HPV infection, cervical cancer and HPV vaccination

Human papillomaviruses (HPV) are viruses that most sexually active individuals come into contact with, both in Slovenia and around the world. According to data from the International Human Papillomavirus Reference Center, there are more than 200 different genotypes, with approximately 45 genotypes of HPV causing infections of the genitals, reproductive tract, anus, and oral part of the throat. HPV infection usually occurs without symptoms or signs, but it can lead to the development of precancerous and cancerous changes. HPV is the main cause of genital warts and cervical cancer, and they are also associated with the development of other cancers and throat papillomas, in both men and women.

HPV is transmitted through close contact with the skin or mucous membranes of an infected person, most commonly through sexual intercourse (vaginal, anal, oral). HPV infections are the most common sexually transmitted infections, and the majority of sexually active individuals become infected with HPV at least once in their lifetime. Most people become infected shortly after initiating sexual activity, so the frequency of infections is highest in adolescents and young adults aged 15–25 years. Infection is common in both men and women.

In most cases, infection occurs without symptoms or signs, so most people do not know they are infected with HPV. However, they can still transmit the infection to their sexual partner. HPV can be transmitted even if the partner shows no symptoms or signs of infection. Infections with HPV are more common in those who have multiple sexual partners or have sexual intercourse with someone who has multiple partners. In rare cases, HPV can be transmitted from an infected mother to her new-born during childbirth.

We can reduce the risk of HPV infection by following the ABC principles of safe and healthy sexuality:

A – “abstinence” or delaying the first sexual intercourse until a period of greater maturity, with a partner whom we know and trust;

B – “be faithful” or fidelity between two partners (individuals who have multiple sexual partners in life are at higher risk of HPV infections and other sexually transmitted infections);

C – “condom” its proper and consistent use to protect against both unwanted pregnancies and sexually transmitted infections (condoms significantly reduce the risk of HPV infection, but they do not completely prevent it due to the presence of HPV on other areas of the skin and mucous membranes).

One of the most effective measures to prevent HPV infections and its consequences is HPV vaccination.

HPV infections mostly occur without characteristic symptoms or signs, so most people are unaware that they are infected. In the majority of individuals (90%), the infection spontaneously clears within two years, but in some (10%), persistent (long-lasting) HPV infection can develop, leading to the formation of genital warts or certain cancers.

Infections with less dangerous HPV genotypes can cause genital warts. These appear as wart-like growths or cauliflower like formations that occur in the genital area, genitals or anus. Genital warts usually appear a few months after HPV infection. Infections with less dangerous HPV genotypes are also associated with papillomas of the larynx, which can cause hoarseness and breathing difficulties. In rare cases, they can lead to life-threatening blockage of the airways.

Long-term infections with more dangerous HPV genotypes can lead to the development of precancerous and cancerous lesions in the genital area, genitals, anus and oropharynx. In general, it takes several years from infection to the development of precancerous and cancerous lesions. Of the cancerous lesions, cervical cancer is the most common. The initial symptoms and signs of cervical cancer usually appear late and may manifest as bleeding or brownish discharge (after intercourse, during the menstrual cycle or in the post-menopausal period), persistent foul-smelling vaginal discharge, pain during sexual intercourse, pain in the lower abdomen.

There is no cure for HPV infection. However, diseases that arise as a result of HPV infection, such as cervical precancerous lesions and cervical cancer, and genital warts, can be treated.

About 45 HPV genotypes can cause minor changes in the cells of the cervix, which are usually without consequences. However, at least 13 HPV genotypes, which are considered to be more dangerous (oncogenic), can cause significant changes in cervical cells, which in rare cases lead to cervical cancer. Virtually all cases of cervical cancer (99%) are causally linked to HPV infection.

Cervical cancer is the 11^th most common cancer in women and the fourth most common cancer in young women (25–49 years) in Europe. In the countries of the European Union and the European Economic Area, around 31,000 women are diagnosed with cervical cancer each year, and more than 13,000 die. Unlike many other cancers, which primarily affect older people, cervical cancer occurs in younger women in childbearing age.

