Karolina Raczkowska-Łabuda, Anna Gorzelnik, *Lidia Zawadzka-Głos
Why is a laryngologist interested in cervical cancer? Summary information about HPV vaccination
Czemu laryngolog interesuje się rakiem szyjki macicy? Podsumowanie informacji dotyczących szczepień przeciwko HPV
Department of Pediatric Otolaryngology, Medical University of Warsaw, Poland
Head of Department: Associate Professor Lidia Zawadzka-Głos, MD, PhD
Szczepionki przeciwko HPV dostępne są na światowym rynku od ponad 10 lat. W Polsce pierwsze preparaty pojawiły się w aptekach w 2007 roku, choć zostały wymienione w PSO dopiero rok później. Obecnie w naszym kraju szczepienia przeciwko wirusowi brodawczaka ludzkiego można przeprowadzić w schemacie 3-dawkowym preparatami 2-walentnymi, 4-walentnymi oraz 9-walentnym. Badania kliniczne podsumowujące 10 lat doświadczeń udowadniają wysoką skuteczność szczepionki względem obniżenia częstości występowania infekcji HPV oraz raka szyjki macicy. Artykuł porównuje politykę programów szczepień przeciwko HPV w Polsce i na świecie i przedstawia najnowsze zalecenia co do stosowania różnych preparatów, przybliża ich charakterystykę. Podkreśla się prewencyjną rolę szczepień w przypadkach HPV-zależnych nowotworów głowy i szyi oraz potrzebę profilaktyki immunologicznej zarówno u dziewcząt, jak i u chłopców. Praca kładzie nacisk na spodziewane korzyści wdrożenia programów populacyjnych, zarówno w wymiarze społecznym, jak i finansowym, na przykładzie Państw, gdzie zastosowano takie rozwiązanie. Celem artykułu jest spopularyzowanie tematu szczepień przeciwko HPV w Polsce i wsparcie inicjatywy włączenia szczepionki przeciwko brodawczakowi ludzkiemu do PSO.
Human papillomavirus (HPV) vaccines have been available on the world market for more than 10 years. They became available in Polish pharmacies in 2007, although they were only included in the National Vaccination Program almost one year later. Currently in our country, the vaccination against human papillomavirus can be performed in a 3-dose schedule with a 2-valent, 4-valent or 9-valent vaccine. Clinical studies after 10 years of the presence of the vaccine in the market indicate that these vaccinations are an efficient measure for reducing the risk of HPV infection and of cervical cancer. The article compares HPV vaccination programs in Poland and around the world, presents the newest guidelines for the use of particular products, and discusses the characteristics of the products. The preventive role of vaccinations in HPV-dependent head and neck tumors, as well as the need for immunoprophylaxis in both girls and boys is underlined. The paper emphasizes the expected benefits of the implementation of population programs, both in social and financial aspects, on the example of countries which had already implemented such a solution. The aim of the article was to popularize the topic of vaccination against HPV in Poland and to support the initiative of the inclusion of HPV vaccination to the obligatory part of the National Vaccination Program.
Human papillomavirus (HPV) belongs to the Papillomaviridae family. It is characterized by a tropism towards the epithelial cells of the skin and mucous membranes. The invasion of the epithelium results from skin injuries. Viral propagation is coupled with epithelial cell differentiation process. According to the latest reports, there are over 200 types of HPV viruses, classified in a few groups: α, β, γ, μ, and v. Group α consists of 60 viruses attacking, among others, the cervical epithelium, which can lead to cervical cancer. Type β viruses infect the skin, are responsible for the formation of warts and are usually not oncogenic. Viruses can be further divided into groups with low, medium and high oncogenic potential. HPV types 16 and 18 are responsible for 70% of cases of cervical cancer. In addition, their key role in the formation of head and neck cancers is underlined. Over the past two decades, it has been proven that HPV infection is particularly common in oropharyngeal cancers. In the light of this information, the great interest of medical specialists from different fields in HPV vaccine is not surprising.
Material and Methods
A review of the literature on HPV vaccination, with particular reference to the publications from the last 4 years (2014-2017). The main focus was put on national guidelines of organizations such as: Centers for Disease Control and Prevention of the United Stated, American Food and Drug Administration, English National Health Service, Public Health Agency of Canada, Immunize Australia Program, Information Centre on HPV and Cancer of the Catalan Institute of Oncology, Norwegian Cervical Cancer Screening Programme, Polish Ministry of Health, and Chief Sanitary Inspector in Poland.
