Human papilloma virus is the second most common cause of death among women from cancer after breast cancer, worldwide and detection can prevent up to 80% (1). Although HPV16 and HPV18 cause 50% and 20% of cervical cancer cases respectively, there are more than a dozen other 'oncogenic' types of genital HPV. A picture of the epidemiology and pathogenesis of genital infections in women has developed during the past two decades, less is known about these infections in men. However, some studies suggest a similar infection pattern in men, who are the most important vectors for transmission of HPV disease to women.(2)
Human papilloma viruses are double-stranded DNA viruses that infect epithelial cells and are significantly associated with low-grade cervical intraepithelial neoplasia (CIN), genital condyloma and cervical cancer. HPVs are judged to be the primary cause of cervical cancer, which is the second most common type of cancer causing deaths in women worldwide (3). Other HPV-related cancers in young women include vulvar and vaginal cancers, which are preceded by dysplastic lesions (vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VaIN). In men anal cancer is the most common HPV-related cancer. The virus is also related to penile and certain oropharyngeal cancers. Other benign HPV-associated conditions include condyloma acuminata (genital warts) located in the genital or perianal region and juvenile recurrent respiratory papillomatosis (JRRP) primarily located in the larynx. (4)
Pathogeniety of oncogenic HPV strains
HPV produces genital, plantar and occasionally oral warts, which may be slow to respond to the therapy given and can, reoccur repeatedly. HPV is associated with more rapid development of cervical and anal intraepithelial neoplasia, which in time may progress to squamous cell carcinoma of the cervix or the rectum especially in HIV infected individuals (5). The main causative of this virus is through genital contact, most often during vaginal or anal sex. It may also be spread through on during oral sex and genital-genital contact; also it can be spread between straight and homosexuals even when the infected partner has no symptom or sign of it. The causative agent is HPV types 6 and 11 with types 16 and 18 being the ones that cause the majority of cervical carcinoma. The incubation period ranges from 2 weeks to 8 months or even longer depending on dose of virus received. Warts develop around the external genetalia in women usually starting at the fourchette and involve the perianal region (6). Flat warts may develop in the cervix and are not easily visible on routine examination.
The peak period of acquisition is soon after the start of sexual activity (7) and the risk of infection increases with the number of sexual partners. Although HPV infections resolve spontaneously in small fraction of women persistent infection with high risk HPV results in cervical intraepithelial neoplasia grade 2/3 and eventually cervical cancer. There are more than 100 subtypes of HPV. HPV 6 and 11 are found in benign condylomata and are only rarely implicated in malignant transformation. HPV 16 and to a lesser extent 18 are found in cervical intraepithelial neoplasia and in nearly 100% of cervical carcinomas. HPV DNA can either be present in the host cell either integrated or extrachromosomally. The integration of the viral genome into the host DNA is usual in high grade cervical squamous carcinoma. The protein coding sequences of the viral early or late opening frame appears to have a major role in oncogenesis. Most interestingly, the E6 protein of HPV type 16 is capable of binding to the cellular p53 protein (tumour suppressor protein) to form a complex that neutralises the normal response of cervical epithelial cells to DNA damage; apoptosis mediated by p53 dysfunction, which may thereby allow the accumulation of genetic abnormalities(8). However E6 protein of low risk HPV types (e.g. 6 and 11) does not appear to form a complex with p53. HPV 16 and 18 E7 proteins also the ability to bind to the product of the retinoblastoma gene (RB1), thus affecting its tumour suppressor role (9). HPV have unique mechanism of infection limited to the basal cells of stratified epithelium the only tissue in which they replicate. As the recent studies on mouse cervicovaginal challenge model indicate that the virus cannot initially bind to the keratinocytes in vivo instead the virus bind to the heparin sulphate proteoglycans (HSPGs) on segments of the basement membrane via its L1 major capsid protein after epithelial trauma and undergoes a conformational change that exposes the N-terminus of L2 minor capsid protein to furin cleavage. L2 proteolysis exposes a previously occluded surface of L1 that binds to cell surface receptor that have migrated over the basal surface to close the wound. HPV are only viruses known to initiate an infectious process extracellulary. (10)
HPV: Burden of Disease
Point prevalence measurements in such women were seen to peak in sexually active teenagers and women in their early twenties and then to decrease substantially with increasing age; even though lesions seen to develop and emerge at ages 35-50 when women are actively involved in their careers or caring for their families. In the past a secondary prevention programme was developed based on screening (11,12); the Pap smear test which took sample of the squamcolumnar cells of the cervix to perform cytological testing for presence of any lesions which is still effective in screening and used, but now HPV DNA testing using PCR can also be done. Although most infections are transiet and asymptomatic due to the action of effective immunity becoming DNA negative (13) through a cell mediated response accompanied or followed by sero-conversion and antibody to major capsid protein L1(14), persistent infection with high risk types of HPV can lead to neoplastic progression in mitotically active cells due to deregulation of E6/E7 oncogenes (15) and thence cancer.