Despite some effective measures such as the ZORA screening programme and vaccination, cervical cancer remains a public health issue in Slovenia. Annually, around 120 women are diagnosed with cervical cancer, and 40–50 of them die. Additionally, over 1,600 women undergo surgical treatment in Slovenia each year due to precancerous lesions resulting from long-term infection with one of the more dangerous genotypes of HPV. However, due to the highly successful detection of the earliest forms of cervical cancer within the national ZORA programme, mortality from this cancer in Slovenia is below the European average.

In addition to cervical cancer, persistent infection with the more dangerous HPV genotypes causes 25–78% of other genital cancers, 88% of anal cancers and 31% of oropharyngeal cancers in both women and men. While these cancers are rarer than cervical cancer, the incidence of some cancers (e.g. oropharyngeal cancer in men) is increasing.

It is possible to protect oneself against HPV infection through vaccination. In Slovenia, a nine-valent vaccine is available, which provides protection against the seven most common, dangerous HPV genotypes that can cause precancerous lesions and cervical cancer, as well as some other genital, rectal and oropharyngeal cancers, and two less dangerous HPV genotypes that cause genital warts.

The nine-valent vaccine is intended for use from the age of 9 years onwards for the prevention of precancerous lesions and cancers of the cervix, external genitalia, vagina and anus caused by HPV genotypes contained in the vaccine, as well as genital warts (condyloma acuminata) caused by certain HPV genotypes.

Vaccination is administered with either two or three doses of the vaccine depending on the age at the start of vaccination. Individuals aged 9 to 14 years are vaccinated with 2 doses of the vaccine (6 months apart). Individuals aged 15 years or older are vaccinated with 3 doses of vaccine (according to the schedule at 0, 2 and 6 months). HPV vaccination may be administered concurrently with other vaccinations.

Yes, the HPV vaccine is very effective in previously uninfected individuals for preventing infections with the HPV genotypes contained in the vaccine. The nine-valent vaccine provides protection against infections with the seven more dangerous HPV genotypes (16, 18, 31, 33, 45, 52, 58), which account for around 90% of cervical cancers and some other genital, rectal and oropharyngeal cancers. It also protects against two less dangerous HPV genotypes (6, 11), which cause up to 90% of genital warts. Vaccination does not treat pre-existing HPV infections and their complications.

Research findings and data from countries with high HPV vaccination coverage demonstrate that the HPV vaccine is extremely effective in preventing HPV infections and their consequences. In these countries, there has been observed a reduction in the prevalence of genital HPV infections among young people, a decrease in the incidence of genital warts in young women and men, a decline in the frequency of precancerous cervical changes, and a reduced incidence of HPV-related cancers among vaccinated women compared to unvaccinated women.

Yes, HPV vaccines are extremely safe and effective, as demonstrated by the results of past and ongoing research as well as data from vaccination programmes conducted in numerous countries around the world. To date, several hundred million doses of these vaccines have been distributed worldwide. As with other vaccines, some adverse effects may occur following HPV vaccination, but are usually mild and transient. The most commonly reported symptoms are redness, pain and swelling at the injection site, moderate fever, nausea, fatigue and headache.

The European Medicines Agency (EMA) and the World Health Organisation (WHO) regularly monitor the safety of HPV vaccines and have not identified any safety concerns for vaccination so far. In 2016, they reviewed the safety of HPV vaccines in relation to two rare conditions: complex regional pain syndrome (CRPS; a chronic pain condition affecting limbs) and postural orthostatic tachycardia syndrome (POTS; an abnormal increase in heart rate upon standing or sitting, resulting in symptoms such as dizziness, fainting, and headache). While cases of these conditions have been described in the medical literature in temporal association with HPV vaccination, a causal link with vaccination has not been confirmed. Both conditions can also occur in unvaccinated individuals. Following the review of research findings and reports of adverse effects, EMA and WHO concluded that the accumulated evidence does not support a causal link between HPV vaccination and these conditions.

