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HPV vaccine: the first cancer vaccine

MEDICAL REPORT

The cells marked with arrows are infected with human papilloma viruses, recognizable by the light halo around the cell nucleus. Photo: Roche
The duration of action of the vaccine for the prevention of cervical cancer, in the development of which researchers from the German Cancer Research Center played a key role, is five years.

A long-cherished dream of cancer researchers has now come true. The first cancer vaccine recently hit the US market. The vaccine is directed against the most important cancer-causing viruses in cervical cancer, the human papillomaviruses HPV 16 and 18. According to the results of extensive studies, it can protect against cervical cancer in 70 percent of all cases. It also prevents infection with the low-risk types HPV 6 and 11, which are responsible for 90 percent of all genital warts.
The development of the vaccine is a success story, in which there were, however, some hurdles to be overcome. The fact that this story can be written is based primarily on research work by the scientists around the virologist Prof. Dr. med. Dr. H. c. mult. Harald zur Hausen (Heidelberg), the longstanding scientific director of the German Cancer Research Center (DKFZ) in Heidelberg. They were able to prove that cervical cancer is actually caused by viruses and thus laid the foundation for vaccine development. The first vaccine approved on the market from the pharmaceutical company Sanofi Pasteur MSD called “Gardasil®” was recently presented at the DKFZ.
Zur Hausen described the path from conjecture to knowledge. Epidemiological studies had long suggested that a pathogen transmitted through sexual intercourse could be responsible for the development of cervical cancer. However, the known pathogens of sexually transmitted diseases examined did not have the oncogenic potential.
At the end of the 1960s, the researchers then came to the fore: In the zur Hausens working group, it was possible for the first time to detect the genetic makeup of the Epstein-Barr virus in fresh tumor material, including Burkitt's lymphoma. In the case of cervical cancer, intensive searches were initially carried out for the herpes simplex type 2 virus because American researchers had postulated a connection: “Completely unsuccessful,” recalls zur Hausen.
An extensive literature search put the virologist on the right track. He found reports that genital warts, albeit rarely, can become malignant. The human papilloma virus (HPV) was already known to cause these warts. The researchers speculated that the wart virus might also have something to do with cervical cancer.
Since the early 1970s, scientists have been working on this group of viruses, which turned out to be extremely heterogeneous, as Lutz Gissmann, a PhD student at the time, first discovered. Between 1980 and 1982 he succeeded in isolating the genital wart viruses. It was disappointing that these viruses were hardly or not at all found in the tumor material of the cervical carcinoma.
A little later, the main cause of this world's second most common type of cancer in women was found in the Freiburg research group at Hausens: HPV 16 was responsible for half and HPV 18 for about a fifth of these tumors.
In the following years, Zur Hausen's colleague Elisabeth Schwarz at the DKFZ found out that the HPV-DNA is incorporated into the genome of the cell in a characteristic way and that two genes of the virus, E6 and E7, are active in the cells of the cervix. Magnus von Knebel-Doeberitz from the laboratory showed that the activity of these two genes is actually responsible for the malignant growth of the cells. Frank Rösl from the research group found out why some of the HPV-infected cells do not transform into malignant cells despite the activity of the oncoproteins E6 and E7.
Normally cells in which proliferation is induced go into apoptosis. Malignant transformation occurs only when mutations accumulate through the action of E6 and E7, which are compatible with cell survival. “This also explains why cervical cancer is only a rare consequence of this extremely common viral infection,” concludes zur Hausen. It is also the reason for the long period of time until malignant degeneration.
Industry disinterest
If viruses are so involved in the development of cancer, it should be possible to develop a vaccine against it. In 1984 zur Hausen approached German pharmaceutical companies with this idea, but met with little enthusiasm. The etiology of cancer is too unclear and there is probably no good market for a vaccine. American companies later took up this idea. Zur Hausen regrets that about five years have been lost in vaccine development.
How do you activate the immune system to prevent HPV infection? This question was at the beginning of the vaccine development, recalls Prof. Dr. rer. nat. Lutz Gissmann, today's head of the genome changes and carcinogenesis department at the German Cancer Research Center. The course of infection with papilloma viruses in dogs, rabbits and cattle gave the clue. It has been shown that so-called neutralizing antibodies, which recognize three-dimensional structures on virus particles, can prevent infection.
How can the human immune system be made to produce such neutralizing antibodies? That was the next question. The classic way of vaccine production - the inactivation and reproduction of infectious viruses - could not be followed because papilloma viruses do not reproduce well in cell cultures.
So you had to use genetic engineering to get a recombinant vaccine. Virus-like particles (VLPs) were encountered: "These virus proteins assemble into a structure that corresponds to the protein capsule of the virus, but is" empty ", explained Gissmann. Because of this property, the VLPs turn out to be ideal for a vaccine: Due to their identical structure, they are perceived by the immune system as an infectious virus, but they are not: They are immunogenic, but not infectious.
