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HPV Vaccine: - More than Cervical Cancer Prevention -. Tam Kar Fai Department of Obstetrics and Gynaecology University of Hong Kong. Diphtheria antitoxin discovered. Measles (live)*. Mumps*. Measles (live attenuated virus)*. Measles, mumps, rubella (MMR)*.

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HPV Vaccine: - More than Cervical Cancer Prevention -

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HPV Vaccine:- More than Cervical Cancer Prevention -

Tam Kar Fai

Department of Obstetrics and Gynaecology

University of Hong Kong

Diphtheria antitoxin discovered

Measles (live)*


Measles (live attenuated virus)*

Measles, mumps, rubella (MMR)*

Pneumococcal (14-valent polysaccharide)*















Haemophilusinfluenzae type b (liquid)*

Hepatitis A (inactivated)*

Varicella (chicken pox) virus*

Haemophilusinfluenzae type b (conjugated)*

Hepatitis B (recombinant)*

Pneumococcal (23-valent polysaccharide)*

Hepatitis B (plasma derived)*

Measles, mumps, rubella virus vaccine live (new rubella strain: RA 27/3)*

Quadrivalent HPV Vaccine(4 in 1HPV vaccine)

Human Papillomavirus*

Zoster (live)*







The First Cancer Vaccine

of the World

Measles, mumps, rubella, varicella*

Haemophilusinfluenzae type b / Hepatitis B*

Cervical Cancer Is Essentially Caused by Oncogenic HPV(致癌性的HPV種類引致的子宮頸癌)

  • HPV is a main cause (主因)of cervical cancer

  • Analysis of 932 specimens from women in 22 countries indicated prevalence of HPV DNA in cervical cancers worldwide = 99.7%.

(致病相關率 99.7%)

1. Muñoz N, Bosch FX, de Sanjosé, et al. N Engl J Med. 2003;348:518–527. 2. Walboomers JM, Jacobs MV, Manos MM, et al. J Pathol. 1999;189:12–19.

Importance of Cervical Cancer

Effortto reduce cervical cancerbegan 50 years ago

Various evidences suggested cervical screening led to a reduction in incidence up to 75%

Second most common cancer among females worldwide1

1.WHO 2003

Cervical Cancer in Hong Kong1

5thmost common cancer

9thleading cause of cancer death

Cervical Screening Programin HK since March 2004

450 new cases per year

120 deaths per year

1.Hong Kong Cancer Registry, 2005

GARDASIL加衛苗™MSD’s Quadrivalent HPV L1 VLP Vaccine1

  • Quadrivalent HPV L1 VLP vaccine

    • (Types 6, 11, 16, 18)

  • VLPs manufactured in:

    • Yeast

    • Recombinant VLPs (empty shell protein L1)

    • Do not contain Virus DNA (not infectious)

  • Amorphous Aluminum Hydroxyphosphate Sulfate Adjuvant (225 μg per dose)

  • No Mercury preservative (thimerosal)

  • Storage: 2 to 8 OC

GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

*VLP = Virus-like particle.

1. Villa LL, Costa RL, Petta CA, et al. Lancet Oncol.2005;6:271–278.


  • Prophylactic vaccine

Approved in 86 Countries/Territories

Europe (EU):Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, The Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, UK

Europe (non-EU): Bosnia, Croatia, Iceland, Liechtenstein, Norway, Russia,Serbia, Switzerland, Turkey

North America:

Canada, Mexico, USA




Aruba, Bahamas, Bermuda, Barbados, Cayman Island, Curacao, Dominican Republic, Jamaica, Puerto Rico,Trinidad, Tobago


Middle East and Africa:

Central African Republic, Chad, Congo Kinshasa, Guinea Equatorial,Gabon, Ethiopia, Israel,Jordan, Kenya, Mauritania,Mauritius, Morocco, Togo, United Arab Emirates

Asia Pacific:Australia, Hong Kong, Indonesia , Macau, Malaysia, New Zealand, Philippines, Taiwan, Thailand , Singapore, Korea


