HPV vaccine

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Genital warts caused by HPV

HPV vaccines protect against certain types of sexually transmitted human papillomavirus (HPV) by building up immunity and thus serve to prevent cancer . The World Health Organization recommends that all countries include HPV vaccination in their national immunization programs, the HPV vaccine is on the World Health Organization's list of Essential Medicines . The high-risk HPV types 16 and 18 are responsible for around 70% of all cervical cancer cases worldwide . According to the Robert Koch InstituteIn 2014, 1,506 women died of cervical cancer in Germany. The papillomaviruses type 6 and 11 are primarily responsible for the development of genital warts (genital warts). Three HPV vaccines are currently approved: a double vaccine that is only effective against HPV types 16 and 18, a quadruple vaccine that is directed against HPV types 6, 11, 16 and 18, and a nine- fold vaccine - Vaccine that protects against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. The effectiveness of the quadruple vaccine in preventing the precursors of cervical cancer caused by the corresponding HPV types was 98 to 100% in clinical studies for subjects who were not previously infected with HPV.

The vaccines are only preventive ( prophylactic ). It cannot treat existing infections. According to the current state of knowledge, HPV vaccines are well tolerated and safe. The most common adverse effects are local reactions such as redness, swelling and pain at the injection site. The preventive medical check-up for early detection of cervical cancer ( Pap test ) is still recommended, as not all cancerogenic HPV types are covered by the vaccination.

Risks of HPV infection

The high-risk HPV types 16 and 18 are held responsible for around 70% of all cervical cancer cases in women worldwide. 55.3% of all cervical cancer precursors of severity CIN  2 and 3 were associated with HPV 16 in two German studies, 6.4% with HPV 18, HPV 45 in 8.5% and HPV 31 in 6.4% of the cases . High-risk virus subsets are not only implicated in causing cervical cancer; they are also found in cancers of the penis , vulva , anus and mouth . In 2005, the WHO classified HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 66 as carcinogenic.

The so-called low-risk HPV types 6 and 11 are responsible for the development of over 90% of genital warts (genital warts), which are the most common viral sexually transmitted disease worldwide . It is estimated that around 1% of the European and German population in the 15 to 49 age group is affected by these benign tumors. Studies in recent years show an increasing frequency. Genital warts often lead to anxiety and psychosocial complications as well as partner problems and thus to a significant reduction in quality of life .

  • Genital warts in the shaved pubic area at the base of the penis, approx. 6 to 10 months after infection

  • Pronounced genital warts on the penis

  • Pronounced genital wart infestation in the vulva

  • Genital wart infestation of the anus

development

A quadruple vaccine manufactured by Sanofi Pasteur MSD was first approved in the USA in June 2006 by the Food and Drug Administration and in September 2006 by the EU Commission following a central approval procedure in the countries of the European Union . In November 2006, it was approved by Swissmedic in Switzerland. In Europe the trade name is Gardasil or Silgard . The vaccine contains purified, recombinantly produced L1 proteins from the capsid of the four papilloma virus types 6, 11, 16 and 18, which spontaneously assemble to form virus-like particles (VLP). According to the European Medicines Agency, 1.5 million patients in Europe had been vaccinated with Gardasil by January 2008 . This was followed by extensions of indications for the prevention of preliminary stages of vaginal and vulvar carcinoma ( USA : September 2008, EU: July 2008) as well as for the prevention of genital warts (USA: in October 2009 extension to men and boys, EU: November 2011) and Prevention of preliminary stages of malignant lesions in the anal area and anal cancer (USA: December 2010, EU: June 2014).

The bivalent vaccine developed by GlaxoSmithKline and sold under the trade name Cervarix was approved in Australia in May 2007 and in the European Union on September 20, 2007 . FDA approval was granted in October 2009. This vaccine also contains recombinant L1 proteins from the capsid in VLPs, but only of papillomavirus types 16 and 18.