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Prophylactic HPV Vaccines
Now a better approach is used to manage HPV is through vaccination,2 vaccine have been approved to work against HPV these are Cervarix and Gardasil (16). These two licensed HPV L1 VLP prophylactic vaccines: cervarix a bivalent HPV 16/18 vaccine from GlaxoSmithKline Biologicals (GSK) and Gardasil a quadrivalent HPV 16/18/6/11 vaccine from MSD Merck has shown in randomised controlled trails to be highly efficacious against HPV 16/18 causing high grade cervical intraepithelial disease (CIN2/3) in 16-26 year old women naive for these HPV types at trial entry and during the 3 dose immunisation boost schedule at (o, 1or 2, and 6 months)(17).
FDA approved Gardasil in june 2006 to be the first vaccine for the prevention of cervical cancer, abnormal and precancerous cervical lesions, vaginal and vulvar lesions, and genital warts. Gardasil is a recombinant vaccine and is effective against HPV types 6, 11, 16 and 18 and is approved for use in females age 9-26. Cervarix a bivalent newly approved vaccine licensed (18) cervarix 3 doge vaccine proven to be effacious (19) in preventing precancerous and cancerous lesions (cervical intraepithelial neoplasia 2+) in girls and women aged 10-25 without evidence of current infection with or prior exposure to the same HPV type at time of vaccination.(17,20)
It does this by activating your immune system to make antibodies against the most common cancer-causing HPV infections (21). Three doses are required, after each vaccine dose antibody levels increase until peak antibody concentration is achieved one month after the 3 dose. After 18 months antibody level stabilises at a plateau level with GMTs on average 10 times greater than in placebo groups as a study shows (22,23). HPV VLP immunisation generates both components of the antibody memory response the serological memory and the reactive memory (24), a prerequisite for long term vaccine induced protection.
How HPV Vaccine Protect: Immunity
The genes that code for a specific protein from each of the four virus types of HPV are expressed in yeast to create large quantities of the protein. The protein that is produced is purified and then used to make the vaccine. Because the vaccine only contains a protein, and not the entire virus, the vaccine cannot cause the HPV infection (25).
The vaccine is effective against type 16 and 18 which cause approximately 70 % of cervical cancers and against HPV types 6 and 11 which cause approximately 90% of genital warts.
VLP vaccines are highly immunogenic generating antibody concentrations after the 3rd immunisation that are 1-4 logs higher than those in natural infections (22,23). The viral antigen poorly acceses the lymphatics and draining lymph nodes where immune responses are initiated. The immunogenic antigen presenting cells and Langerhans cells both will be ineffective in the non-inflammatory reaction of productive HPV infection as HPV is extracellular. VLP vaccines induce dentritic cells in inflammatory milieu to mature and migrate to lymph nodes to trigger the T-Helper cells CD-4. Simultaneously VLP either gets bound to the surface of the APC or other immunocytes to be shuttled into lymph nodes also triggering naive B cells in the follicle and the whole pathway of events that will result in protective immunity.(26,27,28).
Now its the time to question how the virus neutralizing antibody protect HPV as we stated HPV has an exclusively intraepithelial cell cycle so how does it access the cell and how does the antibody prevent this? Well emerging evidence suggests that HPV infects basal epithelial cells via microwounds and microabrasions that remove the full thickness epithelium, but retain the basement membrane (29). The virus bind via L1 first to the basement membrane and then to the cellular receptor on the migrating wound keratinocyte (30). L1 antibodies can block both of these interactions and those antibodies that block basement membrane binding neutralises at extremely low concentrations (31).Exposure to serum antibody will be rapid due to slow entry of virus takes around 12-14 hours to enter (32).
Is it really the End of Cervical Cancer? Barriers and Limitations
The success of HPV vaccination depends on the degree of acceptance of the vaccine by an individual, parent's encouragements and health care professional's willingness to offer vaccinations. The best age group to be vaccinated in order to be protected from HPV infection and thereby cancer is the preadoscelnt and adolescent. Further more research suggests the most parents are interested in having their preadolescents and adolescent children to be vaccinated (33).
A study in Denmark found that main driver for the vaccine was the prevention of cervical cancer followed by parental encouragement and financial support, personal experience of someone with cancer and recommendations from health professionals. However on the other hand the main barrier was its cost, among lack of knowledge about the benefits of the vaccine and the participant being older also the limited availability in developing countries were the barriers (34). To break these barriers additional educational programs, more knowledge about vaccine and talks with women who actually had the vaccine who had the disease can help and if possible in future introduction of cost effective vaccine to be more affordable amongst the low income populations (35).
Conclusion
The introduction of a vaccine against human papilloma viruses 16 and 18 promises to be a significant advance in efforts to minimise the impact of cervical cancer on women globally. When given to previously uninfected women the vaccine appears to prevent most HPV 16,18 related precancerous lesions of the lower genital tract and by implication the cancers that they might develop. L1 VLP vaccines are very effective in preventing new infections by the two most common oncogenic HPV types and will dramatically reduce the rates of HPV-associated cancer provided that the vaccine is widely and properly delivered. To reach these conditions more studies are needed in order to find new broad-spectrum vaccines, possibly more economically produced. Furthermore additional research is required on vaccine uptake in high risk population and the similarities and differences between high risk populations should be considered when designing targeted interventions. Additional research is also needed to identify perceived barriers to vaccination this will foster creative interventions that convert barriers to motivators.