In 2017, the WHO Global Advisory Committee on Vaccine Safety (GACVS) reviewed the updated safety data on HPV vaccines. More and more data on the safety of these vaccines is becoming available as more countries include the vaccine in their vaccination programmes. In particular, they reviewed data on some reported serious adverse events that occurred in temporal association with vaccination, such as the association between aluminium-containing adjuvants and adverse events such as anaphylaxis, syncope, mass psychogenic illnesses, autoimmune diseases (including Guillain-Barré syndrome and multiple sclerosis), venous thromboembolism, stroke, adverse pregnancy outcomes, complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), premature ovarian failure. Except for the risk of extremely severe allergic reaction/anaphylaxis (1.7 cases per million doses) and syncope associated with anxiety or stress induced by vaccine injection, no evidence was found for any of the other adverse events listed above to confirm a causal relationship with HPV vaccination. Similarly, follow-up of pregnancy outcomes in women who were inadvertently vaccinated during pregnancy did not show an increase in adverse pregnancy outcomes or foetal harm. In conclusion, the Committee concludes that HPV vaccines are extremely safe.

In Slovenia, data on adverse reactions after vaccination are collected by the National Institute of Public Health (NIJZ) in the Post-vaccination Adverse Reaction Register, to which all doctors who report adverse reactions are obliged to report. More than 200,000 doses of HPV vaccine have been distributed in our country between 2009 and 2021. During this period, we received 215 reports of adverse reactions after HPV vaccination in the Post-vaccination Adverse Reaction Register. Doctors most frequently reported pain, swelling, redness at the vaccination site, fever, nausea, headache, fatigue and fainting. Almost every year, individual serious adverse reactions are reported, resulting in vaccinated persons being admitted to hospital for short-term observation. All hospitalisations are considered as serious adverse reactions.

However, no serious side effects such as anaphylactic reactions, shock, etc. have been reported so far.

Research to date has shown that protection against HPV infection by vaccination lasts at least 10 years, but protection is expected to last significantly longer. In studies that have been ongoing for more than ten years and follow women and men who have already been vaccinated, the majority have been found to have high levels of protective antibodies and no occurrence of disease prevented by HPV vaccination (precancerous and cancerous lesions, genital warts). For the time being, it is considered that booster doses are not necessary.

The recommended (voluntary) HPV vaccination at the expense of the Compulsory Health Insurance is carried out at the time of the systematic check-up for girls and boys attending grade 6 of primary school, and in the school year 2023/24 also for boys attending years 1 and 3 of secondary school. Vaccination at the expense of the Compulsory Health Insurance is also provided to latecomers (girls who attended grade 6 in the school year 2009/10 or later, and boys who attended grade 6 in the school year 2021/22 or later and have not yet been vaccinated). For all others who wish to be vaccinated against HPV, vaccination is at their own expense. Vaccination is administered in a number of doses according to the age at the start of vaccination (two doses at an interval of at least 6 months is sufficient for those aged 15 years and younger, however, for those who are older than that, 3 doses according to the 0, 2, 6 schedule are required).

All routine vaccinations are usually carried out by paediatricians and school doctors (including student doctors), as are vaccinations for latecomers, which can be given at the first follow-up check-up or by arrangement with the doctor. Other doctors may also vaccinate.

For persons who have been fully vaccinated with the 4-valent vaccine, no additional vaccination with the 9-valent vaccine is required. Most HPV-related cancers are caused by HPV genotypes 16 or 18, which are also protected against by the 4-valent vaccine. We estimate that the benefit of additional vaccination with the 9-valent vaccine is small. Otherwise, the available data do not suggest any safety concerns for vaccination with the 9-valent vaccine in persons who have completed vaccination with the 4-valent vaccine at least 12 months earlier.

