**8. The HPV prophylactic vaccines**

The current HPV prophylactic vaccines are based on VLPs, with two prophylactic HPV vaccines being commercially available: the bivalent (HPV 16/18) vaccine Cervarix® (GlaxoS‐ mithKline, Middlesex, UK) and the quadrivalent (HPV 6/11/16/18) Gardasil® (Merck, NJ, USA). Licensed globally, these two vaccines have produced great expectations that they will prevent infections and tumors induced by different HPV types (Syrjänen, 2010).

The US Food and Drug Administration (FDA) approved Gardasil for females aged 9–26 in 2006. In October 2009, the FDA approved Cervarix for use in females aged 10–25 and approved Gardasil for use in males aged 9–26 to prevent genital warts and to prevent the spread of cervical cancer. Moreover, the FDA (2010 and 2010a) has proclaimed that the dosing and administration schedule should be 0.5 mL administered intramuscularly (preferably in a deltoid muscle) on a 3-dose schedule. The second dose should be administered 1 to 2 months later, and the third dose should be administered 6 months after the first dose.

stills not clear for how long these patients can maintain high levels of immune response, as they have been already infected. The vaccines have also shown, at best, limited efficacy in eradicating established tumors, although the fact that they have mostly been tested in ad‐ vanced stage cancer patients with compromised immune systems may have limited their

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Perhaps the ideal HPV vaccine strategy calls for a vaccine that possesses both prophylactic and therapeutic properties. A chimeric vaccine of this type could both prevent new HPV infections and clear existing infections. Moreover, such a vaccine would benefit and could be administered to both sexually inexperienced young individuals and older individuals who already harbor HPV (Franceschi, 2005). Of course the costs of the rise of individuals been vaccinated needs to be estimated, in order to not turn HPV vaccine in an expensive waste of health budget. It is important to remember that although some groups are in risk group, not all individuals of this risk group will develop an HPV-related cancer. So, before implementing HPV vaccination to a wide range of patients, it needs to be better classified what populations should be included in vaccination process, and further develop new guidelines to better incorporate in this vaccination individuals that, even in risk groups, still have a higher risk in HPV-infection and spread. Opportunities for primary and secondary prevention should be assessed, including the use of HPV vaccines to prevent infection and therapeutic vaccines in the adjuvant setting for locoregional recurrence and distant disease (Marur et al. 2010). Combined with the fact that no therapeutic vaccines currently exist for other diseases, this goal

The most recent report from Quadrivalent Human Papillomavirus Vaccine (HPV4) presents important facts about immunization practices, and provides excellent results. The efficacy for prevention of HPV 6-, 11-, 16- and 18-related genital warts was 89.3%, as a profilatic vaccine from those who have take 3 doses and was seronegative at day 1. From males who have received only one dose, regardless of serology or previous infection was of 68.1%. This efficacy was also confirmed by several other trials in female patients, with >98% efficacy in preventing HPV 6-, 11-, 16- and 18-related grade 2 or 3 cervical intraepithelial neoplasia or adenocarcinoma

Several aspects still remain to be discovered in the field of penile cancers and HPV infection, and although last decade researches were not able to define a causal role for HPV-infection, several progresses have being made in this matter. The genomic detection of HPV DNA, primarily in some subtypes of PSCCs, provides stronger support for a viral etiology in this disease, and corroborates the idea that there are at leas 2 main pathways in penile carcino‐

Targeted therapy for PSCCs now demands more predictive biomarkers, such as the HPV infection status and mutation status of crucial genes, which could contribute to personalized treatment for each individual and decrease the inherent morbidities. However, for a better

makes therapeutic HPV vaccine development a challenging task.

impact (Brinkman et al., 2005).

*in situ* (CDC MMWR, 2011).

**10. Final considerations**

genesis, and one of them is closely related to HPV.

Although clinical trials of Gardasil and Cervarix have been extremely promising, these first generation VLP vaccines may not be the ideal vaccine candidates, especially in already infected patients, and older men and women.

The most recent report from Quadrivalent Human Papillomavirus Vaccine presents important facts about immunization practices, and provides excellent results. The efficacy for prevention of HPV 6-, 11-, 16- and 18-related genital warts was 89.3%, as a profilatic vaccine from those who have take 3 doses and was seronegative at day 1. From males who have received only one dose, regardless of serology or previous infection was of 68.1%. This efficacy was also con‐ firmed by several other trials in female patients, with >98% efficacy in preventing HPV 6-, 11-, 16- and 18-related grade 2 or 3 cervical intraepithelial neoplasia or adenocarcinoma *in situ*(CDC MMWR, 2011).

Another important issue in vaccination process is to determine who are the individuals in more risk populations, in order to a better efficacy, and a reduction of the high costs involved in the vaccine production and distribution. Based on incidence of HPV-infection between several groups, the probabilities of being infected, especially subtypes 16 and 18, are higher in men who have sex with men (MSM) group than in heterosexual men (Heiligenberg, 2010). Several diseases have a higher incidence in MSM group, such as anal intraepithelial neoplasia (AIN), anal cancers, and genital warts (Jin et al., 2007). Another important group which might be benefited by HPV immunization is the HIV-positive patients, although it is not clear whether the immunization could provide a long time antibody titers against HPV 6, 11, 16, and 18, and how immunossupressed patients would react to HPV4 vaccine, in terms of safety and adversely reactions. However, as HPV4 is not a live vaccine, it can be safely administered to person in the most highly risk, such as immunocompromised individuals (like HIV-positive, drug-driven immunossupression, or disease-related immunossupression).

Researchers are now actively working to better develop prophylactic HPV vaccines that may be effective against a broader range of HPV types and have a longer shelf life.