In a Phase III study by MSD of a new recombinant nonavalent vaccine against virus types 6, 11, 16, 18, 31, 33, 45, 52, and 58 called V503, vaccination prevented 97% of high-grade vaginal, vulvar and cervical cancer precursors caused by these types of viruses. The new vaccine produced the same or better immune response than Gardasil in HPV types 6, 11, 16 and 18. V503 was approved in the USA in December 2014 and in the EU in June 2015 under the trade name Gardasil 9 , which in Germany has been available since 2016.

An international working group reported in June 2013 on the development of a multivalent vaccine that could protect in the future not only against the majority of genital high- and low-risk types of the virus, but also against those guys, for the formation of skin warts are responsible . An evaluation in clinical studies is still pending.

effectiveness

As a general rule

In 2018, a Cochrane review rated the HPV vaccination as effective and safe. Scientists from Scotland shared this view. The evaluation of over 100,000 health data has shown that routine HPV vaccinations in girls aged 12-13 years have significantly reduced the likelihood of abnormal cells and cervical intraepithelial neoplasia (CIN; precursors of cervical cancer). The earlier an HPV vaccination took place, the more effective the HPV vaccination was.

A large meta-analysis of over 60 million patient data and an eight-year follow-up has shown that the HPV vaccination has a significant influence on the decline in HPV diseases and the CIN2 + cervical cancer precursor. For example, CIN2 + decreased by 51% in women between 15 and 19 years of age and by 31% in women between 20 and 24 years of age 5-9 years after the HPV vaccination.

In the USA it was observed that after the introduction of the quadrivalent vaccine, the incidence of the corresponding vaccinated, carcinogenic HPV strains decreased significantly compared to the pre-vaccination period: in 14 to 19 year olds from 11.5% to 1.8% and in 20 - up to 24 year olds from 18.5% to 5.3%. In Great Britain, 10 years after the introduction of HPV vaccination, it was found that 16-18 year old women were no longer infected with the two high-risk strains 16 and 18.

Studies on the effectiveness of Gardasil

The effectiveness of the tetravalent vaccine ( Gardasil ) was investigated in four placebo-controlled , randomized and double-blind phase II and phase III studies . In women who were not infected with the corresponding human papillomavirus at the time of vaccination, the vaccination prevented infection in almost all women (96-100%). In the vaccinated study participants, the vaccination prevented the occurrence of cervical intraepithelial neoplasms, a surrogate marker for cervical cancer caused by the corresponding HPV types, in 98–100% of the test subjects. For example, in the so-called Future II study, the occurrence of CIN grade 2 or more severe precursors of cervical cancer was registered. While there was one case of CIN in the group of women treated with the vaccine (5305 women in total ), there were 42 cases in the group of women treated with placebo (5260 women). In addition, the vaccination protected 98-100% of the study participants from developing anogenital warts. For ethical reasons, the independent Data Safety Monitoring Board recommended vaccination of the subjects treated with placebo as soon as possible .

If women with HPV infections existing at the start of the study are included in the analysis and also those who received less than the three required vaccine doses, the effectiveness of Gardasil against HPV-caused precursors of cervical cancer is lower, but it does exist. In the combined interim analysis of the four relevant efficacy studies carried out for approval, the efficacy against CIN 2/3 / AIS caused by HPV types 16 and / or 18 was 39%.

Boys 9 to 15 years of age developed immunity after vaccination . The quadrivalent vaccine was judged to be effective in a study of 4,065 boys and men aged 16 to 26 years. A worldwide clinical study for the prevention of venereal diseases, especially genital warts, is ongoing for homosexual men, as well as studies with the HPV vaccine. The aim is a vaccination to prevent anal and penile cancer , the development of which is also associated with infections with HPV.

In 2011, the first data were published after the introduction of a comprehensive vaccination program with a quadrivalent vaccine. The program was established in Australia in 2007. The vaccination rate there is 80 to 90 percent. Three years after the start of the vaccination campaign, the precancerous stages in need of treatment in girls under 18 years of age were 59 percent lower than before.

