Vaccination against human papillomavirus (HPV)

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

Development of cervical cancer as a result of HPV infection passes through a series of histological progenitors - intraepithelial neoplasia of mucosal 2 and 3 degree (CIN 2/3) and adenocarcinoma in situ (AIS). HPV can cause intraepithelial neoplasia of the vulva (VIN 2/3) and the vagina (VaIN 2/3) and 35-50% of all cancers of this localization. HPV also causes cancer of the penis, anus, and oral cavity.

Infection with HPV occurs with the onset of sexual activity, its intensity increases with the increase in the number of sexual partners. In Denmark at the age of 15-17 years, HPV infection was detected in 60% of the examined, with age, the infection of HPV decreases. Most infections occur subclinically, but often enough changes on infected mucous membranes progress to the development of papillomas or cancer.

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

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

Cervical cancer ranks second among malignant tumors of the reproductive organs in women and second only to breast cancer. The world annually diagnoses about 470 thousand new cases of cervical cancer, which is 14.2% of all malignant neoplasms in women.

Cervical cancer is a significant problem for public health in Russia, in 2004 it was registered in 12,700 women - about 5% of all malignant tumors and 31% of malignant neoplasms of female genitalia (12 per 100,000 women) - 5th ranked place in the structure of cancer.

Immunity and efficacy of the human papillomavirus vaccine

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

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

In non-infected vaccine strains, both vaccines have 96-100% efficacy in preventing HPV vaccine types and their persistence, and 100% with respect to induced mucosal changes. In the vaccinated groups, virtually no cases of precancerous changes in the cervix or genital condylomata were registered. This once again underscores the importance of initiating vaccination before gaining sexual experience.

And in the study of efficacy in large (more than 18,000) groups of women who had an average of 2 sexual partners, Gardasil showed efficacy (in previously uninfected) for CIN1 of 100% for HPV 16 and 95% for HPV 18, and for CIN 2 / 3 - 95% for both serotypes. For the Cervarix vaccine, these rates were 94 and 100% for CIN1 and 100% for CIN 2/3. In the group of women, seropositive (but DNA-negative) to HPV 16 and 18, who received a placebo, there was a development of both a condyloma and a precancerous change in the mucous membrane of the cervix (evidence of reinfection), whereas among the vaccinated (both Gardasil and Cervarix) in one case, CIN 2 was not detected. This indicates that a natural immune response is not always sufficient in preventing pathological changes and that vaccination can enhance it to a protective level.

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

The use of AS04 in the Cervarix vaccine at least doubled the antibody titre throughout the study and provided high efficacy also for pathology caused by non-vaccine viruses. The vaccine provided a reduction in the incidence of persistent infection (over 6 months) for HPV 31 by 42%, HPV 45 by 83%, and HPV 31/33/45/52/58 by 41%. Cross-protection in the whole group of vaccinated (whose HPV status was not determined before vaccination) for infection with HPV 31 was 54%, and HPV 45 - 86%.

The high performance indicators cited in the literature refer to persons free from HPV vaccine type infection at the time of vaccination and who received 3 doses of the vaccine. In the situation of practical application of the vaccine in the group of women with unknown HPV status, some of which could be infected with HPV or have mucosal changes at the beginning of the vaccination, the effectiveness will depend on the age of the vaccinated, their sexual experience, and the number of doses administered and the vaccine . When taking into account women aged 16-26 who received at least 1 dose of vaccine and who received at least 1 time for examination (ITT - intent-to treat), the efficacy for CIN 2/3 and AIS caused by HPV 16 and 18 was for both vaccines 44%, and for changes caused by a virus of any type - 17%.

Such a moderate result of vaccination of women of reproductive age is due to the presence of HPV infection preceding vaccination, as well as a short observation period (only 15 months after the 1st dose), which once again underscores the need for vaccination of adolescents without sexual experience.

Vaccine against human papillomavirus

The association of cervical cancer with HPV infection has placed it in a number of diseases controlled by methods of immunoprophylaxis. The most immunogenic viral proteins (fusion proteins L1 and L2) obtained by genetic engineering are used to create the vaccines; they are transformed on the basis of self-assembling into virus-like particles (VLP), which do not contain DNA, i.e. Not inducing infection. Vaccines are not curative and do not affect the current infection.

In Russia, two HPV vaccines have been registered, differing by their typical composition and adjuvants. Both vaccines prevent the development of changes associated with the effects of HPV 16 and 18 types - 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-reactive oncogenic serotypes. The Gardasil vaccine prevents at least 90% of cases of condylomatosis.

Papillomovirus vaccines
 

Vaccine	Composition	Dosage
Gardasil -quadrivalent, Merck, Sharp & Dome, USA	1 dose (0.5 ml) contains the L1 protein of types 6 and 18 (20 μg each), 11 and 16 (40 μg each), the sorbent is amorphous aluminum hydroxyphosphate sulfate	Introduces adolescents 9-17 years and women 18-45 years old / in 0.5 ml in the scheme of 0-2-6 months, including, simultaneously with the hepatitis B vaccine
Cervarix-bivalent, GlaxoSmith Klein.Belgium	1 dose (0.5 ml) contains the L1 protein of types 16 and 18 (20 μg each), as well as the adjuvant AS04 (50 μg 3-0-dezacil14-monophosphoryl lipid A, 0.5 mg aluminum, 0.624 mg dihydrogen phosphate dihydrate)	Introduced to girls with 10 years and women in / m to 0.5 ml according to the scheme 0-1-6 months.

Vaccines from HPV are released in vials and disposable syringes of 0.5 ml (1 dose), stored at 2-8 ° in a dark place; Do not freeze.

Vaccines from HPV are included in the Calendars of immunization of the leading economically developed countries. Since the maximum effect of any vaccination is reached before exposure to infection, the advisability of vaccinations before the onset of sexual activity is undeniable, especially since the serological response in adolescents is higher than that of women. In Canada, Austria and Belgium are vaccinated, starting at the age of 9-10 years, in the US, Australia and 11 European countries - from 11-12 years. Moreover, in 5 countries vaccinations of women up to the age of 18-20 years are recommended, and in 3 - up to 25 years. Data on maintaining a sufficiently high level of HPV transmission at the age of 25-45 years indicates the justification of vaccination of women at this age.

Given the role of male infection in the spread of HPV, a proposal is also being considered for vaccinating male adolescents, although mathematical modeling shows a small increase in efficacy if a high level of vaccine coverage is reached for women. .

Prior to inclusion in the Calendar, vaccination should be carried out on a voluntary basis through the Centers for Immunoprophylaxis and the Centers for Adolescent Medicine, as well as on a regional basis, especially in regions that are unsuccessful for cervical cancer.

Contraindications for vaccination against human papillomavirus

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

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Side effects of the vaccine against human papillomavirus

The most common pain at the injection site and headache, short-term fever, nausea, vomiting, myalgia, arthralgia. In some cases, dizziness, rash, itching, inflammation of the pelvic organs, whose frequency does not exceed 0.1%, may develop. In the grafted and control groups, the number of conceptions, spontaneous abortions, childbirths, healthy newborns and congenital anomalies did not differ. Number of cases of autoimmune diseases, peripheral neuropathies, incl. Guillain-Barre syndrome, demyelinating processes in vaccinated did not differ from that for the whole population.

The possibility of introducing a vaccine against HPV along with the hepatitis B vaccine has been proved, with respect to the vaccines Menactra, Bustrix and others are being studied.