**3.1 Natural infection protects so there is no need for vaccination**

HPV slithers through the cervical cracks and reaches basal cells in about 30 minutes and enters the cells to infect them. Since it does not stay in the vascular system, the antibody response does not form. Inside the cell, DNA is located episomally at first. Episomally located DNA causes a temporary infection and gets excreted with the cell when the cell is visible on the surface. If the DNA of the HPV gets integrated into the cell DNA, persistent infection will occur and some of them advance to

preinvasive lesions. Only 15 of 100 HPV-infected women will develop cervical intraepithelial neoplasia (CIN) while 60% of them will have regression and 25% of them continue as infection.

In a study by Viscidi et al. with the National Cancer Institute (NCI) on the "Guanacaste, Costa Rica NCI Program," that included 10,049 women examined for over a 5-year period; natural HPV infection occurred on women independent of the type-based serological state. HPV infections from types 16, 18, and 31 rates were equal for both seronegative and seropositive cases. This is the clearest evidence which proves that natural infections do not protect against HPV [14].

### **3.2 Vaccinated children cannot get HPV or HPV-linked cancer in the future**

Many patients as well as physicians have misinterpreted this issue. HPVvaccinated patients that develop HPV-related diseases are shown as exemplary cases. What is the right information, then? Considering the cervical cancer, only 15 high-risk types can cause cancer. Types 16 and 18 that are included in the vaccines are responsible for 71–76% and the seven high-risk types in the nonavalent vaccines are responsible for 88–90% of all cervical cancer. Naturally, even nonavalent vaccines do not protect against all HPV types, and HPV infection can develop in the rest. Furthermore, we know that LSIL (low-grade squamous intraepithelial lesion) may develop not only through high-risk HPV types but also it can be caused by other types of HPV.

In the end, naïve (no prior contact with HPV) group children are protected close to 100% against *the types included in the vaccine*. Adults who have not developed the same type HPV before are also protected close to 100%. If they developed it before, they are instead protected against the other included types.

However, FUTURE III study shows us that the chance of developing both types 16 and 18 infections is less than 1% [15]. In addition to this, Kang et al. studied the efficacy of quadrivalent vaccines in 737 cases treated for CIN 3 over the course of 3 years. In this randomized controlled study, 360 vaccinated cases and 377 non-vaccinated cases were monitored in terms of recurrent diseases associated with certain HPV types. In the vaccinated group, recurrent infection rate was 2.5% while in the nonvaccinated group, the rate was 8.5% (HR = 2.840; CI: 1.335–6.042; p < 0.01) [16].

As a summary, both vaccinated girls and boys can develop HPV infections, which can lead to cancer, with types that are not included in the vaccine. Anogenital warts can occur with HPV types other than 6 and 11, hence the quadrivalent and nonavalent vaccinated group can develop anogenital warts at a rate lower than 10%.

### **3.3 Vaccination cures their related disease**

Vaccines do not treat HPV-associated diseases. They are not therapeutic. However, as stated in previous section, vaccines are effective in preventing recurrent infections.

### **3.4 Antibody levels in blood are quite important; the protection loses its effect if the levels drop**

Both bivalent and quadrivalent HPV vaccines' fundamental studies, FUTURE [15] and PATRICIA [17], recorded related blood antibody levels. In these studies, neutralizing antibody levels were measured for four different age groups: 15–25, 26–35, 36–45, and 46–55 years old. For per protocol groups, both HPV 16 and 18 neutralizing antibodies separately showed a peak at 7 months (after the third dose).

**97**

*HPV Vaccines: Myths and Facts*

*DOI: http://dx.doi.org/10.5772/intechopen.90442*

**3.5 Herd immunity does not exist**

HPV-related diseases at a lower rate.

to follow-up case series not being available yet.

**3.6 Vaccinations are not effective when done at later ages**

ies showed 76% decrease at 24 weeks and 56% at 36 weeks.

Antibody levels were found to be at least 8 times higher compared to natural infections, even in the youngest age group. HPV vaccines were found to have a general characteristic to be effective when done in both childhood and later ages. Neutralizing antibody level of 4V HPV vaccine for type 18 started to fall starting at 24 months and fell to the natural infection level at 55 months. Neutralizing antibod-

Does this decrease in antibody level correspond to a decrease in protection level against type 18? In a 2008 RCT study by Joura et al., the protection level against HPV type 18 was steady at 98.4% (95% CI: 90.5–100) even when the antibody levels fell [18]. Ault et al. also showed that at 4 years mark, CIN 2/3 protection levels were at 100% even when seropositivity dropped to 60% [19]. When we consider the HPV vaccinated population that did not follow the full protocol; or had one or two doses only, by the 15th year mark hepatitis B vaccine shows a similar result. One or two dose vaccination was shown to provide comparable protection to three-dose regimes [20]. Even though hepatitis B vaccinated population's neutralizing antibody level was not measurable, the protection level was known to be still at 100%. This goal is presumed to be reflected on HPV vaccination soon. As in, changes in the neutralizing antibody levels do not affect the protection, which will stay at 100%.

