A Critical Analysis of HPV Vaccination in Children

Worldwide, infection with HPV viruses is the most common sexually transmitted disease. The prevalence of HPV infection varies considerably from country to country and can change significantly with changes in lifestyle and sexual behavior. Every year, about half a million women worldwide develop cervical cancer, with up to four-fifths of them from developing countries. The lack or underutilization of cancer screening programmers in developing countries plays a decisive role in this. It is estimated that around 230,000 women worldwide die of cervical cancer every year [1].


Introduction
Worldwide, infection with HPV viruses is the most common sexually transmitted disease. The prevalence of HPV infection varies considerably from country to country and can change significantly with changes in lifestyle and sexual behavior. Every year, about half a million women worldwide develop cervical cancer, with up to four-fifths of them from developing countries. The lack or underutilization of cancer screening programmers in developing countries plays a decisive role in this. It is estimated that around 230,000 women worldwide die of cervical cancer every year [1].
In Central Europe, cervical cancer is the eleventh most common cancer among women of all age groups. It is the second most common malignant tumor in women under 45 years of age, but accounts for only 3.2% of all cancers and 1.8% of all cancer deaths in women. A multifactorial cause is propagated, whereby primarily proteins and genome parts of different HPV viruses but also other cofactors such as a young age in initial diagnosis, immunosuppression, smoking and co-infections with herpes simplex virus and infections with chlamydia play a not insignificant role. The long latency between HPV primary infection and cancer suggests that the other factors such as sexual behavior, genetic predisposition, nutritional status and social educational status may have an influence.

Etiology and Pathogenesis of Human Papilloma Virus Infection
The papillomavirus is a virus particle about 55 nm in size that includes a double-stranded circular viral genome of 7904 base pairs. HP viruses belong to the Papovavirus family and have an icosahedral protein capsid. There are approximately 100 different HPV types that can infect both the skin and mucous membranes.
In the area of the uro-anogenital tract about 40 different HPV types come to the fore, which are divided into 2 groups. The lowrisk HPV types have a low potential to cause a malignant disease.
High-risk HPV types have a high oncogenic potential. In Europe, the infection rate without clinically relevant change is between 16-33 million people/year. Infection with human papilloma viruses is one of the most common sexually transmitted diseases worldwide.
Approximately 70% of all people have been infected with genital HPV at least once during their lifetime.
Women generally become infected between the ages of 20 and 30, with one in three women showing HPV two years after their first sexual contact [3]. HPV causes persistent infections of the uterus with an increased risk of developing precancerous precursors (CIN). In general, the time span between primary infection and cancer development can be up to 20 years or longer, whereby the incidence of cervical cancer is significantly increased from the age

Molecular Biology and Oncogenesis of HPV Infection
The hullless virus has a simple structure and is divided into an early region, which performs regulatory functions, and a late region, which encodes two structural proteins. The capsid of the virus consists of 80% structural protein L1 and 20% capsid protein L2. In the "early region" there are 6

Risks of HPV Infection
High-risk HPV types 16 and 18 are considered responsible for about 70% of all cervical cancers in women worldwide [6]. 55.3% of all cervical precancerous lesions of severity CIN 2 and 3 were associated with HPV 16 in 2 studies, 6.4% with HPV 18, HPV 45 in 8.5% and HPV 31 in 6.4% of cases [7]. In 2005 the WHO classified the HPV types 16,18,31,33,35,39,45,51,56,58,59 and 66 as carcinogenic [8]. the so-called low-risk HPV types 6 and 11 are responsible for the development of over 90% of genital warts. Genital warts are the most common viral sexually transmitted disease worldwide.

Frequency, Age Distribution and Course of Cervical Cancer
In Germany, about 6200 women develop cervical cancer. With 1700 deaths, cervical carcinoma was not one of the most common cancers with 1.8% of all cancer deaths and not one of the most frequent causes of cancer deaths in women. In the incidence statistics it is currently only in 11th place. This actual state is the result of an effective early detection programme. The comparatively low incidence of cervical cancer is accompanied by a much higher incidence of found dysplasias. The EUROCARE-4 study published in September 2007 calculated a relative 5-year survival rate for invasive cervical cancer.

Early Detection Possibilities-Benefits and Risks
Since the introduction of the cytological examination of cervical smears for the early detection of cervical cancer and its precursors (Pap test) at the age of 20 years at the beginning of the 1970s, the incidence of invasive carcinomas in Germany has decreased by about two thirds. The Pap test is a very successful and effective secondary preventive measure against cervical carcinoma. In countries such as England, Sweden and the Netherlands, screening is much better organised and therefore more effective, with a 90% reduction in the risk of cervical cancer among participants [9]. In countries without appropriate cancer screening programs, cervical cancer contributes significantly to cancer mortality.  and 58 [17][18][19].