Studies on the effectiveness of Cervarix

The bivalent vaccine Cervarix protects against the cancer-causing HPV types 16 and 18. Statistically significant efficacy of this drug could only be demonstrated for HPV 16 in a large study. Clinical data for Cervarix are currently available over a period of 5.5 years. According to new data, Cervarix also protects against infections with HPV types that are not in the vaccine. This so-called cross protection extends to different degrees to virus types 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59. Virus types 31 and 45 (in addition to HPV 16 and 18) in particular have a high oncogenic potential . Cross protection with the phylogenetically related HPV types 45, 52 and 58 is also known from Gardasil . In a study published in PLoS ONE, it was shown that Cervarix also protects against oral infections. This is particularly relevant because of the increasing tumors in the head and neck area, which are increasingly triggered by HP viruses.

According to data from the PATRICIA study ( Papilloma Trial against Cancer in Young Adults ), a phase III study (HPV 008) with Cervarix , in which 18,644 women in 14 countries in North and South America, Europe and the Asia-Pacific region were involved Aged between 15 and 25 years of age, the CIN 2+ findings were reduced by 70% (33 versus 110 cases) and the CIN 3+ findings by 87% (3 versus 23 cases). The rate of conizations decreased by 68.8 percent (i.e. to 31.2%).

Comparison of Gardasil and Cervarix

The first direct comparative study between the two preparations (HPV 010), which included 1,106 healthy women between 18 and 45 years of age from 40 US centers, showed a significantly higher immune response from the bivalent vaccine Cervarix , which is most likely explained by a new adjuvant ( AS04 ) can. It is unclear whether this increased immune response is relevant for protection or its duration.

In November 2008, 13 scientists from various German research institutions demanded a reassessment of the HPV vaccination on the grounds that the effectiveness could be significantly lower than assumed. In this reassessment by the Robert Koch Institute on August 10, 2009, vaccination was still recommended. Information media that give the impression that an HPV vaccination provides 100% protection against cervical cancer were classified as dubious according to the current state of knowledge.

execution

The vaccination schedule depends on the age of the person to be immunized: from 14 years of age ( Gardasil ) or from 15 years of age ( Cervarix ), the basic immunization is carried out using three intramuscular injections , each two and six months after the first injection ( Gardasil ) or after one and six months ( Cervarix ). Children aged nine to 13 years ( Gardasil ) or up to 14 years ( Cervarix ) are vaccinated according to a two-dose scheme with just one additional injection six months after the first injection. Whether a booster vaccination will be necessary is still the subject of further investigations. However, follow-up observations have so far not given any indications of a decrease in vaccination protection, although the informative value of the studies for long-term protection beyond 5 years was worse than for short-term protection up to 5 years. Data from two large phase III studies with the bivalent HPV vaccine Cervarix indicate that a single vaccination is apparently sufficient.

Vaccination recommendation

The vaccination has entered the vaccination program of over 80 countries such as Australia , Canada , New Zealand and South Korea worldwide . In the United States , vaccination has become a legal requirement in many states.

Countries that have made a vaccination recommendation with the date of the recommendation
country Date of vaccination recommendation
Belgium May 11, 2007
Denmark 4th October 2007
Germany March 26, 2007
France March 16, 2007
Greece February 7, 2008
Ireland August 5, 2008
Iceland February 19, 2008
Italy February 28, 2007
Luxembourg February 27, 2007
Netherlands March 31, 2008
Norway April 12, 2007
Austria December 20, 2006
Portugal December 10, 2007
Sweden February 26, 2008
Switzerland June 18, 2007
Spain October 10, 2007
United Kingdom October 26, 2007

In Japan, the vaccination recommendation was suspended after reports of several suspected cases of serious side effects ( complex regional pain syndrome ). The German Federal Institute for Vaccines and Biomedical Medicines ( Paul Ehrlich Institute ) did not see any risk signals for the occurrence of this syndrome in 2013 after evaluating all reported suspected cases and the literature. The European Medicines Agency agreed with this assessment after a review in November 2015. In 2017, members of 17 Japanese specialist societies called for the vaccination recommendation to be renewed.

Germany

The Standing Vaccination Commission (STIKO) recommended HPV vaccination for girls from March 2007.