Central America:

Costa Rica, El Salvador, Honduras, Guatemala, Nicaragua



South America:

Argentina, Brazil,

Chile, Colombia,

Ecuador, Peru


As of 17 May 07

as of 2 October 07

HPV Vaccine: National Immunization Program

15 countries

Eleven European countries (Germany, France, Italy, Belgium, Austria, Norway, Sweden, Greece, Denmark, Luxemburg

and Switzerland), as well as the United States, Canada, Australia and UK have already reviewed the positive public

health impact and recommended the quadrivalent HPV vaccine for universal human papillomavirus vaccination

with accelerated reviews.


  • The only vaccine registered in Hong Kong in the moment

  • Indication: 9 – 26 year old females

Dosage & Administration

  • 3 doses within 6 months

    • (0, 2, 6 months)

  • 0.5 mL volume IM injection

  • Package:

    • Prefilled syringe

    • Shake well before use

  • Injection Site:

    • Upper arm (Deltoid region)

    • Thigh (higher anterolateral area)

Natural History of HPV Infection:Surrogate Markers for Cervical Cancer

0 to 5 Years

Up to 20 Years



Sq. Cell Carcinoma

InitialHPV Infection



Adeno- Carcinoma


Cleared HPV Infection

Basis for Licensure/Cancer Efficacy:Demonstrate Prevention of HPV 16/18-CIN 2/3 + AIS

Natural History of HPV Infection:Surrogate Markers for Cervical Cancer

0 to 5 Years

Up to 20 Years



Sq. Cell Carcinoma

InitialHPV Infection



Adeno- Carcinoma


Cleared HPV Infection

Clinical Program Combined Efficacy Analysis

Ph II–P005 (N=2392)1Proof of Principle 16- to 23-year-old women

  • ~33,000 subjects enrolled

  • Multinational

Ph II–P007 (N=1158)2Dose-ranging

16- to 23-year-old women

Yr 5 Immune MemoryEvaluation

Ph III–FUTURE I CIN/EGL (N=5455)316- to 24-year-old women

Ph III–FUTURE II CIN 2/3 (N=12,167)415- to 26-year-old women

Duration of Efficacy Registry StudyNordic Region

Norwegian HPV Surveillance and Disease Burden/Population Effectiveness Study

Ph III–P016, P018 (N=4836) Safety/Immunogenicity

9- to 15-year-old boys and girls5,6

Efficacy in women up to 45 years old6

Efficacy in 16- to 26-year-old men6









EGL = external genital lesions.

1. Koutsky LA, Ault KA, Wheeler CM et al. N Engl J Med. 2002;347:1645–1651. 2. Villa LL, Costa RLR, Petta CA, et al. Lancet Oncol. 2005;6:271–278. 3. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Submitted. 2006 4. FUTURE II study group. Submitted. 2006. 5. Block SL, Nolan T, Sattler C, et al. Submitted. 2006. 6. Data on file, MSD.

HPV 6/11/16/18-Related High Grade Disease (Cervix, Vulva, Vagina, Genital Warts)

Per-Protocol Efficacy Population - Protocols 007, 013, 015 (n=18780)

PP = received 3 vaccinations within 1 year; no major protocol violations; HPV 16/18 sero(-) at day 1 and HPV 16/18 DNA(-) day 1 to month 7; cases counted starting after month 7. CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ.

Eliav Barr’s Presentation to ACIP (CDC) FEB 2007

Average follow up for 3 years

HPV disease burden: More than Cancer Prevention

Cervical cancer: 0.500 million in 2002 1

HPV 16, 18 and others

High-grade precancerous lesions: 10 million 2

Very high global burden of HPV-related diseases

Low-grade cervical lesions: 30 million 2

Genital warts: 30 million 3

Attributable to oncogenic HPV types

HPV 6, 11 and others

Attributable to non-oncogenic HPV types

HPV infectionwithout detectable abnormalities: 300 million 2

1.Parkin et al. 2005

2.WHO 1999

3.WHO 1990

HPV-6/11 related diseases

HPV and Anogenital Warts

  • HPV 6 and 11 responsible for >90% of anogenital warts1

  • Clinically apparent in ~1% of sexually active US adult population2

  • Estimated lifetime risk of developing genital warts ~10%3,4

Images top left and top right: Reprinted with permission from

NZ DermNet (www.dermnetnz.org)

