Vaccination against human papillomavirus (HPV)

Of the more than 120 types of human papillomavirus, more than 30 types infect the genital tract. Infection of women with HPV is the most important factor in the development of cervical cancer, HPV was detected in 99.7% of biopsies for both squamous cell carcinomas and adenocarcinomas. Vaccination against human papillomavirus (HPV) has significantly reduced the incidence of cervical cancer.

The development of cervical cancer as a result of HPV infection goes through a series of histological precursors - mucosal intraepithelial neoplasia grades 2 and 3 (CIN 2/3) and adenocarcinoma in situ (AIS). HPV can cause intraepithelial neoplasia of the vulva (VIN 2/3) and vagina (VaIN 2/3) and 35-50% of all cancer cases in this location. HPV also causes cancer of the penis, anus, and oral cavity.

HPV infection occurs with the onset of sexual activity, its intensity increases with the number of sexual partners. In Denmark, HPV infection was detected in 60% of those examined at the age of 15-17, with HPV infection decreasing with age. Most cases of infection are subclinical, but quite often changes in the infected mucous membranes progress to the development of papillomas or cancer.

All HPV are divided into two groups: high and low oncogenic risk. The high-risk group includes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, 82 virus types. In Europe, the most common types of oncogenic virus are types 16 and 18, which were detected in 85% of cervical cancer cases. Less common are oncogenic types 31, 33, 45, 52.

The low oncogenic risk group includes HPV types 6 and 11, responsible for 90% of cases of genital condylomatosis (about 30 million new cases of condylomatosis are registered annually worldwide); they are capable of causing only low-grade intraepithelial neoplasia of the cervix (CIN 1). These same HPV types cause recurrent respiratory papillomatosis (RRP) in children and adults, as well as a significant proportion of skin warts.

Cervical cancer is the second most common malignant tumor of the reproductive organs in women, second only to breast cancer. Around 470,000 new cases of cervical cancer are diagnosed worldwide each year, accounting for 14.2% of all malignant neoplasms in women.

Cervical cancer is a significant problem for Russian healthcare; in 2004, it was registered in 12,700 women - about 5% of all malignant tumors and 31% of malignant neoplasms of the female genital organs (12 per 100,000 women) - 5th place in the structure of oncological diseases.

Immunity and efficacy of the human papillomavirus vaccine

Since the development of cervical cancer may take 15-20 years from the moment of infection, the effectiveness of vaccines is judged by the immune response and the reduction in the frequency of precancerous changes in the mucosa (CIN 2/3, AIS, VIN 2/3, VaIN 2/3). Both vaccines induce the formation of neutralizing antibodies in titers that are much higher than those due to natural infection. The HPV vaccine Gardasil leads to the formation of specific antibodies to 4 HPV types in a protective titer in more than 99% of vaccinated persons (with negative serology and DNA of vaccine viruses at the time of vaccination) for a period of at least 5 years. The geometric mean titers (in cLIA) in adolescents of both sexes were 2 times higher than in women aged 15-26 years.

The Cervarix vaccine results in the formation of specific antibodies to HPV types 16 and 18 in a protective titer in all seronegative vaccinated women aged 15-25 years, the maximum titer was detected in the 7th month, antibodies in a protective titer persist for at least 6.4 years (76 months) after vaccination. In adolescents aged 10-14 years, antibody titers after vaccination were twice as high.

In individuals uninfected with vaccine strains, both vaccines are 96-100% effective in preventing infection with vaccine HPV types and their persistence, and 100% effective against mucosal changes induced by them. In the vaccinated groups, virtually no cases of precancerous changes of the cervix or genital condylomatosis were registered. This once again emphasizes the importance of starting vaccination before sexual experience.

And in a study of efficacy in large (over 18,000) groups of women with an average of 2 sexual partners, Gardasil demonstrated efficacy (in previously uninfected women) against CIN1 of 100% for HPV 16 and 95% for HPV 18, and against CIN 2/3 - 95% for both serotypes. For the Cervarix vaccine, these figures were 94 and 100% for CIN1 and 100% for CIN 2/3. In the group of women seropositive (but DNA-negative) for HPV 16 and 18 who received placebo, the development of both condyloma and precancerous changes in the cervical mucosa (evidence of reinfection) was observed, whereas among the vaccinated (both Gardasil and Cervarix) no cases of CIN 2 were detected. This indicates that the natural immune response is not always sufficient to prevent pathological changes and that vaccination can enhance it to a protective level.

The effectiveness of vaccines is also increased by cross-influence on non-vaccine HPV. Gardasil is effective (up to 75%) against CIN 2/3 and AIS changes caused by oncogenic HPV type 31 and moderate (30-40%) against HPV types 33, 39, 58, 59.

The use of the AS04 adjuvant in the Cervarix vaccine increased the antibody titer at least twofold throughout the study and ensured high efficacy also against pathology caused by non-vaccine viruses. The vaccine ensured a 42% reduction in the frequency of persistent infection (over 6 months) with HPV 31 in previously uninfected individuals, by 83% with HPV 45, and by 41% with HPV 31/33/45/52/58. Cross-protection in the entire group of vaccinated individuals (whose HPV status was not determined before vaccination) against infection with HPV 31 was 54%, and against HPV 45 - 86%.

