current update on hpv vaccine

1. Dr.Sunaina Wadhwa
Dr. Pratima Mittal
Department Of Obstetrics &Gynecology, Vmmc & Sjh

2. Cervical Cancer – Disease Burden
New Cervical Cancer Cases Deaths due to Cervical cancer
India ~1,32,000
World ~ 4,93,000
India ~ 74,000
World ~ 2,73,000
India ~27%
Rest of World - 73%
Rest of World - 73%
Population of India – 16% of World
India - 27%
India ~Rest of World - 73%
Bhatla N et al; Vaccine 2008; 26 2811-17

3. Estimated incidence of cervical cancer in 2002 and projected in 2025
Projected burden in 2025 is estimated by applying current population forecasts for the country and assuming that current incidence rates of cervical cancer are constant over time.
WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2009. [Accessed
on 24 th Aug 2009. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer

4. Estimated mortality due to cervical cancer in 2002 and projected in 2025
Estimates suggest more than 365 women will die/ day due to cervical cancer in 2025
WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2009. [Accessed
on 24 th Aug 2009. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer

5. > 200 women die every day
8 women die every hour Cervical Cancer :
Every 7 minutes a women dies
India
.
Introduction
WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2009. [Accessed
on 24 th Aug 2009. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer

6. What is HPV ?
 Family:Papillomaviradae
 Only infects squamous
epithelia
 Small DNA virus
 Common virus with >100
types identified
 60-70 types infect the
skin- common warts
 30–40 infect the genital
area of women and men
 2 groups
 low risk types causing
warts
 high risk types causing
cancer
oncogenic types

7. The 4 most important types of HPV
HPV 16 HPV 18 HPV 6 HPV 11
>83.2% of Cervical Cancer5,6
>50% of Vaginal & Vulvar Cancer5
90% of Anogenital warts5

8. Mature
squamous
layer
Squamous
layer
Parabasal
HPV Lifecycle in the Cervix
Basement membrane
Normal
epithelium
cells
Basal (stem)
cells
Infected
epithelium
Cervical canal
.
Shedding of virus-laden
epithelial cells
Viral assembly
(L1, L2, E4)
Viral DNA replication
(E6 & E7)
Episomal viral DNA
in cell nucleus
(E1 & E2, E6 & E7)
Infection of basal
cells (E1 & E2)

9. Associations of HPV with Diseases
 HPV – Causative Factor in
 Cervical Cancer (99.7%)
 Vaginal & Vulvar Cancer (50%)
 AnogenitalWarts ( 90%)
 Recurrent Respiratory Papillomatosis
 HPV known as Associated Factor in
 Anal Cancers (85%)
 Penile Cancer ( 50%)
 Oropharyngeal Cancers (20%)
 Laryngeal Cancers ( 8%)

11. HPV Diseases - Prevention
 Immunization -one of the most cost-effective health
interventions known to mankind.
 Concept of preventive medicine through
immunization have become the main stay of modern
medicine.

12. The Way Forward
HPV Vaccines

13. HPV Vaccine
The only Primary Prevention
available

14. The Nobel Prize in Physiology or
Medicine 2008
Harald zur Hausen
This year's Nobel Prize awards discoveries of two
viruses causing severe human diseases.
Harald zur Hausen went against current dogma
and postulated that oncogenic human papilloma
virus (HPV) caused cervical cancer, the second
most common cancer among women. He realized
that HPV-DNA could exist in a non-productive
state in the tumours, and should be detectable by
specific searches for viral DNA. He found HPV to
be a heterogeneous family of viruses. Only some
HPV types cause cancer. His discovery has led to
characterization of the natural history of HPV
infection, an understanding of mechanisms of
HPV-induced carcinogenesis and the development
of prophylactic vaccines against HPV acquisition.