1. Jansen KU, Shaw AR. Annu Rev Med.2004;55:319–331. 2. Koutsky L. Am J Med. 1997;102:3–8. 3. Franco EL, Villa LL, Richardson H, Rohan TE, Ferenczy A. In: Franco EL, Monsonego J, eds. Oxford, UK: Blackwell Science; 1997:14–22. 4. Tortolero-Luna G. Hematol Oncol Clin North Am. 1999;13:245–257, x.

  • In Hong Kong, between 3 – 4 thousand patients with genital warts attended the Social Hygiene Clinic every year in the past decade, which account for about 9% of all attendances

  • Incubation period – 3 weeks to 8 months, majority around 2-3 months

  • Reported spontaneous complete clearance rate was low ~ 5%

  • No report on the rate of spontaneous regression in long term

  • Recurrence is common after treatment, 25% occurs within 3 months


  • Antiproliferative agents – podophlyllin

  • Destructive therapies – trichloroacetic acid, electrosurgery, laser, excision

  • Immunomodulators - Imiquimod

HPV-6/11 related cervical neoplasia

  • HPV-6 and –11 are associated with LSIL

  • A meta-analysis of 55 studies – HPV-6 and -11 were present in 8.1% and 3.2% of HPV-positive LSIL

  • Causal relationship still not clear

Recurrent Respiratory Papillomatosis(RRP)

  • A rare condition

  • Can occur anywhere in the respiratory tract, most commonly in the larynx

  • Hoarseness of voice and respiratory obstruction are the commonest presentations

  • Commonly recurrent after treatment

  • HPV-6 and -11 are the causative agents for almost all the RRP

Juvenile onset RRP

  • Before age of 4

  • Source of virus - most probably from the genital tract during birth

  • Condyloma during pregnancy increases the risk for more than 200 folds

  • Risk still < 1%

Adult onset RRP

  • Peak at 21 - 30

  • Adult onset RRP – result from sexual or non-sexual contact with an infected lesion


  • Surgical

  • In case of multiple recurrence, surgical excision is still the mainstay of the treatment

  • Use of other therapies – remain controversial

  • GARDSIL is highly effective in the prevention of HPV-6 and -11 related genital warts in women

  • Cost-effectiveness of including GARDSIL as part of the immunization programme for the prevention of genital warts among different countries, public acceptability and efficacy in men have to be evaluated

  • Role of GARDSAIL in RRP has to be evaluated

Vaginal and Vulval

Intraepithelial Neoplasia

Vaginal Intraepithelial Neoplasia (VaIN)

  • Main predisposing factor for VaIN is likely exposure to HPV.1

    • VaIN is often found in conjunction with cervical intraepithelial neoplasia (CIN).

  • Average age of women with VaIN: 35–50 years2

    • On average, older than those presenting with CIN

  • True incidence unknown, but lower than for CIN1

    • Incidence expected to rise due to wider use of cytological screening and colposcopy, as well as increased awareness of disease2

  • VaIN is often asymptomatic and difficult to diagnose.2

  • While untreated VaIN can spontaneously regress, there is a potential for VaIN to progress to invasive vaginal cancer.2

1. Winter-Roach B, Monaghan JM, de Lopes A. Colposcopy of the vagina. In: Bosze P, Luesley D, eds. EAGC Course Book on Colposcopy. Budapest: Primed-X Press; 2004:120–123. 2. Dodge JA, Eltabbakh GH, Mount SL, et al. Gynecol Oncol. Nov 2001;83:363–369.

