WILL VACCINES AGAINST HUMAN ADDITIONAL VIRUS HELP PREVENT Cervical Cancer?

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

Summary

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

 

Summary

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

 

INTRODUCTION

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

Second in the world among women in the incidence of oncological diseases 250,000 new cases per year; most often in the world in 30-50 years. aged women about 500 women get sick in Lithuania every year Develops over many years with persistence of HPV infection, especially in high-oncogenic risk types Pre-neoplastic diseases (CINs) develop early after infection with HPV In CIN and invasive cancer, HPV DNA is integrated and viral proteins are expressed Genetic predisposition exists (MHC interface – HLA-DQ? Locus, race) Increased morbidity after immunosuppression (HIV infection and immunosuppressive drugs) The influence of environmental factors (smoking or the use of oral contraceptives) is controversial

Protection and treatment

Cytological screening programs for cervical pathology Surgical and radiotherapeutic methods are used to treat early-stage cancer Late-stage cancer deaths are caused by a locally advanced process rather than distant metastases.

 

 

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).

literature:

1. Bosch F.X., Lorincz A., Munoz N., Meijer C.J., Shah K.V. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol, 2002, 55, 244–265.
2. Aleknavičienė B., Smailytė G., Elaawar B., Kurtinaitis J. Gimdos kaklelio vėžys. Sergamumo bei mirtingumo pokyčiai lietuvoje. Medicina, 2002, 38(2), 223-230.
3. Frazer I.H. Prevention of cervical cancer through papillomavirus vaccination. Nat Rev Immunol, 2004, 4(1), 46-54.
4. Chang M.H. et al. Hepatitis B vaccination and hepatocellular carcinoma rates in boys and girls. JAMA, 2000, 284, 3040–3042.
5.  Zur Hausen H., de Villiers E.M., Gissmann L. Papillomavirus infections and human genital cancer. Gynecol Oncol 1981, 12, S124–S128.
6. Mu?oz N. et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med, 2003, 348, 518–527.
7. 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.
8. Zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst, 2000, 92(9), 690-698.
9. Milde-Langosch K., Riethdorf S., Loning T. Association of human papillomavirus infection with carcinoma of the cervix uteri and its precursor lesions: theoretical and practical implications. Virchows Arch, 2000, 437, 227-233.
10. Kisseljov F.L. Virus-associated human tumors: cervical carcinomas and papillomaviruses. Biochemistry, 2000, 65(1), 68-77.
11. Sillman F.H., Sentovich S., Shaffer D. Ano-genital neoplasia in renal transplant patients. Ann transplant, 1997, 2, 59–66.
12. Ferenczy A., Coutlee F., Franco E. Hankins C. Human papillomavirus and HIV coinfection and the risk of neoplasias of the lower genital tract: a review of recent developments. CMAJ, 2003, 169, 431–434.
13. Frazer I.H. Immunology of papillomavirus infection. Curr Opin Immunol, 1996, 8, 484–491.
14. Carter J.J. et al. Comparison of human papillomavirus types 16, 18, and 6 capsid antibody responses following incident infection. J Infect Dis, 2000, 181, 1911–1919.
15. 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.
16. Srewart B.W., Kleihues P. World cancer report, IARC Press, Lyon, 2003, 148-150.

 

2 table: Classification of papillomaviruses

Group	Prototypes	Place of infection	Acute onset of infection	Chronic manifestation of infection	Other features
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 Warts	Progressing to squamous cell carcinoma (?)	Squamous cell carcinoma in immunocompromised patients