Efficacy Aspects of The Bivalent Vaccine (Cervarix)
Cervarix is a bivalent vaccine effective against HPV 16

Up-To-Date Data on Security and Effectiveness
According to the data available so far, a follow-up of up to 6.4 years for women who were not infected with the highly carcinogenic HPV types 16 and 18 at the time of vaccination, almost 100% protection against cervical dysplasias induced by these two HPV serotypes was found. This fact is supported by a current German HPV vaccination guideline and a systematic review of 6 randomized trials with over 40000 women and girls aged 15 to 26 years to investigate the efficacy of the vaccines confirmed [21][22][23]. About the effectiveness of the vaccination against HPV 16 and 18, the study situation is increasingly consolidating. Looking at all randomized studies carried out so far, the mean observation period was 3 years, in one study 5.5 years [24] and 6.4 years [21] respectively.
During this period, the vaccination fully met expectations. This is confirmed by the systematic review of Rambout [23].
In women who were tested negative for HPV 16  So far, only a reduction of the obligatory precancerous stages has been proven in studies. It is completely unclear how long the vaccination will last. Evidence of protection lasting beyond 5 years was provided by results after renewed administration of Gardasil after 5 years; this "antigen challenge" led to a renewed increase in antibody titres within one week.

Boys and HPV Vaccination
Boys aged 9-15 years developed immunity after vaccination.
The quadrivalent vaccine was judged effective in a study of 4065 boys and men aged 16-26 years [26]. The aim is to provide a protective vaccine to prevent anal and penile cancer, which is also associated with HPV infections.

Vaccination Research
Various key questions are at stake in the research of new vaccines against HPV: There are more than 100 different types of HPV. Which HPV types have clear oncogenic potential in the development of cervical cancer has not yet been fully clarified.
An oncogenic potential is known in about 15 HPV types. A crossprotection is discussed. The prevalence of HPV infections and the spread of different HPV types varies considerably geographically [27]. HPV 16 types and HPV 18 types are most frequently detected, with 85% being found in women with adenocarcinoma [28]. In a quarter of invasive cervical cancer cases, 16 HPV types other than 16 and 18 are detected.
The distribution of these 16 HPV types shows a considerable geographical variation. If critical epidemiological data are analyzed, a bivalent HPV vaccine with HPV 16 and 18 in Europe protects 71% against cervical cancer; however, depending on the geographical location, this protection may be higher or lower (74% in Asia, 64% in parts of Africa) [29]. Ultimately, the goal should be to develop a multivalent vaccine that includes all HPV viruses with oncogenic potential. For example, a vaccine containing the most common 7 oncogenic HPV viruses 16,18,45,31,33,52 and 58 would provide up to 85-91% cervical cancer protection (depending on geographical location) [29]. Although technically feasible, the production of a multivalent HPV vaccine is currently extremely difficult, not to mention the significant production costs.

Cost Aspects of HPV Vaccination
Some studies conclude that HPV vaccination is cost-effective [17,30,31]. In Germany, a single injection costs approximately Since 2002, the pharmaceutical "vaccine industry" has experienced rapid growth. In 2002, the turnover of pharmaceutical companies in the USA from HPV vaccination was 135 million dollars, in 2012 it was already 1.4 trillion dollars [33]. Even Nobel Prize winner Professor Harald zur Hausen [34] has pointed out at every opportunity that the vaccine is too expensive. This is particularly true in developing countries, where cervical cancer is partly the most common cancer in women [30]. In Kenya, the vaccine costs about half an average annual income [35,36]. In developing countries, where cervical cancer is by far the most prevalent, vaccination is an almost unrealizable cost factor for the population. Severe was defined as a condition that leads to hospital admission, a life-threatening condition, or a serious illness, an irreversible disability or death. For example, cases of Guillain-Barre syndrome (the synonym "Gardasil-Guillain Barre syndrome" is frequently used due to its frequency), thromboses and deaths have been reported in close temporal connection with vaccination. Unexpectedly, no causal link between the vaccination and the disease was found [37]. The US consumer protection group "Judical Watch" had already published a first list with 1637 reported side

