HPV Type 6/11/16/18 Vaccine:

Objectives: A 3-dose regimen of quadrivalent vaccine was highly effective in preventing cervico-genital disease caused by HPV6/11/16/18. We provide the first demonstration of cross-protection for any HPV vaccine against CIN 2/3 and AIS caused by oncogenic HPVs in addition to 16/18. Data on persistent infection are also presented.

Methods: Subjects underwent cervicovaginal sampling and Pap testing at Day 1 and 6-12 month intervals for up to 48 months. Specimens were HPV typed with histologic diagnoses via pathology panel. Analyses were conducted in a generally HPV naïve population that approximates the primary target for HPV vaccination: subjects received ≥1 dose, were naïve to HPV6/11/16/18 and PCR(-) to 10 non-vaccine types (31/33/35/39/45/51/52/56/58/59) and had a normal Pap at Day 1.

Results: See table for combined results for HPV 31/45 and 31/33/45/52/58. In addition, combined efficacy for CIN2/3 or AIS caused by all 10 non-vaccine HPV types was 38% (95% CI: 6, 60).

Conclusion: Administration of quadrivalent vaccine to a generally naïve population reduces the incidence of persistent infection and CIN2/3 or AIS caused by other non-vaccine oncogenic types which cause >20% of cervical cancers worldwide. This may increase the expected cancer reduction of this vaccine.

• HPV is extremely common¹

     – By age 50, at least 75% of men and women have acquired HPV

• Cancers are caused by HPV^2-5

     – Cervical (sole cause)
     – Vaginal, vulvar, anal (primary cause)

• Non-cancerous tumors are caused by HPV^6-7

     – Genital warts
     – Laryngeal tumors (Recurrent Respiratory Papillomatosis)

• HPV types are organized into genera and species on the basis of homology in the sequence of the L1 (major capsid protein) gene (Figure 1)⁸

• HPV16 is the prototype of the A9 species, which includes 6 cancer-causing HPV types(16/31/33/35/52/58), Table 1⁸

• HPV18 is the prototype of the A7 species, which includes 5 cancer-causing HPV types (18/39/45/59/66), Table 1⁸

• A pooled analysis of 11 studies conducted in 9 countries showed that the 12 most common types in cervical cancer worldwide were, in descending order of frequency: HPV16, 18,45, 31, 33, 52, 58, 35, 59, 51, 56, and 39 (Table 1).⁸ This distribution varied by regions.
Ranking of role in cervical neoplasia differs.

• Together, HPV16 and HPV 18 are responsible for ~70% of all invasive cervical cancers.
The members of the A9 and A7 species listed above (other than HPV16 and HPV18) are responsible for >20% of all cervical cancers worldwide and a large proportion of high and low-grade cervical lesions^9-10

Quadrivalent Human Papillomavirus (types 6, 11, 16, 18) Recombinant Vaccine

• Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine targets the HPV types responsible for a majority of HPV-related disease

• VLPs manufactured in Saccharomyces cerevisiae

     – Yeast-derived vaccines given to millions of children and adults

• Adjuvanted with amorphous aluminum hydroxyphosphate sulphate (AAHS) 225 μg per dose

• 0.5 mL injection volume

• 3 doses within 6 months

• First approved by United States Food and Drug Administration (FDA) on June 8, 2006 (see table 2 for prophylactic efficacy data)

     – Indications

          • cervical cancer
         • genital warts
         • vulvar pre-cancerous lesions (VIN 2/3, see table 3 for glossary)
         • vaginal pre-cancerous lesions (VaIN 2/3, see table 3 for glossary)

• Now licensed in ~ 80 countries including US and Europe (EMEA approval on September 20, 2006)

Figure 1. Cancer-Causing HPV Species - HPV Phylogenetic Tree.

Table 1. Contribution of HPV Types to Cervical Cancer, World Average (Varies by Region)⁸.

Table 2. Prophylactic Efficacy Results.*

Table 3. Glossary of Terms.

• It is hypothesized that HPV16 and HPV18 neutralizing antibodies generated by vaccination may bind and neutralize virions of HPV types related to HPV16 and/or HPV18, thereby preventing infection and disease caused by these related types (cross-protection)

• Such a capability could potentially increase the expected cancer reduction of this vaccine

• To provide the first demonstration of cross-protection for any HPV vaccine against cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS), endpoints which are cervical cancer precursors and which formed the basis of vaccine licensure. Data on persistent infection are also presented

• Studies Used in Analysis of Cross Protection

     – Combined Phase III Efficacy Studies (Protocol 013 [FUTURE I] and Protocol 015 [FUTURE II])

          • 17,622 15- to 26-year-old women

          • Subjects were randomized to either quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine or placebo

               – Vaccine or placebo administered (IM) at Day 1, Months 2 and 6

               – ThinPrep™ Pap smears and swabs for HPV DNA were taken at Day 1 and at 6–12 month intervals thereafter for a maximum of 48 months

               – All Pap tests and biopsies processed/read at a central laboratory or at 1 of 5 regional central labs

               – Expert pathology panel read all slides for endpoint determination

• Populations for Analysis of Cross Protection

     – Primary analysis

          • The pre-specified primary analysis for infection and disease was done in populations that required women to be negative for the type being analyzed, but who could be positive for other HPV types. In the primary analysis populations, efficacy for HPV 31/33/45/52/58 persistent infection was 25% (95%CI:9, 38) and efficacy for HPV 31/33/45/52/58 CIN of any grade or AIS was 19% (95%CI: 1, 33). As the magnitude of benefit was confounded by coinfection, we did supportive analyses in a generally HPV-naive population. The generally HPV-naïve population is the focus of the current presentation.

