**7. Age for HPV vaccination**

#### **7.1. Preadolescent girls and young women**

Vaccination with Gardasil® or Cervarix® does not lead to clearance of pre-existing HPV infections [56]. Considering the decreasing age of sexual debut in many countries, both vaccines target preadolescent girls and young women. The Advisory Committee on Immuni‐ zation Practices (ACIP) recommend vaccination of females aged 13 to 26 years for Cervarix® and vaccination of 9 to 26 year old males and females for Gardasil® [57, 58].

Most of the clinical trials performed to evaluate efficacy of the prophylactic vaccines included subjects older than the primary target population. This is explained by a) the need of a population where the HPV infection happens at higher frequency for efficacy proof-ofprinciple purposes and b) legal and ethical limitations regarding the evaluation of sexual activity in the preadolescent population.

Even though several mathematical models suggest that the inclusion of males in vaccination programs will not be a cost-effective strategy [67], the potential reduction of the health burden associated with HPV infection in males (e.g.: anal cancer and anogenital warts) and the possibility to reduce the risk of HPV transmission to women argue in favor of extending HPV

Human Papillomavirus Prophylactic Vaccines and Alternative Strategies for Prevention

http://dx.doi.org/10.5772/55852

159

One of the arguments against the vaccination of males is that immunization of females might already lead to enhanced herd immunity and thereby reduce male lesions as well. One factor not considered with this argument is the scenario of men who have sex with men (MSM) who

The MSM population is one of the most affected by HPV warts and anal cancer. It is clear that this population will not benefit from female vaccination. Recently, a clinical trial enrolling 602 healthy men who have sex with men (16 to 26 years of age) showed efficacy and safety of

Based on data of Gardasil® safety, efficacy against AIN2/3, estimates of disease and cancer resulting from HPV and cost-effectiveness, the Advisory Committee on Immunization Practices (ACIP) recommended routine use of the quadrivalent HPV vaccine in males aged 11

Immunocompromised women and men are known to have higher incidences of HPV infection and HPV-related diseases including cervical and anal cancer. However, little is known about

Few HPV clinical trials have been studying HIV positive populations. Among those, a clinical trial evaluated Gardasil® safety and immunogenicity in HIV infected children from 7 to 12 years, separated into three different groups according to their CD4+ T cells count. The vaccine was considered highly safe, with no CIN3 lesions being observed in the vaccinated group when compared to the control. Vaccination led to seroconversion of 99% of the immunized subjects; however, antibody titers for HPV16 and HPV18 were much lower (30-50%) than for the historical control (HIV uninfected children – Gardasil® vaccinated) [69], indicating a reduced

As levels of HPV16 and HPV18 antibodies were still comparable to HIV-uninfected women (16-26 years old) in whom the vaccine efficacy was confirmed, long-term studies with more

As outlined above, the two commercial vaccines induce long lasting high titer, protective antibody responses against the HPV types included in the vaccines. The efficacy of preventing vaccine type induced lesions can reach up to 100%. This success is based on the exceptional

subjects are necessary to determine vaccine efficacy in the HIV infected population.

**8. Is there room and need for second generation vaccines?**

Gardasil® against high-grade anal intraepithelial neoplasia (AIN2/3) [68].

the efficacy and safety of the prophylactic vaccine in this population.

vaccination programs to males.

or 12 years [58].

cannot benefit from female vaccination.

**7.4. Vaccination of immunocompromised**

response in this target population.

A Cervarix® clinical trial, performed in Denmark, Estonia, Finland, Greece, Netherlands and Russia, with an extension study (4 years follow-up) conducted in Denmark, Estonia and Finland, was designed to evaluate safety and immunogenicity of the bivalent vaccine in two age groups (10-14 and 15-25 years). According to the follow-up study, Cervarix® induced higher systemic and mucosal immune responses, which sustained for more than four years, in the 10-14 years group compared to the 15-25 years group [59].

### **7.2. Older women**

Women can acquire HPV infections at any age. However, epidemiological data report that the highest prevalence of HPV infections occur in sexually active women under 25 years of age and decline with age progression [60].

Recent meta-analysis studies have been showing a second peak of HPV prevalence in women over 44 years [61]. There are several hypotheses explaining this phenomenon but the most plausible one is associated with changes in sexual behavior of women and their partners at this age.

Humoral responses to HPV vaccines are known to decrease gradually with age progression but the antibody levels remain several fold higher for years in vaccinated (46-55 years) than in non-vaccinated subjects who developed natural immunity in response to infection [62]. A recent analysis of the FUTURE I and FUTURE II clinical trials evaluated the efficacy of Gardasil® in HPV DNA positive women who were treated for cervical, vulvar, or vaginal disease. This study showed that vaccination with Gardasil® decreases by more than 40% the incidence of subsequent HPV-related diseases including genital warts and CIN1/2 lesions, irrespective of the HPV type in the lesion [63]. This finding suggests that including women older than 26 years in the vaccination program might prevent HPV persistent infection in naïve women and reduce re-infection for those that were already infected.