The high efficacy rates reported in the literature apply to individuals free of vaccine-type HPV infection at the time of vaccination and who have received 3 doses of the vaccine. In the situation of practical use of the vaccine in a group of women with an unknown HPV status, some of whom could have been infected with HPV or had mucosal changes at the start of vaccination, the efficacy will depend on the age of the vaccinated, their sexual experience, as well as the number of vaccine doses administered and the time elapsed since vaccination. Taking into account women aged 16-26 who received at least 1 dose of the vaccine and came at least once for examination (ITT - intent-to treat), the efficacy rate for CIN 2/3 and AIS caused by HPV 16 and 18 was 44% for both vaccines, and 17% for changes caused by any type of virus.

Such a moderate result of vaccination of women of reproductive age is explained by the presence of HPV infection preceding vaccination, as well as the short observation period (only 15 months after the 1st dose), which once again emphasizes the need to vaccinate adolescents who have no sexual experience.

Human papillomavirus vaccine

The association of cervical cancer with HPV infection has placed it among diseases controlled by immunoprophylaxis methods. The most immunogenic viral proteins (fusion proteins L1 and L2) obtained by genetic engineering are used to create vaccines; they are converted by self-assembly into virus-like particles (VLP) that do not contain DNA, i.e. do not induce infection. Vaccines are not therapeutic and do not affect the current infection.

In Russia, two HPV vaccines are registered, differing in their typical composition and adjuvants. Both vaccines prevent the development of changes associated with the impact of HPV types 16 and 18 - for the European population, this is the prevention of more than 80% of cervical cancer cases; to this should be added cases of cancer caused by other - cross-reacting oncogenic serotypes. The Gardasil vaccine prevents at least 90% of cases of condylomatosis.

Papillomavirus vaccines

Vaccine	Compound	Dosage
Gardasil -quadrivalent, Merck, Sharp and Dome, USA	1 dose (0.5 ml) contains protein L1 types 6 and 18 (20 mcg each), 11 and 16 (40 mcg each), sorbent - amorphous aluminum hydroxyphosphate sulfate	It is administered to adolescents aged 9-17 years and women aged 18-45 years intramuscularly at 0.5 ml according to the scheme 0-2-6 months, including simultaneously with the hepatitis B vaccine.
Cervarix - bivalent, GlaxoSmith Kpain. Belgium	1 dose (0.5 ml) contains protein L1 types 16 and 18 (20 mcg each), as well as adjuvant AS04 (50 mcg 3-0-desacyl14-monophosphoryl lipid A, 0.5 mg aluminum, 0.624 mg dihydrogen phosphate dihydrate)	It is administered to girls from 10 years of age and to women intramuscularly at 0.5 ml according to the scheme 0-1-6 months.

HPV vaccines are available in vials and disposable syringes of 0.5 ml (1 dose), stored at a temperature of 2-8° in a place protected from light; do not freeze.

HPV vaccines are included in the Immunoprophylaxis Calendars of leading economically developed countries. Since the maximum effect of any vaccination is achieved before contact with the infection, the advisability of vaccinations before the onset of sexual activity is indisputable, especially since the serological response in adolescents is higher than in women. In Canada, Austria and Belgium, vaccinations are administered starting at the age of 9-10 years, in the USA, Australia and 11 European countries - starting at the age of 11-12 years. Moreover, 5 countries recommend vaccination of women up to the age of 18-20 years, and in 3 - up to 25 years. Data on the maintenance of a fairly high level of HPV transmission at the age of 25-45 years indicates the justification for vaccinating women at this age.

Given that male infection plays a role in the spread of HPV, the proposal to vaccinate male adolescents is also being considered, although mathematical modeling shows a small increase in effectiveness if high levels of female vaccination coverage are achieved.

Before inclusion in the Calendar, vaccination should be carried out on a voluntary basis through Immunoprophylaxis Centers and Adolescent Medicine Centers, as well as on a regional basis, primarily in regions with high rates of cervical cancer.

Contraindications to vaccination against human papillomavirus

Hypersensitivity to components of the HPV vaccine, hypersensitivity reactions to a previous dose of the vaccine.

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Side effects of the human papillomavirus vaccine

The most frequently recorded are pain at the injection site and headache, short-term increase in temperature, nausea, vomiting, myalgia, arthralgia. In some cases, dizziness, rashes, itching, inflammation of the pelvic organs may develop, the frequency of which does not exceed 0.1%. In the vaccinated and control groups, the number of conceptions, spontaneous abortions, live births, healthy newborns and congenital anomalies did not differ. The number of cases of autoimmune diseases, peripheral neuropathies, including Guillain-Barré syndrome, demyelinating processes in vaccinated people did not differ from that for the entire population.

The possibility of administering the HPV vaccine together with the hepatitis B vaccine has been proven; it is being studied in relation to the Menactra, Boostrix and other vaccines.