     – Supportive analysis in a generally HPV-naïve population approximating the primary HPV vaccination cohort

          • Naïve to all 14 tested HPV types (6/11/16/18/31/33/35/39/45/51/52/56/58/59) AND

          • Negative Pap test at Day 1

          • Case counting starting 1 month Postdose 1

               – Case counting includes infections that started prior to completion of the vaccination regimen

• Rationale for Studying an HPV-Naïve Population

     – The vaccine is intended for prophylactic use

          • Highly effective in preventing infection and disease

          • Does not treat disease or clear established infection

     – The primary target for HPV vaccination programs are HPV-naïve girls and women^16-17

          • Pre-sexually active girls/women

          • Young Women shortly after sexual debut

          • HPV-naïve clinical trial population thus represents the primary target population for vaccination programs

• We followed the WHO opinion regarding cross-protective efficacy standards13

     – Cross-neutralization studies cannot be used to predict efficacy against non-vaccine types

     – Efficacy data are needed to demonstrate cross-protection

          • Incidences of lesions (such as CIN of any grade, CIN2/3 or AIS) due to the types inquestion and/or

          • Viral persistence

• Endpoints Used in Analysis

     – Persistent Infection

          • Detection of the same HPV type DNA at 2 consecutive visits spaced ≥6 months apart (±1 month visit windows) or presence of cervical/genital disease caused by the relevant type with DNA for type found in swab at visit directly before or after biopsy

     – Ascertainment of HPV infection involved HPV PCR analysis of genital swabs. For all subjects, we tested for 14 HPV types (see below) at Day 1. At Months 3, 7, 12, 18, 24, 30, 36, and 48, swabs from subjects enrolled in a substudy of FUTURE I were tested for 9 HPV types (HPV16/18/31/33/35/45/52/58/59)

     – Disease

          • A pathology panel consensus diagnosis of CIN1-3, AIS, or cancer, with HPV DNA detected in an adjacent section of the same lesion

     – Cervical biopsies, Endocervical Curettage (ECC) specimens, specimens from Loop Electrosurgical Excision Procedures (LEEPs), and conization procedures, obtained at any time during the studies were tested for 14 types (HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59) using a PCR-based assay^14-15

• Figure 2 shows the participant flow diagram.

     – A total of 2,065 subjects, representing 53% of enrolled subjects in the FUTURE I substudy, were generally HPV naïve and, therefore, included in the analyses for persistent infection

     – A total of 9,291 subjects, representing 53% of enrolled subjects in FUTURE I/II, were generally HPV naïve and, therefore, included in the analyses for cervical disease

• Tables 4-6 describe the cross-protection efficacy results, including:

     – HPV 31/45 (the two most common HPV types found in cervical cancers after HPV 16 and HPV 18)

     – HPV 31/33/45/52/58 (the five most common HPV types found in cervical cancers after HPV 16 and HPV 18)

     – All tested non-vaccine HPV types (31/33/35/39/45/51/52/56/58/59)

Figure 2. Participant Flow Diagram.

Table 4. Analysis of Cross-Protection for Persistent Infection.

Table 5. Efficacy of Quadrivalent Human Papillomavirus (types 6, 11, 16, 18) Recombinant Vaccine against CIN 1-3 or AIS Due to Vaccine or Non-Vaccine Types.*

Table 6. Efficacy of Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) recombinant vaccine against CIN 2/3 or AIS (Obligate Precursor Lesions to Cervical Cancer) Due to Vaccine or Non-Vaccine Types.*

Figure 3. Incidence of CIN 2/3 or AIS Through 2.9 Years of Follow-Up in the Generally HPV-Naïve Population of FUTURE I/II.

• We provide the first demonstration of crossprotection for any HPV vaccine against CIN2/3 and AIS, endpoints which are cervical cancer precursors and which formed the basis of vaccine licensure

• Prophylactic administration of quadrivalent HPV6/11/16/18 AAHS adjuvanted vaccine to a generally HPV naïve population of 16- to 26-yearold women results in cross-protective efficacy

     – 38% reduction in CIN 2/3 or AIS caused by 10 non-vaccine HPV types which cause >20% of cervical cancers worldwide

     – Reductions most apparent for A9 species – which cause most cases of CIN 2/3 or AIS

• The high degree of cross-protection against additional oncogenic HPV types may provide an extra measure an extra measure of protection for young women vaccinated with the quadrivalent HPV vaccine