In 1992 the first papilloma virus VLPs were made public. The breakthrough came a year later when Gissmann, in cooperation with American researchers at the National Institute of Health (NIH), was able to show that only one specific virus protein, the L1 gene of the "high-risk virus type" HPV 16, is capable of producing large amounts of Form VLPs. After initial problems with copyright, the patent rights to the gene were finally awarded jointly to the DKFZ and the NIH. This created the basis for the now approved vaccine, and the pharmaceutical companies stepped in.
The vaccine developed by Sanofi Pasteur MSD was first approved by the US Food and Drug Administration in June and is now available in the US and Mexico. As Prof. Dr. med. Peter Hillemanns (Director of the Department of Obstetrics and General Gynecology at the Hannover Medical School), the safety and effectiveness of the vaccine were already shown in the phase II studies and now in the phase III studies (Villa LL et al. ; Lancet Oncol 2005, 6 [5]: 271–8) convincingly proven with more than 25,000 test subjects. Hillemanns explicitly discussed the results of a phase III study on the effectiveness of the tetravalent vaccine Gardasil with 5,455 women in the age groups between 16 and 23 years (Villa LL et al .; Eurogin Congress, Paris 2006; SS 15–2: 106 ). The end point was the occurrence of HPV 6/11/16/18 induced cervical dysplasia (CIN) and genital warts. The women were followed up after a mean follow-up of 20 months with HPV smear, cytology and biopsy.
Not a single dysplasia was seen in the 2,240 vaccinated volunteers. There were 37 in the placebo group. External genital lesions, such as genital warts and dysplasias on the vulva and vagina, were also 100 percent prevented by the vaccination. In contrast, 40 lesions were seen in the placebo group. The three vaccinations (day one, month two and six) were tolerated very well. In 90 percent there was only a local reaction at the injection site with pain and redness. A fever occurred in ten percent of the cases.
Hillemanns emphasized that the vaccination is only indicated for the prevention of papillomavirus infection. Existing dysplasias could not be influenced by this. The proven duration of action of the vaccine is five years. A follow-up study in Scandinavia will examine whether a booster vaccination might be necessary.
According to Hillemanns, the introduction of a comprehensive vaccination - up to 70 percent of all men and women go through an HPV infection at some point - could prevent numerous interventions in precancerous stages. 50,000 conizations are carried out in Germany every year. The vaccination does not make the early detection examination with cervical swab superfluous, warned the gynecologist. The danger then is that undiscovered dysplasias will appear that cannot be eliminated by the vaccination.
With the European approval of the vaccine by the EMEA, according to Dr. med. Erika Harzer (Sanofi Pasteur MSD) expected at the beginning of next year. The peak exposure to the virus would be between 15 and 17 years of age when sexual activity sets in. The ideal time to vaccinate would therefore be the beginning of puberty. In order to implement this, cooperation and the commitment of different specialist groups are required, such as paediatricians, gynecologists and general practitioners and family doctors. In their opinion, the best option would be to implement the HPV vaccination as part of a program similar to the rubella vaccination.
Developing countries need vaccine most
Every year around half a million women develop cervical cancer worldwide, the majority of them in developing countries. In Europe the new disease rate is 33,500, in Germany 8,000 women per year. After breast cancer, cervical cancer is the second leading cause of cancer-related death in Europe among young women under the age of 44: In 2002, 14,638 women died in Europe. The infection rate with HPV is high in sexually active people, but in the vast majority of cases it is eliminated again by the body's own defenses. About ten to 20 percent have persistent infections and cervical lesions of varying degrees. Cervical cancer ultimately only develops in one percent of cases, explained Gissmann.
According to zur Hausens, the problem of a nationwide vaccination strategy lies less in the western industrialized countries than in the countries of the third world. Due to the lack of early detection programs, cervical cancer is three to four times more common in countries such as Africa, India and Thailand. He appealed to the manufacturing companies to consider how the prices for the vaccine could be reduced in the long term. Possibly new ways of vaccine production would have to be found that would make it financially possible to use these vaccines in developing countries.
The triple vaccination currently costs $ 360 in the US. According to the company spokeswoman, the price in Europe will be around 300 euros. Ingeborg Bördlein


Epidemiology of the human papillomavirus

Human papilloma viruses (HPV) are the most common causative agents of sexually transmitted viral diseases worldwide. The most common clinical manifestation of sexually transmitted HPV infections are benign genito-anal warts. In the United States and Europe, genito-anal warts are found in approximately one percent of sexually active adults between the ages of 15 and 45.
Latent HPV infection with only laboratory detection of viral DNA without clinical, histological or cytological abnormalities is found in around ten percent of sexually active people. The proportion of HPV antibody positive people is estimated at 60 percent of the population. The detection of antibodies is indicative of a previous or current infection with HPV.
The incubation period of genitoanal warts is very variable from at least four weeks to several months. Accompanying circumstances such as balanitis, weeping eczema, discharge and edema as well as malformations can promote the infection with HPV.
The most important independent risk factor is the number of sexual partners during life. Other sexually transmitted diseases such as HIV infection, genital herpes, syphilis and infection with Chlamydia trachomatis can have an influence on the course and also on the treatment of genital warts. An important cofactor is cigarette smoking. Drugs such as cannabis, cocaine and immunosuppressive drugs also play a role.
Source: AWMF online
HPV vaccine: the first cancer vaccine

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