HPV vaccines have been available on the American market for more than 10 years. In Poland, they first appeared a little later – in 2008, the first recommendations of the Minister of Health and the Chief Sanitary Inspector regarding HPV vaccination were issued (1). Unfortunately, unlike multiple countries in the world, including United States, Great Britain, Norway, as well as Philippines and Malaysia, where a full reimbursement of HPV vaccination has been introduced (tab. 1), in Poland, the vaccinations are recommended, but the costs are not reimbursed by the National Health Fund. In August 2016, the Ministry of Health announced that funding for the inclusion of HPV vaccination into the National Vaccination Program was not currently possible, and in the perspective of the coming years, the Department of Mother and Child had no possibility of planning the expense of 250-300 million Polish zlotys in order to buy the HPV vaccine and include it in the obligatory vaccines (2).
Tab. 1. List of countries where HPV vaccination is compulsory and reimbursed
Luckily, under the Article 48 of the Health Care Act of 27th August 2004, it is also possible for local governments to develop their own health programs, and some of them taking the initiative to finance the HPV vaccination. In the years 2009-2011, only 3% of the target population in Poland was vaccinated in such programs (3), however, the local government’s activity is popularizing the problem and raising public awareness.
The incidence of cervical cancer in Poland is 15% higher than the European Union average and mortality is 70% higher (3, 4). This translates into 3,000 new cases and nearly 1,750 premature deaths every year (data from 2010) (3, 4). However, it should be borne in mind that cervical cancer is not the only neoplasm caused by HPV. Unfortunately, there is no comprehensive data for all HPV-related cancers in the National Cancer Registry. HPV has been shown to be directly related to cancers of the vagina, vulva, penis, anus, oral cavity, tonsils, pharynx and larynx. Recurrent laryngeal papillomatosis, present in both children and adults, must also be enumerated among the HPV-related diseases (5).
The most available data in the literature concerns cervical cancer (6-8). The scale of the problem is presented in table 2.
Tab. 2. Incidence and mortality due to cervical cancer in the year 2017 (data concerning USA from the year 2016)
|Country||Incidence [pers./year]||Mortality [pers./year]||Lethality|
The relationship of cervical cancer and HPV is unquestionable. Viral DNA is detected in 95-100% of the patients affected with cervical cancer (9).
HPV is one of the most common human pathogens. There are over 200 types of the virus, over 40 of which are sexually transmitted. The latter are classified in two groups:
1. low risk – usually do not induce oncogenesis, but cause mild condylomata acuminata in the genital and anal area, as well as respiratory papillomas. This group consists primarily of HPV types 6, 11, 42, 43, 44;
2. high risk (oncogenic) – promote oncogenesis. This group includes HPV types 16 and 18, as well as 31, 33, 35, 39, 40, 43, 51, 52, 53, 54, 55, 56, and 58. Viral DNA is detected in:
– 95-100% of cases of cervical cancer, 70% of the DNA detected is HPV-16 and -18;
– 95% of rectal cancer – mainly HPV-16;
– 70% of the oral and pharyngeal cancers (pharynx, soft palate, tongue, tonsils) – more than 50% caused by HPV-16;
– 65% of vaginal cancers – HPV-16 predominates;
– 50% of vulvar cancers – HPV-16 predominates;
– 35% of penile cancers – HPV-16 predominates (10, 11);
– 20% of laryngeal cancers – HPV-16 predominates (12).
It is estimated that over 90% of men and 80% of women will be infected with at least one HPV type in their lifetime (13, 14). Half of these infections will be caused by oncogenic types (high-risk types) (13, 14). The course of the infection is asymptomatic and often self-limiting (lasting between 1 and 2 years), therefore, it is possible for a person to unknowingly transmit the virus to their partners.
Three prophylactic HPV vaccines are currently registered in Poland and in the world: 2-valent – Cervarix (by GSK), 4-valent – Silgard/Gardasil (by MSD/Merck), and 9-valent – Gardasil9 (by MSD/Merck) (tab. 3). All are recombinant and highly purified and contain no genetic material of the virus – they belong to the group of inactivated vaccines. They contain protein antigens which are unable to cause an infection in the form of virus-like particles (VLPs), consisting of the papillomavirus major capsid protein L1.