15. HPV Vaccines
 Presently two Vaccines available globally
 Quadrivalent HPV Vaccine – Gardasil by Merck & Co
 Bivalent Vaccine – Cervarix by GSK
 50 million doses used worldwide of Quadrivalent Vaccine
 QV available in public health programmes of many
countries like USA, Australia
 Australia has already vaccinated 85% of its target
population with QV ( 9-26 y) within a year.
 Male Vaccination with QV is now approved in Aus, NZ,
Philippines & recently USA
 BV available in public health program of UK

16. Vaccine profile
Product Quadrivalent vaccine –
HPV 6,11,16,18
Bivalent vaccine
HPV 16,18
Manufacturer Merck: Quadrivalent HPV vaccine
(US FDA Approved)
Glaxo Smith Kline: Bivalent vaccine
Indications
Prevention of: HPV 6, 11, 16, 18
related
• Cancer Cervix
• Adenocarcinoma in Situ (AIS)
• Vulvar & Vaginal cancers
• Ano -Genital warts
• Recurrent Respiratory
Papilomatosis
Prevention of HPV 16, 18 related
• Cancer Cervix
•Adenocarcinoma in Situ (AIS)
Age 9-45 years 10-45 years
Tolerability
Well-tolerated Well-tolerated

17. Vaccine profile
Product Quadrivalent vaccine –
HPV 6,11,16,18
Bivalent vaccine
HPV 16,18
Efficacy in
16-26 years
women
98-100% as per the Phase 3
FUTURE trials
91% Efficacy as per the Phase 3
Patricia trial of GSK
Efficacy in
Adult women
(> 26 years )
Proven with FUTURE 3 Trials with
91% efficacy
Efficacy Studies not done ,
only immunobridging studies done
Immune
Memory at 6
years
Proven Not yet done
Cross-
Protection
Proven against 10 serotypes other
than the Vaccine serotypes
Proven against 4 serotypes other
than Vaccine serotypes

19. Natural History of HPV Infection:
Surrogate Markers for Cervical
Cancer
[Quadrivalent Human Papilloma virus (Types 6, 11, 16, 18) Recombinant Vaccine]
0–1 Year 0–5 Years 1–20 Years
Invasive
Cervical
Cancer
Continuing
Infection
CIN 1
90% In 2 Years 10-20% in 1 year
Cleared HPV Infection
Initial
HPV
Infection
Adapted from Pinto AP et al. Clin Obstet Gynecol. 2000;43:352–362.
CIN 2/3
or AIS
Primary efficacy objective of
HPV vaccine program:
Demonstrate prevention of
HPV 16/18-CIN 2/3 + AIS
CIN = cervical intraepithelial neoplasia.
AIS = adenocarcinoma in situ.

20. Whom to Vaccinate?
 Most countries Recommend Vaccination in all girls in
the Primary age group from 9-12 years.
 Catch-up Vaccination till 45 years for both the
Vaccines
 Some countries recommend Quadrivalent Vaccination
in Males also.

21. schedule for the HPV vaccine
 For Quadrivalent Vaccine, it is 3 doses, at 0, 2 & 6
months.1,2
 For Bivalent Vaccine it is, 3 doses, at 0, 1 & 6 months.1,3
 Both are given by IM injection in deltoid region.
 (0 stands for first dose)
1.Centers for Disease Control and Prevention: Quadrivalent human papillomavirus vaccine. Recommendations of the Advisory Committee on Immunization Practices.
MMWR 2007, 56(Early Release): 1–24.
2.Gardasil® India Prescribing Information 2008.
3.CervarixTM Prescribing Information Ver 01 IND 08.

