Printed by: Ž. Gudlevičienė , J. Ivanucha. “Will vaccines against the human papillomavirus help prevent cervical cancer?” Internistas, 2005, 4 (45), 91-94
Živilė Gudlevičienė, Julija Ivanucha. Institute of Oncology, Vilnius University
Cervical cancer is one of the most common cancers in lithuania. Cervical cancer is attributed to persistent infection with a ‘high-risk’ subset of human papillomaviruses (HPV). At present, optimal treatment of cervical cancer combines surgery or radiotherapy with adjuvant chemotherapy. Prevention and early detection of cervical cancer relies on cytology screening programmes. Further, present treatments and to a large extent present screening strategies do not acknowledge the viral etiology of this common cancer. Vaccines to prevent human papillomavirus infection and cervical cancer are part of a new era of cancer immunotherapy.
Keywords: cervical cancer, HPV, vaccination, immunotherapy
in Lithuania, cervical cancer ranks 4th in terms of the incidence of malignant neoplasms among women. Long-term persistent human papillomavirus (HPV) infection is essential for the development of cervical cancer. Currently, the main treatment for cervical cancer is surgery, combined with radiotherapy or chemotherapy. The prevention and early diagnosis of cervical cancer is based on cytological screening programs. However, the viral etiology of this disease is not taken into account in the treatment of this pathology and in the implementation of existing screening programs. The development of vaccines that protect against human papillomavirus infection and, at the same time, cervical cancer is the direction of a new era in cancer immunotherapy.
Keywords: cervical cancer, HPV, vaccination, immunotherapy
Cervical cancer is one of the most common oncological diseases in women worldwide. About 250,000 women die from the disease each year (1). in lithuania, cervical cancer ranks 4th in terms of the incidence of malignant neoplasms among women. Mortality from cervical cancer in our country is one of the highest in Europe (2). A selective screening program for women for cervical pathology was launched in Lithuania only in 2004. A long-lasting viral infection, the human papillomavirus, is particularly important for the development of cervical cancer, especially in high-risk oncogenic types (1). Currently, the main treatment for cervical cancer is surgical combination with radiotherapy or chemotherapy (Table 1). In this way, almost 100 percent. cases of localized non-advanced cancer. Widespread cancer, which is most commonly diagnosed in developing countries, is not thought to be curable. At present, the prevention and early diagnosis of cervical cancer is based on screening programs aimed at reducing cervical cancer mortality. Cervical cancer is more common (about 80% of all cervical cancers) diagnosed in countries that do not have screening programs and adequate treatment. However, the viral etiology of this disease is not taken into account in the treatment of this pathology and in the implementation of existing screening programs. (3).
|1 lentelė. Cervical Cancer|
|Protection and treatment|
LINK BETWEEN Cervical CANCER AND HUMAN ADDITIONAL VIRUS INFECTION
Viral or bacterial infection is important for the development of cancer in some localities. Prevention of hepatocellular carcinoma using hepatitis B virus (HBV) vaccines is already underway (4). The first of the researchers in viral carcinogenesis, Zur Hausen (5), observed an association between human papillomavirus (HPV) infection and cervical cancer. This view was later confirmed by many other researchers in in vivo studies. The studies investigated the molecular mechanisms: immortalization of cells caused by HPV infection and the associated development of cervical cancer.
Only a few types of HPV infect the genital mucosa. This infection usually resolves spontaneously without any clinical consequences. However, long-term persistent infection – lasting more than 5 years in one or more high-risk types of HPV – can lead to the development of cervical cancer or other malignancies of the genital tract. Infection with HPV type 16, one of the most malignant types of the virus, is detected in more than 50% of cases. of all cases of cervical cancer (6). But even 95 percent. these infections go away on their own within 3-5 years and only 5 percent. infected people develop cervical cancer (7).
HUMAN ADDITIONAL VIRUS VIRUSES AND THEIR PATHOLOGY
About 120 different HPV genotypes are known (8). The largest subgroup consists of viruses of mucosal infecting types, and about forty types of HPV infect the anogenital tract (Table 2). About twenty types of HPV are associated with cervical cancer. HPV in this subgroup is divided into low (HPV 6, 11, 42, 43 and 44) and large (HPV 16, 18, 31, 33, 35, 39, 45, 50, 51, 53, 55, 56, 58, 59, 64 and 68) types of cancer risk viruses. Some of these are called moderate (HPV 31, 33, 35, 51, and 52) types of cancer-risk viruses because they occur with equal frequency in both healthy and damaged tissues (9). All HPVs have two structural genes (L1 and L2) and seven functional genes (E1-E7) in their structure. The E6 and E7 genes have strong oncogenic capacity (10).
IMMUNE RESPONSE TO HPV INFECTION
HPV infection elicits a specific immune response, such as immunosuppression in transplant recipients (11) or in patients infected with the human immunodeficiency virus (HIV) (12). The natural immune response to HPV infection is weak compared to the response to other viral infections (13). It is believed that papillomaviruses can prevent the host’s immune response – the host “ignores” the infection. The natural immune response to primary viral infection is delayed, even if the viral proteins are immunogenic. Type 16 HPV L1 capsid protein-specific antibodies (the most easily detected virus-specific response) are formed from 4 months of age. up to 5 m. from the time the infection enters the body. 30-50 percent. it is not possible to detect antibodies specific for female capsid (very low antibody titer) (14). Antibodies specific for the E7 unstructured protein occur only in the early stages of invasive cervical cancer. Meanwhile, the protein is detected already during acute infection and in the progression of chronic infection to invasive cancer (10-20 years after primary infection with HPV). It is difficult to determine whether the immune response protects the host from re-infection with the virus. It is thought that protective immunity may develop after a full response to the primary infection (15).