Tab. 3. The characteristics of the vaccines (8, 15)
| ||2-valent (2vHPV)||4-valent (4vHPV)||9-valent (9vHPV)|
|Registration date (USA)||October 2009 – girls||June 2006 – girls, October 2009 – boys||December 2014 – girls and boys|
|HPV types||16, 18||6, 11, 16, 18||6, 11, 16, 18, 31, 33, 45, 52, 58|
|Production process||Thrichoplusia-derived cell line infected with a recombinant baculovirus containing L1 gene ||Saccharomyces cerevisiae with the expression of L1 ||Saccharomyces cerevisiae with the expression of L1|
|Adjuvant||ASO4: 500 μg aluminum hydroxide, 50 μg 3-O-desacyl-4’ monophosphoryl lipid A||AAHS: 225 μg amorphous aluminum hydroxyphosphate sulfate||AAHS: 500 μg amorphous aluminum hydroxyphosphate sulfate|
|Recommended for||? girls 11-12 y.o. (> 9 years);|
? women between 13 and 26 y.o. who have not undergone the whole vaccination cycle.
|? girls and boys 11-12 y.o. (> 9 years);|
? women between 13 and 26 y.o. who have not undergone the whole vaccination cycle;
? men between 22 and 26 y.o. that are immunosuppressed, homosexuals, bisexuals
|? girls and boys 11-12 y.o. (> 9 years);|
? women between 13 and 26 y.o. who have not undergone the whole vaccination cycle;
? men between 22 and 26 y.o. that are immunosuppressed, homosexuals, bisexuals
|Volume||0.5 ml||0.5 ml||0.5 ml|
|Contraindications||anaphylactic reaction to latex||immediate hypersensitivity |
|immediate hypersensitivity to yeast|
In the United States, from the end of 2016, only the 9-valent vaccine will be available for reimbursement (8).
The differences between the vaccines available in Poland are presented in table 3. They concern the antigenic composition and adjuvants used. Currently most European countries, USA and Australia introduce 2-dose schedule (even for Gardasil9). In Poland, a 3-dose schedule is still used.
The basic 4vHPV vaccination is performed in a 0-2-6 months schedule. The minimal interval between the first and the second dose is 1 month, and between the second and the third – 3 months. Silgard in patients aged 9-13 can be administered exclusively in the 2-dose schedule (0-6 months). However, if the patient receives the second dose earlier than 6 months after the first one, a third dose must be given. The 2-dose schedule can be used as an alternative to the 3-dose schedule for girls under 14 years of age. After that age, only 3-dose schedule is used.
2vHPV vaccine is administered in 3 doses: 0-1-6 months in girls less than 15 years of age, taking into account that the second dose should be administered 1-2.5 months after the first one and the third one – 5-12 months after the first one. In girls aged 9-14 years of age, 2 doses are administered, 5 to 13 months apart. If the second dose is given less than 5 months after the first one, a third dose is required. 9vHPV vaccine can be administered to patients above 9 years of age in a 3-dose schedule (0-2-6 months).
Numerous clinical trials have shown high efficacy of the vaccines against HPV. The PATRICIA study (16, 17) revealed that in a typical female young adult population (18,644 patients aged 15-25), the Cervarix vaccine reduced the average risk of CIN2 by 30% and of CIN3 by 33%, regardless of the HPV type and the presence of HPV in the lesion (some women had been previously exposed to HPV). Over the 4 years of the follow-up, the risk of developing CIN3 was reduced by on average 46%, and the risk of cancer in situ – by 77%. The protective effect was 2-3 times higher in women who had not been previously infected with HPV (which explains the need to vaccinate teenage girls before their sexual initiation). In the non-infected women, the risk of developing CIN2 decreased by 70% and of CIN3 – by 87% in 3 years of follow-up. After 4 years follow-up, a 93% decrease in the incidence of CIN3 and a 100% decrease in the incidence of cancer in situ was observed (16, 17).
The results of an analysis of 4 clinical trials evaluating the efficacy of Silgard (20,583 sexually active women, mean age 20 years old, SD = 2 years) (18) showed that the vaccination reduced the risk of CIN2 by 18% and of CIN3 – by 17% (regardless of the HPV type in the lesion). Unfortunately, the analysis did not include a separate group of women that had not been HPV-infected. Clinical trials on the 4vHPV vaccine additionally reported a decrease in the incidence of condylomata acuminata resulting from the HPV-6 and HPV-11 infection (18).