22. ACIP - Recommendations for Use
of HPV Vaccine
 Routine Vaccination of Females Aged 11–12 Years
Vaccination series can be started as young as age of 9 years
 Catch-Up Vaccination of Females Aged 13–26 Years
Recommended for females aged 13–26 years who have
 No vaccination history and
 Not completed the full series.
Sexually active females (Not Infected) receive full benefit from
vaccination.
Vaccination would provide less benefit to females infected with one or
more of the four vaccine HPV types.
7. MMWR, March 12, 2007 / Vol. 56

23. ACIP - Recommendations for Use
of Quadrivalent HPV Vaccine
 Dosage and Administration
 Vaccine should be shaken well before administration.
 Dose - 0.5 mL, Intramuscularly (IM)
 In the deltoid muscle or upper anterior thigh.
 Recommended Schedule
 3-dose schedule (0-2-6) for QV & (0-1-6) for BV
 Minimum Dosing Intervals
First and second dose - 4 weeks
Second and third dose -12 weeks
7. MMWR, March 12, 2007 / Vol. 56

24. ACIP - Recommendations for Use
of Quadrivalent HPV Vaccine
Special Situations Among Females Aged 9–26 yrs
 Equivocal or Abnormal Pap Test or Known HPV
Infection
Vaccination protects against infection with HPV types not already acquired
No Therapeutic Effect of the vaccine on already acquired infection
So vaccination recommended
7. MMWR, March 12, 2007 / Vol. 56

25. ACIP - Recommendations for Use
of Quadrivalent HPV Vaccine
 Management of Persons Incorrectly Vaccinated
Inadequate doses or doses received before a shorter-than
recommended dosing interval should be re-administered
 Interrupted Vaccine Schedules
Interruption after the first dose –
Administer second dose as soon as possible, and the third
dose
after an interval of at least 12 weeks.
Delay in 3rd Dose – Administer as soon as possible.
7. MMWR, March 12, 2007 / Vol. 56

26. ACIP - Recommendations for Use
of Quadrivalent HPV Vaccine
Simultaneous Administration with Other vaccines
 Can be administered at the same visit with other age
appropriate vaccines such as Tdap, Hepatitis B or
Meningococcal vaccines
 Vaccines should be administered using a separate syringe
at a different anatomic site.
NO CONTRA INDICATIONS
7. MMWR, March 12, 2007 / Vol. 56

27. ACIP - Recommendations for Use
of Quadrivalent HPV Vaccine
Special Situations Among Females Aged 9–26 yrs
 Vaccination in females with an history of Genital
Warts
Vaccination Provide protection against infection not already acquired.
So vaccination recommended
7. MMWR, March 12, 2007 / Vol. 56

28. ACIP - Recommendations for Use
of Quadrivalent HPV Vaccine
Cervical Cancer Screening Among Vaccinated
Females
 No change in screening recommendations for females
receiving HPV vaccine
(as it does not cure the already existing infection)
7. MMWR, March 12, 2007 / Vol. 56

29. ACIP - Recommendations for Use of
Quadrivalent HPV Vaccine
Precautions and Contraindications
 Vaccine can be administered to persons with minor
illnesses
 Defer in Moderate or Severe acute illnesses
 Contraindicated for persons hypersensitive to yeast or to
any vaccine component.
7. MMWR, March 12, 2007 / Vol. 56

30. ACIP - Recommendations for Use of
Quadrivalent HPV Vaccine
Vaccination During Pregnancy
 Not recommended for use in pregnancy.
 If patient becomes pregnant - Delay Remaining doses
 If Vaccinated during pregnancy - No intervention
needed
7. MMWR, March 12, 2007 / Vol. 56

31. ACIP - Recommendations for Use
of Quadrivalent HPV Vaccine
Special Situations Among Females Aged 9–26 yrs
Lactating Women
Can receive HPV vaccine (only QV).
7. MMWR, March 12, 2007 / Vol. 56

32. QV - Demonstrated Immune Memory
Rapid and Strong Anamnestic Response to Antigen Challenge
5714
60 61
Time
4466
Antigen challenge
Re-exposure to antigen
at Month 60.
0 2 3 6 7 12 18 24 30 36 54
Time (months)
3870
7000
6000
5000
4000
3000
2000
1000
0
Anti-HPV 16*
response
(GMT levels
with 95% CI)
GARDASIL n=78
Placebo n=70
108
GMT = geometric mean titer
*Similar response with the other three types of HPV within vaccine
Olsson SE et al. Vaccine 2007;25:4931-4939.