#### **7.3. Vaccination of males**

HPV infection of males is associated with genital warts, anogenital cancer, oral cancer, and recurrent respiratory papillomatosis. The overall incidence of HPV infection is very similar for men and women, although, in contrast to the situation in women, HPV infection in males does not seem to be age related [64].

Currently, Gardasil® is the only HPV prophylactic vaccine licensed for use in males. Their target population is boys and men aged 9 to 26 years. Its high immunogenicity, safety and efficacy against anogenital warts and perianal/perineal intraephitelial neoplasia in males has been reported in several clinical trial studies [65, 66].

Even though several mathematical models suggest that the inclusion of males in vaccination programs will not be a cost-effective strategy [67], the potential reduction of the health burden associated with HPV infection in males (e.g.: anal cancer and anogenital warts) and the possibility to reduce the risk of HPV transmission to women argue in favor of extending HPV vaccination programs to males.

One of the arguments against the vaccination of males is that immunization of females might already lead to enhanced herd immunity and thereby reduce male lesions as well. One factor not considered with this argument is the scenario of men who have sex with men (MSM) who cannot benefit from female vaccination.

The MSM population is one of the most affected by HPV warts and anal cancer. It is clear that this population will not benefit from female vaccination. Recently, a clinical trial enrolling 602 healthy men who have sex with men (16 to 26 years of age) showed efficacy and safety of Gardasil® against high-grade anal intraepithelial neoplasia (AIN2/3) [68].

Based on data of Gardasil® safety, efficacy against AIN2/3, estimates of disease and cancer resulting from HPV and cost-effectiveness, the Advisory Committee on Immunization Practices (ACIP) recommended routine use of the quadrivalent HPV vaccine in males aged 11 or 12 years [58].

### **7.4. Vaccination of immunocompromised**

Most of the clinical trials performed to evaluate efficacy of the prophylactic vaccines included subjects older than the primary target population. This is explained by a) the need of a population where the HPV infection happens at higher frequency for efficacy proof-ofprinciple purposes and b) legal and ethical limitations regarding the evaluation of sexual

158 Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective

A Cervarix® clinical trial, performed in Denmark, Estonia, Finland, Greece, Netherlands and Russia, with an extension study (4 years follow-up) conducted in Denmark, Estonia and Finland, was designed to evaluate safety and immunogenicity of the bivalent vaccine in two age groups (10-14 and 15-25 years). According to the follow-up study, Cervarix® induced higher systemic and mucosal immune responses, which sustained for more than four years,

Women can acquire HPV infections at any age. However, epidemiological data report that the highest prevalence of HPV infections occur in sexually active women under 25 years of age

Recent meta-analysis studies have been showing a second peak of HPV prevalence in women over 44 years [61]. There are several hypotheses explaining this phenomenon but the most plausible one is associated with changes in sexual behavior of women and their partners at

Humoral responses to HPV vaccines are known to decrease gradually with age progression but the antibody levels remain several fold higher for years in vaccinated (46-55 years) than in non-vaccinated subjects who developed natural immunity in response to infection [62]. A recent analysis of the FUTURE I and FUTURE II clinical trials evaluated the efficacy of Gardasil® in HPV DNA positive women who were treated for cervical, vulvar, or vaginal disease. This study showed that vaccination with Gardasil® decreases by more than 40% the incidence of subsequent HPV-related diseases including genital warts and CIN1/2 lesions, irrespective of the HPV type in the lesion [63]. This finding suggests that including women older than 26 years in the vaccination program might prevent HPV persistent infection in naïve

HPV infection of males is associated with genital warts, anogenital cancer, oral cancer, and recurrent respiratory papillomatosis. The overall incidence of HPV infection is very similar for men and women, although, in contrast to the situation in women, HPV infection in males does

Currently, Gardasil® is the only HPV prophylactic vaccine licensed for use in males. Their target population is boys and men aged 9 to 26 years. Its high immunogenicity, safety and efficacy against anogenital warts and perianal/perineal intraephitelial neoplasia in males has

activity in the preadolescent population.

and decline with age progression [60].

**7.2. Older women**

this age.

**7.3. Vaccination of males**

not seem to be age related [64].

been reported in several clinical trial studies [65, 66].

in the 10-14 years group compared to the 15-25 years group [59].

women and reduce re-infection for those that were already infected.

Immunocompromised women and men are known to have higher incidences of HPV infection and HPV-related diseases including cervical and anal cancer. However, little is known about the efficacy and safety of the prophylactic vaccine in this population.

Few HPV clinical trials have been studying HIV positive populations. Among those, a clinical trial evaluated Gardasil® safety and immunogenicity in HIV infected children from 7 to 12 years, separated into three different groups according to their CD4+ T cells count. The vaccine was considered highly safe, with no CIN3 lesions being observed in the vaccinated group when compared to the control. Vaccination led to seroconversion of 99% of the immunized subjects; however, antibody titers for HPV16 and HPV18 were much lower (30-50%) than for the historical control (HIV uninfected children – Gardasil® vaccinated) [69], indicating a reduced response in this target population.

As levels of HPV16 and HPV18 antibodies were still comparable to HIV-uninfected women (16-26 years old) in whom the vaccine efficacy was confirmed, long-term studies with more subjects are necessary to determine vaccine efficacy in the HIV infected population.