Herd immunity, or the increase in protection rate of the unvaccinated population as the overall vaccination rate increases, is a well-known fact for all types of vaccines. In Sweden, even though quadrivalent HPV vaccination rates are very low, 15–44 years old unvaccinated men and women had significant decrease on the annual rate-of-change percentage [21]. Therefore, as the community vaccination rate increases, those who are not vaccinated with HPV-related vaccines will develop

It was shown that HPV vaccination generates high neutralizing antibody levels when done in early childhood as well as at later ages. PATRICIA and FUTURE studies, at four age groups of 15–25, 26–35, 36–45 and 46–55 years old, shows consistent antibody levels for all of them. Even if there is not a statistical significance on vaccination of the naïve population, it is expected to be more effective. However, for all three vaccinations, EMA (European Medicine Agency) does not provide a set age limit. After considering the available data and studies, EMA decided to lift the age limit on women. However, there is a soft 25 years-old upper limit for men. This age limit is due

**3.7 Smear or other HPV tests should be performed before the vaccination**

Vaccination will not protect against infections that occurred prior to it. FUTURE III study shows us that developing both HPV 16 and 18 together has a chance less than 1%. According to abnormal smear results, HSIL and cancer are only correlated with high-risk HPV types. On the other hand, LSIL is correlated with both high-risk HPV types as well as others. Hence, HPV DNA test prior to vaccination can only tell for less than 1% of women if the vaccine cannot protect against the most prevalent types 16 and 18. Studies also show that vaccinations help reduce reinfection rate for prior type 16 and/or 18 infections. On top of the infections, a randomized control study on LEEP treated cases due to HSIL, shows us that vaccinated group had a

### *HPV Vaccines: Myths and Facts DOI: http://dx.doi.org/10.5772/intechopen.90442*

*Human Papillomavirus*

other types of HPV.

them continue as infection.

preinvasive lesions. Only 15 of 100 HPV-infected women will develop cervical intraepithelial neoplasia (CIN) while 60% of them will have regression and 25% of

In a study by Viscidi et al. with the National Cancer Institute (NCI) on the "Guanacaste, Costa Rica NCI Program," that included 10,049 women examined for over a 5-year period; natural HPV infection occurred on women independent of the type-based serological state. HPV infections from types 16, 18, and 31 rates were equal for both seronegative and seropositive cases. This is the clearest evidence

**3.2 Vaccinated children cannot get HPV or HPV-linked cancer in the future**

Many patients as well as physicians have misinterpreted this issue. HPVvaccinated patients that develop HPV-related diseases are shown as exemplary cases. What is the right information, then? Considering the cervical cancer, only 15 high-risk types can cause cancer. Types 16 and 18 that are included in the vaccines are responsible for 71–76% and the seven high-risk types in the nonavalent vaccines are responsible for 88–90% of all cervical cancer. Naturally, even nonavalent vaccines do not protect against all HPV types, and HPV infection can develop in the rest. Furthermore, we know that LSIL (low-grade squamous intraepithelial lesion) may develop not only through high-risk HPV types but also it can be caused by

In the end, naïve (no prior contact with HPV) group children are protected close to 100% against *the types included in the vaccine*. Adults who have not developed the same type HPV before are also protected close to 100%. If they developed it before,

However, FUTURE III study shows us that the chance of developing both types 16 and 18 infections is less than 1% [15]. In addition to this, Kang et al. studied the efficacy of quadrivalent vaccines in 737 cases treated for CIN 3 over the course of 3 years. In this randomized controlled study, 360 vaccinated cases and 377 non-vaccinated cases were monitored in terms of recurrent diseases associated with certain HPV types. In the vaccinated group, recurrent infection rate was 2.5% while in the nonvaccinated group, the rate was 8.5% (HR = 2.840; CI: 1.335–6.042; p < 0.01) [16]. As a summary, both vaccinated girls and boys can develop HPV infections, which can lead to cancer, with types that are not included in the vaccine. Anogenital warts can occur with HPV types other than 6 and 11, hence the quadrivalent and nonavalent vaccinated group can develop anogenital warts at a rate lower than 10%.

Vaccines do not treat HPV-associated diseases. They are not therapeutic. However, as stated in previous section, vaccines are effective in preventing recur-

**3.4 Antibody levels in blood are quite important; the protection loses its effect if** 

Both bivalent and quadrivalent HPV vaccines' fundamental studies, FUTURE [15] and PATRICIA [17], recorded related blood antibody levels. In these studies, neutralizing antibody levels were measured for four different age groups: 15–25, 26–35, 36–45, and 46–55 years old. For per protocol groups, both HPV 16 and 18 neutralizing antibodies separately showed a peak at 7 months (after the third dose).

which proves that natural infections do not protect against HPV [14].

they are instead protected against the other included types.

**3.3 Vaccination cures their related disease**

**96**

rent infections.

**the levels drop**

Antibody levels were found to be at least 8 times higher compared to natural infections, even in the youngest age group. HPV vaccines were found to have a general characteristic to be effective when done in both childhood and later ages. Neutralizing antibody level of 4V HPV vaccine for type 18 started to fall starting at 24 months and fell to the natural infection level at 55 months. Neutralizing antibodies showed 76% decrease at 24 weeks and 56% at 36 weeks.

Does this decrease in antibody level correspond to a decrease in protection level against type 18? In a 2008 RCT study by Joura et al., the protection level against HPV type 18 was steady at 98.4% (95% CI: 90.5–100) even when the antibody levels fell [18]. Ault et al. also showed that at 4 years mark, CIN 2/3 protection levels were at 100% even when seropositivity dropped to 60% [19]. When we consider the HPV vaccinated population that did not follow the full protocol; or had one or two doses only, by the 15th year mark hepatitis B vaccine shows a similar result. One or two dose vaccination was shown to provide comparable protection to three-dose regimes [20]. Even though hepatitis B vaccinated population's neutralizing antibody level was not measurable, the protection level was known to be still at 100%. This goal is presumed to be reflected on HPV vaccination soon. As in, changes in the neutralizing antibody levels do not affect the protection, which will stay at 100%.