After the introduction of the HPV vaccination, a discussion broke out in Germany about its costs, cost efficiency, advertising measures by the manufacturers and the risks of vaccination. In November 2008, 13 health scientists published a “manifest” on a website of Bielefeld University in which they called for an end to “misleading information” on the effectiveness of the HPV vaccination and a renewed review of the STIKO recommendation. In particular, it was criticized that no data on protection against cervical cancer were available and that the STIKO had decided on the HPV vaccination recommendation before the decisive study data were published. The professional association of gynecologists (BVF), the German Society for Gynecology and Obstetrics (DGGG), the Society for Virology (GfV) and the German Association for Combating Virus Diseases (DVV) as well as the Nobel Prize winner Harald zur Hausen rejected the criticism. In a statement on the vaccination in 2009, the STIKO referred to the criticism and, after evaluating all available scientific data, came to the conclusion that the vaccination is still recommended for girls aged 12 to 17 years. Data from nationwide programs with high vaccination rates, such as in Australia, confirm the STIKO's recommendation.

In 2014, the STIKO lowered the age limit for girls in its recommendations. Since summer 2014 she has been recommending vaccination against HPV types 16 and 18 for all girls between the ages of 9 and 14 using a 2-dose scheme. Thereafter, missed vaccinations against HPV by the age of 18 should be made up with a total of 3 vaccine doses. The full series of vaccinations should be completed before the first sexual intercourse.

In 2018, the German Society for Urology (DGU) and the Professional Association of German Urologists (BDU) also rated the vaccination as recommended for boys.

On June 5, 2018, the STIKO passed a resolution recommending the HPV vaccination of boys aged 9 to 14 years. In the event that this period is not observed, a catch-up vaccination is recommended up to the age of 17 years. The recommendation will formally come into force with its publication and the scientific justification in Epidemiological Bulletin 26/2018 on June 28, 2018.

Austria

Since 2007, the Supreme Sanitary Council has recommended vaccination against oncogenic HPV types for all 9 to 17 year old girls and women, if possible before their first sexual contact. The vaccination of boys or male adolescents is described in the Austrian vaccination plan 2009 as "in principle sensible" in order to break the chain of infection. When using a vaccine that also protects against condyloma- causing viruses, the male adolescents would also have a personal advantage.

Switzerland

The Federal Office of Public Health (FOPH) and the Federal Commission for Vaccination (EKIF) recommend vaccinating all girls between the ages of 11 and 14 against human papillomavirus with two doses of vaccination every 4 to 6 months. A catch-up vaccination in the three-dose scheme (0 / 1-2 / 6 months) is recommended for adolescent girls up to their 20th birthday. Afterwards, young women between 20 and 26 years of age are offered the HPV vaccine as a supplementary vaccination based on individual recommendations. Vaccination of boys and young men between the ages of 11 and 26 has also been recommended in Switzerland since March 2015.

costs

With the exception of Finland, all Western European countries have so far decided to finance the HPV vaccination. International studies show a cost-benefit analysis of vaccination assuming a lifelong period of vaccination protection, a cost-effectiveness ratio that is below the threshold of 50,000 euros per additional quality-adjusted year of life (QALY), a year of life with a good quality of life. As a result, most studies conclude that HPV vaccination is cost-effective. However, an assessment can currently only be made using model calculations, the result of which depends on the factors considered (such as assumptions about the unknown effect against cervical cancer and unknown duration of vaccination protection) and the framework conditions in the respective country. In the Netherlands, for example, it was concluded that vaccination is not cost-effective. Vaccinating women 35 years of age and older is not cost effective in the US. Nobel laureate Harald zur Hausen himself “… pointed out at every opportunity that the vaccine is currently too expensive. This applies in particular to developing countries, in which cervical cancer is in part the most common cancer in women. ”In Kenya , the vaccine costs around half the average annual income.

Germany

The cost of the vaccine is around 150 euros per required single dose. In 2008, the health insurance companies in Germany spent 244 million euros on the two vaccines Gardasil and Cervarix , according to the figures from the 2009 Drug Prescription Report . After the vaccination has been included in the guideline of the Federal Joint Committee on protective vaccinations according to Section 20d (1) SGB V , the statutory health insurance companies will cover the vaccination costs for girls between the ages of 9 and 17. Some health insurance companies cover the cost of vaccinating women up to the age of 26 as a voluntary statutory benefit.

