**5. Immunity**

Cervarix® is a bivalent vaccine containing VLPs from the two most prevalent high-risk HPV types 16 and 18. The VLPs are produced in insect cells and formulated with the adjuvant system AS04 (composed of aluminium hydroxyphosphate sulfate combined with MPL- 3-O-deacyl-4' monophosphoryl lipid A) [17]. Gardasil® is a quadrivalent vaccine that in addition to HPV16 and HPV18 VLPs also contains HPV6 and HPV11 VLPs. These two low-risk types are respon‐ sible for nearly 90% of the genital warts. The VLPs in Gardasil® are produced in a yeast system

and adjuvanted with aluminium hydroxiphosphate sulfate salt [18] (Table 1).

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

**Vaccine Gardasil® Cervarix® Manufacturer Merck & Co., Inc. GlaxoSmithKline**

> Saccharomyces cerevisiae CANADE 3C-5 (Stamm 1895)

40 µg HPV11 L1 VLP 40 µg HPV16 L1 VLP 20 µg HPV 18 L1VLP

Vaccination schedule Months 0, 2, 6 Months 0, 1, 6

(catch-up: 13-26 years old).

Vaccination of female at age 11 or 12 years

Vaccination of male aged 9 through 26

Since the main target groups for the HPV vaccines are children and young women that have not initiated sexual activity, safety was the highest priority for the two vaccine producers.

Over the past years many studies have been conducted to ensure safety and tolerability of Cervarix® and Gardasil® [21, 22]. Independent of age, sex or ethnicity, the HPV vaccines are highly safe and well tolerated with very little adverse effects and no significant differences between Gardasil® and Cervarix®. However, in a direct comparison study between the two vaccines, Cervarix® was associated with higher rates of local injection site reactions than Gardasil® [23] (Table 2). This effect might be associated with the differences in adjuvant

Ampules 0.5 mL

years.

**Table 1.** Comparison of the two prophylactic HPV vaccines, Gardasil® and Cervarix®.

Insect cells

Ampules 0.5 mL

at 9 years ).

Spodoptera frugiperda Sf-9, Trichoplusia ni Hi-5

Vaccination of female aged 11 or 12 years old (can be started

20 µg HPV16 L1 VLP 20 µg HPV 18 L1VLP

Producer cells Yeast

Vaccine recommendation

Modified from [19] and [20]

formulation between the two vaccines.

(ACIP)

**4. Safety**

Antigen 20 µg HPV6 L1 VLP

Package Ready-to-use syringe

#### **5.1. Immunity of natural HPV infection**

As HPV infection is limited to basal epithelial cells, the virus is normally "hiding" from circulating immune cells during initial stages of infection, limiting the host's immune respons‐ es. Additionally, to evade the host's immune system and achieve persistent infection, HPV has developed several mechanisms to down-regulate host immunity [27, 28]. The virus's success in evading the immune system is corroborated by the finding that of the women infected with HPV, only 50% develop anti-HPV antibodies (mainly anti-L1). Whether these antibodies can protect against re-incident infection remains unclear.

#### **5.2. Vaccine induced immunity and duration of protection**

The mechanisms of immunity induced by the HPV vaccines are not fully understood but it seems that humoral immunity (virus-specific neutralizing immunoglobulin G antibodies) plays an important role. Passive transfer of immune serum in pre-clinical animal models, for example, have demonstrated that L1 virus-specific antibodies are sufficient to prevent papillomavirus infection [14, 29, 30].

Cervarix® and Gardasil® induce production of high levels of anti-L1 antibodies that reach their peak seven months after the administration of the third dose. The level of antibodies gradually decreases over time but even after several years the titers remain higher than in naturally infected women.

**6. Efficacy in clinical trials**

warts for Gardasil® and Cervarix®.

HPV serostatus or cytology baseline.

**6.1. Cervarix®**

assessment) [34, 47].