In the phase 3 study comparing the 9vHPV and 4vHPV vaccines (circa 14,000 women aged 16-26), Gardasil9’s efficacy in preventing CIN2, as well as VaIN2/3 and VIN 2/3 due to HPV types 31, 33, 45, 52, and 58 in the study population was 96.7% (18, 19). The efficacy in prevention of CIN2 associated with HPV types 31, 33, 45, 52, and 28 was 96.7%, and in prevention of persistent infection lasting 6 months or longer – 96% (20). In both study groups (Gardasil9 and Silgard), a small number of HPV infections associated with types 6, 11, 16, and 18 was noted (8 cases in total). The efficacy of the 9-valent vaccine against these types of viruses was at least the same as for 4vHPV. Again, in the 9-15 age group, the antibody titer was significantly higher than in the 16-26 age group (20).
Despite the proven efficacy of the HPV vaccines, parents are concerned about their adverse effects. The anti-vaccination movement has gained so much popularity that the Polish Academy of Sciences have issued a comment on the subject. The members of the Polish Academy of Sciences expressed their concern that the number of children covered with compulsory vaccinations in Poland has been declining year by year. In 2012, 5,340 patients from the target group did not undergo compulsory vaccination, in 2013 – 7,248 patients, in 2014 – 12,681, and in 2015 – 16,689 patients (21, 22). The Committee on Epidemiology and Bioterrorism of the Sanitary and Epidemiological Council stated that ‘well-planned and properly conducted clinical studies performed in multiple countries have excluded any causal link between vaccination, include the measles, mumps, and rubella vaccine, and the incidence of autism spectrum disorders’ (22). The expert also pointed out that other vaccines, including the HPV vaccine, as well as their ingredients, such as a preservative thiomersal, suspected of adverse effects, are safe (22).
Between the years 2006 and 2014 in the United States alone, governmental organizations collected circa 25,000 reports of the side effects of HPV vaccines. Over 90% of them have been classified as mild. Most frequently reported adverse effects included:
– subfebrile temperature – 1/10 of the patients,
– itching at the injection site – 1/30 of the patients,
– moderate fever – 1/60 of the patients.
The symptoms resolved quickly without treatment.
The reported moderate side effects included:
– shoulder pain at the vaccination site.
Up to September 2015, no serious adverse reactions of the HPV vaccine had been recorded. During the indicated period, 117 deaths were reported among vaccinated patients, none of which resulted directly from the vaccination (23). Silgard, Cervarix and Gardasil9 are safe, well-tolerated and have been proven to be effective.
Over 10 years of experience and observations of the 4vHPV vaccine were summarized by a research team led by Dr. Suzanne Gerald from the Royal Women’s Hospital in Melbourne, Australia (24). The analysis included 58 articles assessing the efficacy of Silgard. This product was first registered in Gabon in March 2006, then in Mexico, Australia, United States, and finally, in September 2006, in Europe. Today, it is available in 129 countries, in 60 of which it is part of the general vaccination programs. Since the introduction of the 4vHPV vaccine, a decline in the prevalence of HPV type 16 and 18 infections has been noted in:
– Australia by 75-80% (in women under 25 years of age),
– United States by 62-80% (in teenage girls),
– Sweden by 35-45% (in women aged 13-22),
– Germany by 35-45% (in women aged 20-25),
– Belgium by 35-45% (in women aged 15-19).
What is more, an 86% decrease in the incidence of infections with HPV types 6, 11, 16, and 18 in persons vaccinated with 3 doses of the 4vHPV vaccine has been noted in the subpopulation of women aged 18-24 in Australia. Moreover, a 76% decrease in the group of patients vaccinated with ≥ 1 dose has been observed. Similarly, in the United States, an 89% decrease in the incidence of infection with these types of HPV in the subpopulation of women aged 14-24 was noted following ≥ 1 dose of the 4vHPV vaccine (24).
In the view of the above described studies, there is no doubt that human papillomavirus vaccines are highly effective in the target group. It is clear that the best results are observed after the administration of the vaccine prior to any exposure to the virus, but benefits are also observed in patients unde going vaccination after the exposition. Undoubtedly, the inclusion of the HPV vaccination in the National Vaccination Program can effectively reduce morbidity and mortality of HPV-related conditions, which include not only cervical cancer, but also head and neck cancers.
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