The Standing Vaccination Commission (STIKO) has recommended vaccination for 9 to 14-year-old boys since 2018 , the costs are covered by all statutory health insurances up to the age of 17, some health insurances assume it as a voluntary statutory benefit up to the age of 26.

Austria

The HPV vaccination for girls and boys was included in the school vaccination program on August 12, 2013 and has therefore been free of charge for children aged 9 to 12 since February 2014. Discounted prices apply to young people up to 15 years of age.

The vaccination could already be obtained at reduced prices in individual federal states as part of school or public vaccination campaigns. In Lower Austria , for example, a vaccination campaign started in 2007, in which all girls and women between 9 and 26 years of age could be vaccinated at the Lower Austrian regional clinics at a discounted price of 90 euros per dose (instead of 208 euros). In Burgenland , the vaccination was offered at a reduced price to all girls in the 5th to 8th grade from September 2008 through a school vaccination campaign. The promotional price including state funding was 90 euros (instead of 208 euros) per vaccination. Girls and women between the ages of 15 and 26 and boys between the ages of 9 and 15 were also able to obtain the vaccine at a reduced price through a public vaccination campaign in Burgenland. Here the promotional price was 150 euros (instead of 208 euros) per vaccination.

In 2007, the Ludwig Boltzmann Institute saw the vaccination recommendation only as a third option due to the high level of uncertainty and high costs, and thus unclear cost effectiveness.

Switzerland

For female and male adolescents aged 11 to 26, the costs of the HPV vaccination are covered by the mandatory health insurance . The prerequisite is that the service is provided as part of a cantonal vaccination program. The bivalent (HPV type 16/18) and quadrivalent (HPV type 6/11/16/18) HPV vaccination is reimbursed to the canton by insurance companies at a price of CHF 91.50 per dose. The total flat rate reimbursement for health insurers is 159 francs per vaccination. From July 2016 this will also be granted to boys and young men in the same age group.

unwanted effects

At the time of approval, data from several clinical studies with over 20,000 participants were available on the tolerability of the HPV vaccination. Since Gardasil was approved , several million girls and women around the world have been vaccinated. The occurrence of adverse effects , which may be caused by the HPV vaccination, is recorded in special monitoring programs.

On the basis of the available study data, the HPV vaccination is included in the German Health Technology Assessment, the US regulatory authority for drugs (FDA), the Centers for Disease Control and Prevention (CDC), the European Medicines Agency (EMA), the Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) and the Global Advisory Committee of the World Health Organization (WHO) have been rated as safe and well tolerated.

The most common undesirable effects observed in the controlled studies were local reactions (redness, swelling and pain) at the injection site with both vaccines. In the Gardasil studies , local reactions occurred in around 83% of women in the vaccine group and 73% of women in the placebo group. In almost all cases, the study participants received a mixture of water and the adjuvant amorphous aluminum hydroxyphosphate sulfate as an (active) placebo . The most common systemic reactions were headache, fatigue, muscle pain, and nausea; they occurred with the same frequency in the vaccine and placebo groups. Fever was recorded in 10-15% of women in both the vaccine and placebo groups. Serious adverse effects also occurred equally frequently in the vaccination and placebo groups and consisted of narrowing of the airways ( bronchospasm ), gastroenteritis , increase in blood pressure, severe headache, pain at the injection site and reduced mobility in the adjacent joint. A study that looked at the incidence of chronic illness up to four years after receiving the HPV vaccine or placebo found that 3% of women in the vaccine group had a chronic illness. In the placebo group, the proportion of new chronic diseases was 5%. With regard to the number of deaths that have occurred, a meta-analysis of the clinical studies showed that deaths were equally common in the vaccine and placebo groups and were mostly caused by accidents. Vaccination was not considered the cause of any of the deaths.