**6.2. Gardasil®**

(AIS) lesions [48, 49]

HPV DNA in lesions, was 30%.

were pregnancy and abnormal Pap smears [21, 42-46].

Six major clinical trials enrolling around 44.000 females were conducted to evaluate the efficacy of Cervarix® (2 trials) and Gardasil® (4 trials). Most of the trials included subjects from the age of 15 to 26 years (except for Muñoz *et al*, 24-45 years) with a limited lifetime number of sexual partners (≤4-6, except for Muñoz *et al.*, with no restriction). The sole exclusion criteria

Human Papillomavirus Prophylactic Vaccines and Alternative Strategies for Prevention

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

155

Since cervical cancer is an unethical endpoint for the HPV prophylactic vaccines efficacy evaluation, the clinical trials concentrated on prevention of pre-cancerous high-grade cervical intraepithelial neoplasias (CIN 2 and 3). Results from these trials have shown the high efficacy of the prophylactic vaccines in preventing persistent infection and CIN 2/3 lesions and genital

The double-blind randomized controlled PATRICIA (PApilloma TRIal against Cancer In young Adults) is the largest Cervarix® vaccine trial performed to date and it was conducted in more than 14 countries from Asia-Pacific, Europe, North America and Latin America. It included over 18.000 healthy women between 15 and 25 years of age with no more than six lifetime sexual partners; these women were enrolled irrespective of their HPV DNA status,

Cervical cytologies and biopsies for 14 oncogenic HPV types were assessed by PCR. The primary endpoint for the vaccine efficacy was the development of CIN 2+ associated with HPV16 or HPV18 and as well non-vaccinated oncogenic HPV types (for cross-protection

Data from three different cohorts (ATP-E: according to protocol cohort for efficacy vaccinated: n=8093; control: n=8069; TVC: total vaccinated cohort = women receiving at least one dose of the Cervarix®: n=9319; control: n=9325; and TVC-naïve = no evidence of oncogenic HPV infection at baseline vaccinated: n=5822; control: n=5819) over a mean of 34.9 months was analyzed. The efficacy of the vaccine against CIN2/3 lesions associated with HPV16/18 was similarly high (around 98% for CIN2+ and 100% for CIN3+) in the ATP-E and TVC- naïve cohorts. For the TVC group the efficacy of the vaccine against CIN3+ lesions, irrespective of

The randomized, double-blind, placebo-controlled trials FUTURE I and FUTURE II included 18.174 women between 16-26 years of age from 24 different countries from Asia-Pacific, North America, Latin America and Europe. The primary endpoints for the Gardasil® efficacy clinical trial were a) incidence of genital warts, vulvar or vaginal intraepithelial neoplasia or cancer and b) the incidence of cervical intraepithelial neoplasia CIN2/3 and adenocarcinoma *in situ*


HPV = Human papillomavirus. According to protocol population = women HPV16 or HPV18 DNA negative during the vaccination schedule, that received 3 doses of the vaccine; Per protocol population = participants received 3 doses of vaccine or placebo within 12 months and were seronegative on PCR analysis for HPV6-, HPV-11, HPV-16, or HPV18 at day 1 through 1 month after the third dose.\* Persistent infection correspond to infection detected for ≥6 months. N/A: not available.

#### **Table 3.** Cervarix® and Gardasil® efficacy

Both vaccines lead to seroconversion of nearly 100% of the immunized subjects. Cervarix® was shown to sustain relatively stable immunity against HPV16/18 for more than eight years [31]. Subjects immunized with Gardasil® were shown to be consistently seropositive for more than four years for HPV11, HPV6 and HPV16 but a decline in antibody titers was recorded for HPV18 (from 100% to approximately 47%) [32]. However, it cannot be excluded that this observed decline is a result of assay insensitivity. Nevertheless, the protection against HPV18 induced lesions did not decrease suggesting that low levels of anti-HPV18 antibodies are sufficient to confer protection. The Table 3 shows the efficacy of Cervarix® and Gardasil® for different clinical trials followed up for different periods of time.