VACCINES AGAINST HPV INFECTION
Two types of HPV vaccines have recently been developed – prophylactic and therapeutic.
Prophylactic vaccines against HPV infection. Vaccines that cause the production of neutralizing antibodies against HPV structural L1 and L2 proteins are called prophylactic. Epithelial cell differentiation is required for viral replication and capsid protein production. Therefore, the virus cannot be produced in the traditional way of vaccine production using cell cultures in vitro . Therefore, recombinant DNA vaccines expressing HPV large capsid protein L1 are used. With the help of the latest technology, virus-like particles (VLPs) are used in the development of vaccines, which are almost indistinguishable from authentic virions, except that they do not have a viral genome. To date, 5 HPV VLP vaccines have been developed and tested in preclinical studies. Phase I and II clinical trials have already been initiated to evaluate safety, immunogenicity, posology, frequency of administration and route of administration. The ideal HPV vaccine should be polyvalent (it should contain the major types of HPV that are commonly associated with cancers of various uterine localizations, VLP), inexpensive, and elicit long-term immunity. HPV-related genital tumors are more often diagnosed in women than men, with men being the only carriers of the virus. Therefore, prophylactic vaccines for men should also be considered recently. Phase III clinical trials to evaluate the efficacy of the vaccine against HPV infection and, at the same time, cervical intraepithelial neoplasias can only be planned after evaluation of phase I-II studies. VLP-based prophylactic vaccines can protect against infection with high-risk HPV if given to a woman before she is infected with the virus. If we start preventive vaccination now, it is likely that we will avoid the 5 million deaths from cervical cancer that could occur in the next 20 years as a result of the current HPV infection.
Therapeutic vaccines against HPV infection. Vaccines that induce cellular immunity against virally expressed proteins and are able to cause regression of HPV-related lesions are called therapeutic. Therapeutic vaccines are developed using synthetic peptides, recombinant proteins, or live vectors encoding HPV proteins. The targets of these vaccines are HPV E6 and E7 proteins. Vaccines targeting HPV types E6 and E7 oncogenes 16 and 18 are already being tested in phase I and II clinical trials. The studies included patients with advanced cervical cancer or women with pre-neoplastic changes in the genital tract. (16).
SUMMARY AND FUTURE PERSPECTIVES
Vaccines that are designed against high-risk oncogenic HPV cause the production of high-titer neutralizing antibodies and protect the host from infection and its consequences (tumor development). Phase III clinical trials of vaccines and evaluation of their efficacy are ongoing worldwide. Clinical trials of a vaccine based on VLP are planned for the future. Research data will make it possible to rationally introduce these vaccines to the appropriate group of women before the onset of sexual life. Well-designed cytological screening programs can largely protect against cervical cancer. Vaccination programs cannot cover all HPV genotypes and only 70% protects against cervical cancer. Interactions between the two programs need to be carefully planned, as the introduction of vaccination will result in significantly less pathology during cytological examination. Immunotherapy may have a direct effect in reducing the incidence of cervical cancer, but the effect of prophylactic vaccines on reducing mortality will only become apparent after many years. (3).
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- Zur Hausen H., de Villiers E.M., Gissmann L. Papillomavirus infections and human genital cancer. Gynecol Oncol 1981, 12, S124–S128.
- Mu?oz N. et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med, 2003, 348, 518–527.
- Schlecht N. F. et al. Human papillomavirus infection and time to progression and regression of cervical intraepithelial neoplasia. J Natl Cancer Inst, 2003, 95, 1336–1343.
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- Kadish A.S. et al. Regression of cervical intraepithelial neoplasia and loss of human papillomavirus (HPV) infection is associated with cell-mediated immune responses to an HPV type 16 E7 peptide. Cancer Epidemiol Biomarkers Prev, 2002, 11, 483–488.
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2 table: Classification of papillomaviruses
Place of infection
Acute onset of infection
Chronic manifestation of infection
|Skin||HPV1, HPV2||Skin||Warts||No violations||Rapid regression, long-term immunity|
|Mucous membranes||HPV6, HPV11||Genital mucosa||Warts||No violations||Slow regression in immunocompromised patients|
|High risk of oncogenic mucosa||HPV16, HPV18, HPV31, HPV33, HPV45||Mucous membranes of the genital tract and the outlet (other mucous membranes)||Flat epithelial lesions (CIN1)||2 percent persists
1 percent progresses to invasive cancer
|Slow regression in immunocompromised patients and the possibility of developing various tumors|
|Skin with a high risk of oncogenic risk||HPV5, HPV8||Skin||Flat epithelial lesions or no lesions
|Progressing to squamous cell carcinoma (?)||Squamous cell carcinoma
in immunocompromised patients