Photo courtesy of Dr. J. Monsonego

Photos courtesy of Dr. E.J. Mayeaux

Vulval Intraepithelial Neoplasia (VIN)

  • Incidence of VIN is increasing in the United States and worldwide.1

    • In the United States, the incidence has nearly doubled between 1973 and 1987 (1.1 to 2.1 per 100,000 woman year)2

  • Mean age of women with VIN is decreasing2–4

    • The peak incidence has shifted from women ≥50 to women aged >35 to 50.

  • Symptoms occur and may be present for a long time prior to diagnosis (median of 1 year)4

    • The most common symptoms include pruritus (56%), vulval pain and soreness (29%), and vulval swelling (16%).

1. Joura EA. Curr Opin Obstet Gynecol. 2002;14:39–43. 2. Sturgeon SR, Brinton LA, Devesa SS, Kurman RJ. Am J Obstet Gynecol. 1992;166:1482–1485. 3. Jones RW, Rowan DM, Stewart AW. Obstet Gynecol. 2005;106:1319–1326. 4. Herod JJ, Shafi MI, Rollason TP, et al. Br J Obstet Gynaecol. May 1996;103:446–452.

Vulval Intraepithelial Neoplasia (VIN)

  • No biological continuum between histological grades of VIN has been shown:1

    • Rarely has progression from VIN 1 to VIN 3 been documented.

    • The annual progression rate of untreated VIN 3 to invasive cancer is at least 10%.

  • Surgically treated VIN have a high rate of recurrence, and in untreated women >30 years there is an appreciable invasive potential.2

  • HPV 16 appears to be the dominant HPV type associated with high-grade VIN (up to 81% in VIN 3)3

    • Majority of VIN 1 cases are associated with HPV types 6 and 113

    • HPV 6, 11, 16, or 18 can be found in VIN 2 or 34

1. Jones RW. Eur J Gynaecol Oncol. 2001;22:393–402. 2. Jones RW, Rowan DM, Stewart AW. Obstet Gynecol. 2005;106:1319–1326. 3. Buscema J, Naghashfar Z, Sawada E, et al. Obstet Gynecol. 1988;71:601–606. 4. Koutsky L. Am J Med. 1997;102:3–8.

  • VaIN and VIN are of concern because they are considered as precancerous lesions with about 40 - 50% associated with HPV infection

  • In UK, vulval cancer is 6 times and vaginal cancer 20 times less common than cervical cancer1

  • No screening programme exists

1. Gonzalez Inchaurraga MA et al. HPV and carcinogenesis. Acta Dermatovenerol. 2002;1:1-8.

2. Parkins DM et al. International Agency for Research on Cancer, 2002;8.

HPV 6/11/16/18-Related High Grade Disease (Cervix, Vulva, Vagina, Genital Warts)

Per-Protocol Efficacy Population - Protocols 007, 013, 015 (n=18780)

PP = received 3 vaccinations within 1 year; no major protocol violations; HPV 16/18 sero(-) at day 1 and HPV 16/18 DNA(-) day 1 to month 7; cases counted starting after month 7. CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ.

Eliav Barr’s Presentation to ACIP (CDC) FEB 2007

Average follow up for 3 years

Updates on HPV Vaccines

  • Safety

  • Duration of protection

  • Cross protection

  • Age



  • VACCINE ADVERSE EVENT REPORTING SYSTEM (VAERS)http://vaers.hhs.gov/info.htm

    - A passive reporting system which records any hearsays and Adverse Events (AEs) from any sources

    - CDC Will investigate the casual relationship of AEs and vaccines

  • Deaths – 11 cases from VAERS (9 from the FUTURE studies)

  • Guillain-Barre Syndrome – 13 cases


  • 11 deaths in recipients of GARDSIL among approximately 18.3 million doses of distribution (another 9 cases in FUTURE I & II)

  • Causal relationship between the events and the vaccination has not beenestablished

  • From the studies, number of death cases were not different between vaccine groups and placebo groups