HPV infection can cause cancer of the buttocks, penis, oropharynx and genital warts in men. Vaccinating boys against HPV infections can reduce the incidence of these conditions. As men are also carriers of HPV, vaccination may also have an indirect impact on reducing the incidence of cervical cancer and other HPV-related diseases in women. The inclusion of boys in the national vaccination programme is an important step towards building collective immunity against the most common HPV genotypes. Clinical studies have shown that the HPV vaccine is immunogenic (triggers an immune response and the production of antibodies) and safe also in men, and is effective in preventing precancerous lesions of the anus and genital warts, which are causally linked to certain HPV genotypes, also in men.

Since 2021, boys have also been included in the HPV vaccination programme alongside girls, meaning that girls and boys attending grade 6 of primary school can be vaccinated at the expense of the Compulsory Health Insurance. In the school year 2023/24, boys attending years 1 and 3 of secondary school can also be vaccinated under the Compulsory Health Insurance. Vaccination under the Compulsory Health Insurance is also provided for latecomers (girls who attended grade 6 in the school year 2009/10 or later, and boys who attended grade 6 in the school year 2021/22 or later and have not yet been vaccinated). For all others who wish to be vaccinated against HPV, vaccination is at their own expense.

Vaccination is most effective before the onset of sexual activity, when individuals have not yet been exposed to HPV. The immune response to HPV vaccination is also best between the ages of 9-15 years, when two doses of the vaccine are sufficient for protection. For those aged 15 years and older, three doses of HPV vaccine are required.

Vaccination is recommended up to the age of 26 years, preferably before the onset of sexual activity (before possible exposure to HPV). After the age of 26 years, vaccination is recommended on a case-by-case basis, depending on the risk of infection. The vaccine protects against infection with certain HPV genotypes that the person has not yet been infected with, so if the person has already been infected with one of the HPV genotypes that the vaccine protects against, the vaccine is less effective. The vaccine does not treat pre-existing HPV infections or their complications.

Yes. Vaccination does not protect against all HPV genotypes that cause precancerous lesions and cervical cancer, so regular gynaecological examinations and cervical smears (screening) are essential, even for women who have been vaccinated, as is recommended. Women who have regular screening are 70-80% less likely to ever get cervical cancer, as are women who have had the HPV vaccine before their first infection. If a woman is vaccinated against HPV and attends regular screening, she is extremely unlikely to get cervical cancer.

Vaccination with the 9-valent vaccine, which also protects against HPV genotypes 6 and 11, provides 90% protection against genital warts. However, the vaccine does not treat existing warts.

HPV vaccination provides safe and long-lasting protection against infection with certain HPV genotypes.

HPV vaccination is an important and modern public health measure for the prevention of genital warts and HPV-related precancerous and cancerous lesions in both sexes. This vaccination reduces the risk of precancerous lesions and cervical cancer, as well as certain other genital, anal and oropharyngeal cancers, and their treatment with possible complications (e.g. premature birth due to removal of part of the cervix) later in life in vaccinated people.

Choosing “non-vaccination” can have health consequences. An individual who has not been vaccinated has a significantly higher risk of developing certain cancers or precancerous lesions, as well as a higher risk of other HPV-related diseases and complications from their treatment.

Girls who attended grade 6 in the school year 2009/10 or later and boys who attended grade 6 in the school year 2021/22 or later, and have not yet been vaccinated, are eligible for the HPV vaccine as latecomers. All routine vaccinations are usually carried out by paediatricians and school doctors (including student doctors), as are vaccinations for latecomers, which can be given at the first follow-up check-up or by arrangement with the doctor. Other doctors may also vaccinate.

Since 2021, boys have also been included in the HPV vaccination programme alongside girls, meaning that girls and boys attending grade 6 of primary school can be vaccinated at the expense of the Compulsory Health Insurance. In the school year 2023/24, boys attending years 1 and 3 of secondary school can also be vaccinated under the Compulsory Health Insurance. Vaccination under the Compulsory Health Insurance is also provided for latecomers (girls who attended grade 6 in the school year 2009/10 or later, and boys who attended grade 6 in the school year 2021/22 or later and have not yet been vaccinated). For all others who wish to be vaccinated against HPV, vaccination is at their own expense.