccines, and this is why researchers worldwide are working on vaccines that can also be used in developing countries.

Prof. Dr. Harald zur Hausen © German Cancer Research Centre

When Professor Harald zur Hausen was awarded the Nobel Prize in Physiology or Medicine in 2008 for his discovery that human papillomaviruses (HPV) trigger the development of cervical cancer, a vaccine against HPV infections had already been on the market for two years. This vaccine became known around the world as the first "cancer vaccine". Marketed as Gardasil®, the vaccine is produced by the American pharmaceutical company Merck & Co. and is sold in Germany by Sanofi Pasteur MSD, a joint company of Sanofi-Aventis and Merck & Co. In the same year that Gardasil received marketing authorisation, the drug became a blockbuster drug in Germany, achieving a turnover of 267 million euros. 

In 2007, GlaxoSmithKline (GSK) launched its Cervarix® vaccine which also protects women against HPV infections. Both vaccines lead to an immune response through virus-like particles (VLP) consisting of the L1 capsid protein of papillomaviruses. In the case of Gardasil, L1 is produced in yeast, and in Cervarix, it is produced in a baculoviral expression system in insect cells.

Prof. Dr. Lutz Gissmann © German Cancer Research Centre

Both Cervarix and Gardasil contain adjuvants to boost the immune response. The vaccines provide virtually 100 per cent protection against infections caused by HPV types 16 and 18, which are responsible for around 78 per cent of all cervical cancers. Gardasil also protects against HPV type 6 and 11 infections, which cause around 90 per cent of genital warts.

The development of these vaccines is mainly the result of research carried out at the German Cancer Research Centre (DKFZ) in Heidelberg. Professor zur Hausen, virologist and long-term scientific director of the DKFZ, carried out groundbreaking research (which at the time flew in the face of scientific consensus) that led to the discovery of the relationship between HPV infections, in particular those caused by HPV types 16 and 18, and the development of cervical carcinomas. He was awarded the Nobel Prize in Physiology or Medicine in 2008. Professor Lutz Gissmann, head of the Department of Genome Modifications and Carcinogenesis, and Matthias Dürst, formerly also a scientist at the DKFZ and now a professor at the University Hospital in Jena, carried out experiments on VLPs which put in place a number of key prerequisites for the development of HPV vaccines.

The rocky road to success

The fact that in the end the American company Merck and the British company GSK profited most from these discoveries is something that Professor Hausen has often been highly critical about, and was due to the lack of interest the German pharmaceutical industry showed in the vaccine. In order to advance the development of the vaccines, the DKFZ eventually licensed the vaccine rights to the American biotech company MedImmune. MedImmune (now a subsidiary of AstraZeneca) quickly realised the economic potential of HPV vaccines and moved to secure the rights of other research institutions that were working on HPV vaccines, including the National Institutes of Health (NIH) in Bethesda, USA and the Loyola University in Chicago. Merck & Co. acquired the remaining licensing rights from the NIH and from Queensland University, Australia. In early 2005, Merck & Co. and GSK, which by then had also acquired the rights from MedImmune, signed cross-licenses that gave the two companies mutual use of the respective patent rights. Following tough negotiations, the academic institutions involved finally came to an agreement on their patent rights, and the DKFZ emerged as co-owner of the NIH patents and was thus able to receive a share of the turnover from Gardasil and Cervarix.

Human papillomaviruses - electron microscope photo © DKFZ

HPV infections occur usually in young girls as a result of sexual intercourse. The vaccines can prevent infections and hence suppress prestages of cervical cancer. It is recommended that young people be vaccinated before they become sexually active, which is the moment at which they risk being exposed to HPV. However, there is no evidence that the cancer itself can be prevented by the vaccines. "Nevertheless, it is extremely important for women to prevent the development of cancer prestages," said zur Hausen. "In Germany, around 6,500 women contract cervical cancer every year and 1,800 die as a result. In addition, more than 100,000 surgical interventions are undertaken following smears that indicate the presence of cancer prestages. It is believed that many of these surgical interventions could be prevented.

The vaccination is recommended for girls and young women between nine and 26 years of age. Zur Hausen also strongly recommends vaccinating boys and young men who, although they do not develop this cancer, also have a responsibility to help prevent the development of cervical cancer in women as they pass on the HPV viruses to women during sexual intercourse.

Incorrect treatment of figures and risks

According to information provided by the Robert Koch Institute, approximately 7.5 million units of HPV vaccines had been used in Europe up to September 2009. In the same period in the USA, 23 million young women had been vaccinated against HPV. The vaccinations created an uproar in the media following the deaths of two women in Germany and one in Great Britain who had been vaccinated against HPV. Some scientists and doctors also raised concerns that the vaccination was far too risky. This is a typical case of “muddled thinking when looking at figures and risks” (G. Gingerenzer: Das Einmaleins der Skepsis, BvT Berlin 2004, p. 43f.), which unfortunately often occurs in so-called experts. Due to the high number of vaccinations, it is statistically both predictable and inevitable that deaths occur due to unknown causes. Unfortunately, when the media has the bit between its teeth, it is difficult to come up with a counter-argument, which was the situation the Robert Koch Institute found itself in, despite being at great pains to explain that there was no noticeable relationship between the deaths and the vaccination and that the HPV vaccines are as safe as the tetanus, diphtheria and hepatitis B vaccines that have been used for many decades. “The discussion has lead to unnecessary uncertainties in the wider public. The vaccination rate has decreased from 38 to 33 per cent. I think this is a genuine catastrophe because young girls who are not vaccinated against HPV run a greater risk of developing cervical cancer in later life,” said Harald zur Hausen.

Further developments and plans

Although Gardasil and Cervarix have been approved for the vaccination against HPV infections, there remain a number of unsolved issues regarding vaccinations that protect against cervical cancer. For example, the price (approximately 450 euros for a triple vaccination in Germany) is far too high for women in developing countries, where the majority of the 500,000 infections and 270,000 deaths occur every year. Production costs could be greatly reduced by using simpler capsomeres consisting of six subunits of the antigen instead of the virus-like particles that are currently used. Tests have shown that the capsomeres, which in contrast to VLP can be produced in bacteria, trigger a sufficient immune response.

However, whilst there is huge need for vaccines that are cheaper, there is an equally huge need for vaccines that are also easier to handle. In many countries cool storage of the vaccines cannot be guaranteed. In addition, it would be preferable to avoid the use of needles for injections as their repeated use generates the risk of transmitting infectious diseases. Scientists at the DKFZ are working on a novel vaccine that can be taken up through the nasal mucosa. The researchers have incorporated the L1 capsid protein of HPV into adenovirus-associated viruses which do not transmit diseases, but instead are able to trigger an immune response against papillomaviruses. Since adenovirus-associated viruses can be freeze-dried and hence do not require cooling, they are particularly suited for use in developing countries.

Another major goal being pursued by researchers at the DKFZ, is the development of a therapeutic vaccine that can prevent the development of cancer as well as treat cervical cancer prestages (so-called precanceroses). This vaccine can be used in women who are already infected with HPV since it not only protects them against the development of cervical cancer but is also able to treat precanceroses. The researchers are also planning to increase the range of the therapeutic use of the vaccine to other papillomaviruses. Ideally, this would involve a vaccine that would provide protection against all of the 112 different types of papillomavirus and hence also protect against viruses that potentially lead to the development of cancer.

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