Cases in FUTURE I & II

  • 4 cases of traffic accident

  • 1 case of suicide

  • 1 case of drug overdose

  • 1 case of pneumonia and sepsis

  • 1 case of pulmonary embolism

  • 1 case of infective thrombosis

Other cases

  • Several of these reports are hearsay and did not have first hand information and may be duplicates (one case was confirmed as false report and the subject is still alive). These cases generally were associated with underlying life threatening or chronic cardiovascular diseases

  • 1 died before vaccination

  • 1 due to pulmonary embolism

  • 1 died of influenza B viral infection with secondary staphylococcal infection

  • 1 had severe heart problems, died of myocarditis 6 days after vaccination of 3 vaccines including Gardasil

Guillain-Barre Syndrome

  • 13 reports of GBS are within the numbers of reports that could be expected to occur by chance alonewith or without a vaccination

  • 6 of 13 reports also involved simultaneous injection of Menactra (meningococcal vaccine). Current studies are underway to evaluate the small increased risk of GBS, which might be associated with Menactra

  • Only 2 reports met the case definition of GBS, occurred within six weeks after vaccination, and had received Gardasil alone

Summary: Safety of Gardasil

  • CDC and FDA were satisfied withthe safety data in the context of more than18 millions doses of Gardasil distributed.

  • Large scale clinical trials have also shown well tolerated safety profile.

  • Therefore, CDC and FDA continue to support the universal vaccination program of Gardasil. There are no changes of recommendations.

Duration of Protection

Sustained clinical efficacy and antibody titer for at least 5 years

GMT (mMU/mL)



10 000


1 000

Neutralising antibodies

(HPV type 16)

Clinical efficacy*



Natural infection











5 years






* against infection, CIN (Cervical intraepithelial neoplasia) and genital warts due to

HPV types 6,11,18; 5 yrs follow up (after dose 1) of a subset (241 women, vaccine

& placebo) from a phase II efficacy study

Villa L High Sust Eff Proph Quad HPV Vacc 5 Year Followup Br J Can 2006 95 1459

Poliovirus Vaccine (Inactivated)


  • Recommended to give series of four doses at two, four, and 18 months, and a booster dose at 4 to 6 years1

  • 18-year follow-up shows that vaccine remains effective.2

  • The need for subsequent boosters has not been established.1

Hepatitis B Vaccine

1981 and 19861

  • 15-year follow-up shows that vaccine remains effective.3,4

  • To date, routine booster is not recommended.1

Hepatitis A Vaccine


  • 12-year persistence of antibodies and anamnestic response5

  • To date, based on mathematical models, it is estimated that the protection could last 20+ years.1,5

Vaccines’ Long-Term Protection: 3 ExamplesAt licensing,vaccines are typically used broadly, despite that full knowledge of their duration of protection is unknown.

1. Mast E, Mahoney F, Kane M, Margolis H. Hepatitis B vaccine. In: Vaccine, 4th Ed. Plotkin SA, Orenstein WA editors. Elsevier Inc. USA publisher; 2004. 2. Bottiger M. Vaccine. 1990;8:443–445. 3. McMahon BJ, Bruden DL, Petersen KM, et al. Ann Intern Med. 2005;142:333–341. 4. Ni Y-H, Chang M-H, Huang L-M, et al. Ann Intern Med. 2001;135:796–800. 5. Van Herck K, Van Damme P, Lievens M, et al. J Med Virol. 2004;72:194–196.

Hepatitis B Immune Response Level Through 5 Years Post-Vaccination1

  • Protection against hepatitis B virus (HBV) is based on the presence of specific antibodies against anti-HBs antigen.2

    • Anti-HBs levels disappear in 10-50% of vaccinees after a few years.2

    • No booster has been recommended to date.3







Months After First Vaccine Dose

1. Wainwright RB, McMahon BJ, Bulkow LR, et al. JAMA. 1989;261:2362–2366. 2. Bauer T and Jilg W. Vaccine. 2006;24:572-577. 3. Mast E, Mahoney F, Kane M, Margolis H. Hepatitis B vaccine. In: Vaccine, 4th Ed. Plotkin SA, Orenstein WA editors. Elsevier Inc. USA publisher; 2004.