Since the US approval of the HPV vaccine Gardasil in June 2006, the FDA and the Centers for Disease Control and Prevention had received 17,160 reports of potential adverse drug reactions from approximately 26 million vaccine doses through September 2009 through surveillance programs. The majority of the undesirable effects (92%) were classified as not serious and consisted of local reactions, headache, nausea, fever and syncope . 8% of the reported adverse effects were serious. Serious cases were defined as those that resulted in hospital admission, life-threatening illness, irreversible disability or death. For example, diseases of Guillain-Barré syndrome , thromboses and deaths were reported in connection with the vaccination . All serious cases were investigated for possible causation by Gardasil ; in no case could a causal connection between the vaccination and the respective disease be proven. The suspected increased risk of thrombosis could not be confirmed by a Danish case-control study. Another large cohort study from Scandinavia was able to show that the HPV vaccination is not associated with an increased risk of multiple sclerosis (MS) and other demyelinating diseases .

Cervarix had a spectrum of side effects similar to Gardasil : the most common side effects observed after administration were pain at the injection site (78%) and headache and muscle pain . For both vaccines, swelling of the lymph nodes ( lymphadenopathy ) and anaphylactoid reactions have been reported in isolated cases . An infertility by ovarian failure is considered another very rare adverse event reported.

In November 2015, the European Medicines Agency (EMA) announced that it had investigated HPV vaccines in a review that did not question the benefit-risk ratio, but instead examined whether two undesirable effects rarely reported in connection with the vaccination Effects, complex regional pain syndrome ( CRPS ) and postural orthostatic tachycardia syndrome (POTS), occur more frequently in vaccinated women than in unvaccinated women. The evaluation of all available scientific information and reports with regard to the two syndromes showed that the reporting rates of these diseases observed in the temporal connection with HPV vaccinations correspond to the expected frequency of occurrence in the age group examined (female adolescents aged 10 to 17 years) and thus there is no indication of a connection. Following a criticism of this review by the Danish scientist Louise Brinth published in December 2015 , the director of the Nordic Cochrane Center, Peter C. Gøtzsche , filed a formal complaint about the official assessment report of the EMA in May 2016.
In 2018, a Cochrane review rated the vaccination as effective and safe. This review was also criticized by Gøtzsche and his colleagues. He was expelled from the Cochrane Collaboration on September 26, 2018 for "continuing bad behavior that is inconsistent with the principles and governance of Cochrane".

pregnancy and breast feeding period

There is limited data from clinical studies regarding the safety of vaccination with HPV vaccines during pregnancy. However, these did not show an increased risk for the embryo or the fetus . For example, in almost 1,800 women who were unintentionally vaccinated during pregnancy, no evidence of a negative outcome was observed. There is also no evidence of adverse effects of the vaccination during breastfeeding. Although neither animal experiments nor the available data from clinical studies in humans give any indications of direct or indirect harmful effects, the STIKO does not currently classify vaccination during pregnancy as “safe” and the manufacturers advise against its use during pregnancy. Gardasil has been tested against placebo in clinical studies in breastfeeding mothers. The frequency of side effects in mother and infant was similar in both groups. The immunogenicity of the vaccine in nursing mothers was similar to that of the vaccine in women who were not breastfeeding at the time of vaccination. Gardasil can therefore be given to women who are breastfeeding. Cervarix should only be used during breast-feeding if the potential benefits outweigh the potential risks, as the effects on breast-fed infants whose mothers received Cervarix have not been studied in clinical studies.

The authors of the S3 guideline on vaccination prevention of HPV-associated neoplasms of the Paul Ehrlich Society for Chemotherapy (AG HPV Management Forum), the German STD Society and the German Dermatological Society generally consider vaccination during breastfeeding to be justifiable.

Therapeutic HPV vaccines

In addition to the preventive vaccines, such as B. Gardasil and Cervarix, a therapeutic HPV vaccine under the name VGX-3100, MEL-1 or MVA-E2 is being developed for those who are already infected. This potential vaccine is currently in phase 3 of clinical development, i.e. not yet approved . The study is expected to be completed in August 2020.
Scientists at the German Cancer Research Center developed a therapeutic vaccine that could be used to combat cervical cancer caused by HPV in animal experiments on mice. The tumors regressed in half of the vaccinated animals.

literature

Web links

Individual evidence

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