Demand for Re-Evaluation of HPV Vaccination
In November 2008, scientists from various German research institutions called for the HPV vaccine to be re-evaluated on the grounds that its efficacy could be significantly lower than assumed [39,40]. In a re-evaluation of the Robert Koch [41] Institute on 10 August 2009, the vaccination was still recommended. However, information media that give the impression that HPV vaccination provides 100% protection against cervical cancer were currently considered to be dubious [41]. In Germany, the initial euphoria of HPV vaccination has quickly subsided. At present, the vaccination rate should be below 30%. In June 2011, vaccine manufacturers cheered for an Australian study showing a significant decrease in cervical cell changes in HPV-vaccinated 17-year-old girls [42].
However, cheers drowned out that this effect was not detectable in the 18-year-old girls who had also been vaccinated [42]. In addition, the current data do not show any efficacy in girls and women already infected with HPV. One study even suspected that vaccination could promote the development of cell dysplasia in women already infected with HPV types 16 and 18 [38]. Therefore, vaccine manufacturers and authorities recommend vaccination only before first sexual contact. In France, the French Ministry of Health recommended that virginity be checked before vaccination.
Clinical efficacy studies with girls before and during sexual maturity have not yet been carried out -manufacturers are content with the less meaningful detection of antibodies in the blood in the months following vaccination. The STIKO recommendation to vaccinate all girls before their first sexual contact is therefore on a shaky footing and is not evidence-based. These data should be available if an insufficiently studied vaccine is publicly recommended for half of the adolescent population.

Conflicts of Interest
The European Cervical Cancer Association (ECCA) is funded by more than 50 percent by vaccine manufacturers Sanofi Pasteur, Roche, and Glaxo Smith Kline. The German Cancer Research Centre is co-owner of the cervical vaccine patents. This means that virtually every instance/person who has approved or recommended the vaccination can derive financial benefit from each individual vaccination.

Conclusion
HPV vaccination must be critically evaluated for various reasons. The approval of Gardasil was based in advance on 4 studies, for Cervarix [14] only on one phase III study. This was not enough for a meaningful assessment of the clinical benefit [43]. The clear evidence of protection against cervical cancer is not conclusive, only in cervical cancer precursors. The regulatory authorities have accepted CIN II, CIN III and Carcinoma in situ as surrogate parameters when investigating the efficacy of the potential cancer precursors. Vaccination is currently being carried out with vaccines whose clear efficacy against cervical cancer is not sufficiently known. There are no long-term studies. It is assumed that the development of cervical cancer takes 15-30 years [44].
Studies from currently only up to 6.5 years are not able to show any clarity. The protection is very often proven and determined by the level of the antibody titre; whether the level or the presence of high antibodies against HPV protects absolute protection against the development of cervical cancer is rather questionable.
In summary, it can be said: There is not yet enough knowledge available on long-term side effect risks. Cervical cancer can be adequately controlled by safer sex (good protection against risk HPV) and effective screening programmes. Its incidence has been declining for years. The vaccine is genetically engineered. What consequences it has for vaccinated people is unclear. Genetically engineered vaccines penetrate the cell material and alter it. What consequences this has for our offspring is unclear. So far, no direct causal connection has been shown that would prove that the cause of cervical carcinomas is HP viruses. Even the NCI, the National Cancer Research Institute in the USA, admits this. It is only known that factors such as the long-term use of oral contraceptives and the number of births, as well as genetic changes, smoking or an acquired immunodeficiency promotes tumor development [45][46][47].
It is unknown how long the vaccination protection lasts with both current vaccine alternatives. No study provides evidence for lifelong immunity; one study proves protection for at least 5 years. In this context, the question of a "booster vaccination" will become an issue. It is unknown how the vaccine will be effective.
No study provides evidence of lifelong immunity; one study proves protection for at least 5 years. In this context, the question of a "booster vaccination" will become an issue. It is unknown how the vaccination affects the distribution of the other HPV types. It is unknown whether HPV 16 and 18 are increasingly replaced by other HPV types that can also have a carcinogenic effect. The vaccination creates a "sham safety" because it reduces the motivation for the early detection examination and for limiting further risks (e.g. smoking).
It is not known how the vaccination works if an infection with HPV has already occurred. It is possible that the vaccination has aggravating effects if the virus infection has already occurred but is still without symptoms. The vaccination may change the character of the other virus types not reached by the vaccination. The consequence of this situation is unknown. It is not known whether the result will be an advantage or an increase in risk. HPV vaccines are extremely expensive. Extending the early detection programme without vaccination would save high costs for the health care system, which could be invested elsewhere in social projects. Health policy is not always rational. An objective, wellfounded and balanced information of the population about benefits and limitations of HPV vaccination is desirable but probably not feasible.