Anti-HBs After Immune Challenge1

  • Immune memory persists beyond the time at which anti-HBs levels may no longer be detectable.

  • Immune memory leads to a rapid anamnestic response after exposure to HBV, which prevents acute infection (and disease).

    • To demonstrate this, a typical anamnestic response is observed to immune challenge.

In vivo anti-HBs response



Anti-HBs [IU/I]









Immune Challenge

1. Bauer T, Jilg W. Vaccine. 2006;24:572–577.

Immune Memory Study of Gardasil

Vaccine 25 (2007) 4931–4939


  • Vaccines that induce long-term protection are usually characterized by the generation of immune memory

  • Gardasil have demonstrated high efficacy through 5 years of follow-up

  • Evaluated whether Gardasil is able to generate HPV type-specific immune memory

Ph II–P007 Dose-Ranging 16- to 23-year-old women

Neutralizing Antibodies Suggest an Anamnestic Response (Immune Memory) to GARDASIL™1*


by vaccine

The hallmark of long term protection

HPV 11


HPV 18

HPV 16

*In subjects naïve to the relevant HPV type from Day 1 through Month 60.

Sven-Eric Olsson Induction of immune memory of quadrivalent vaccine Vaccine 25 (2007) 4931–4939

Ph II–P007 Dose-Ranging 16- to 23-year-old women

Durable Protection Through at least 5 Years

PPE Population Efficacy Results


A total of 241 subjects were entered into the 5-year extension phase of Protocol 007.

*One case of confirmed persistent infection: HPV 18 DNA detected at months 12 and 18 only; not a case in the 5-year extension phase. One case of HPV 16 DNA detected at the last visit (month 36); not a case in the 5-year extension phase.













Follow-up Through Nordic Registries Provides a Sentinel Cohort1

Clinical program

Phase III Study Registry-based Monitoring

Reports from clinical program

4 years

7 years

10 years

Routine use postlaunch

1 year

7 years

4 years


* United States, Mexico, Australia, Canada, Togo

1. Data on file, MSD.

Cross Protection

What is being shown on the poster presentation at ICAAC?

First analysis of data assessing whether GARDASIL is efficacious against disease caused by 10 additional cancer-causing HPV types (in addition to 6, 11, 16 and 18). Specifically:

  • The cross-protection analysis evaluated disease endpoints:

    Reductions in CIN 2 /3 and AIS

  • CIN 2/3 and AIS are the immediate and obligate precursors of cervical cancer as recommend by WHO and FDA

  • The 10 additional HPV types evaluated were: 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59

What endpoints did this analysis evaluate?

  • The first study endpoint was the combined incidence of HPV 31/45-related CIN 2/3 or AIS after three years of follow-up.

  • The second endpoint was the combined incidence of HPV 31-, 33-, 45-, 52- and 58-related CIN 2/3 or AIS after three years of follow-up.

  • An analysis of reductions in CIN 2/3 and AIS caused by all 10 HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58 and 59) also was conducted.

Phylogenetic Tree of HPV Family

HPV 16 Related

HPV18 Related

- Beyond HPV 6, 11, 16, 18 -

Gardasil potentially offers disease protection against

additional oncogenic HPV types

For the bivalent HPV vaccine

  • HPV type 45, 31, 52

    (6 months persistent infection)

  • Currently available HPV vaccines potentially offer cross protection against other HPV types, efficacy has to be confirmed by further studies


Interim analysis of a study

  • Safety, Efficacy, and Immunogenicity of Quadrivalent HPV Vaccine (GARDASILTM) in Women Aged 24 – 45

  • Poster & oral presentation in the 24th International Papillomavirus Congress in Nov. 2007

Combined incidence of persistent infection, CIN, or external genital lesions (EGLs) caused by HPV 6, 11, 16, or 18

Ref: IPV congress 2007 NOV Presentation # PA1-04

Gardasil in 24-45 women

Generally well tolerated

- Injection site AEs higher than placebo

Eradication of Cervical Cancer and HPV Related Diseases

Not a Dream Anymore…

Thank you!

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