33. Duration of Protection
 Long term studies are ongoing since 2002
 Studies have shown continued immunogenecity and
protection with demonstration of immune memory.
 Antigen Challenge test done after 5 years of clinical
trial- showed strong anamenestic response in QV
 Mathematical models predict 30 years or life time
protection
 No evidence for requirement of booster dose as on
date.

34. What is the duration of protection with HPV
Vaccine?
 The quadrivalent HPV vaccine has demonstrated
anamnestic/recall response to antigen challenge, 5
years post-immunization.
 The bivalent vaccine has been studied for efficacy,
immunogenicity and safety for up to 6·4 years.
 Recently data from Nordic countries has established
the effectivness of QHPV vaccine upto 7 yrs

35. Vaccine Profile: Side Effects
Side Effects Quadrivalent Bivalent
Local: Pain at inj. Site
( mild to moderate)
83% 90%
Local: Swelling and erythema 25% 40%
Systemic: Fever 4% 12%
No serious vaccine related adverse effects with both vaccine
Consensus Recommendations on Immunization, Indian Academy of Pediatrics Committee On Immunization (IAPCOI). Indian Pediatrics 2008; (45)635-648

36. Effectiveness By Lesion Type
100 % 100 % 100 % 100 % 100 %
0 0 0 0 0
100
80
60
40
20
0
Vaccine effectiveness
(N=1,080)
Vaccine effectiveness
Vaccine effectiveness
Vaccine effectiveness
Vaccine effectiveness
Zero number
of cases
Zero number
of cases
Zero number
of cases
Zero number
of cases
Zero number
of cases
(N=1,080) (N=1,080) (N=1,080) (N=1,080)
CIN 2 CIN 3 CIN 3 + AIS CC
Percentage
Vaccine effectiveness measures the relative reduction of the disease incidence in vaccine recipients compared to the baseline incidence rate of 0.0287 per 100 person-years established from the incidence
rate in an unvaccinated cohort and under the assumption vaccine efficacy is 90%.
Data on File

37. Efficacy v/s Antibody Titers?
On what parameter the efficacy of HPV vaccine
should
be evaluated?
A. Antibody titers
B. Efficacy against CIN2/3 or AIS
CIN – Cervical Intraepithelial Neoplasia, AIS – Adenocarcinomain situ

38. Efficacy of the Vaccine in Adult
women
 WHO guidelines (2006) suggest that Efficacy Trials should
be done in Adult women (26-45 years).
 Only Immuno-bridging trials should not be used to
extrapolate efficacy of the HPV Vaccines.
 Efficacy of Quadrivalent vaccine for Adult women is
reported to be 91% in naïve population.
 No Efficacy Trials reported in Bivalent vaccine in this age
group. Only immuno-bridging data reported.

39. Can men also be benefitted from HPV
Vaccine?
 All sexually active men are at risk for genital warts.
Men who have sex with men are at risk for anal cancer.
Men transmit HPV infection to women.
 As efficacious in men as it is in women
 Protection against warts, penile or anal cancer, and
prevent transmission to females.
 It is anticipated that in the future, the vaccine will be
available for both of these groups.

40. What are the issues in introduction of the
vaccine in a developing country like India?
 There are a number of issues that will arise in using
this vaccine in India [1]
 Cost: The cost of this vaccoine has been subsidized for
Indian Market. Present cost (MRP) is Rs 2800/- for
quadrivalent HPV Vaccine/dose and for bivalent is Rs.
2000/-. Since 3 doses are required for complete
protection, this vaccine is still unaffordable for a
majority of people.
 Vaccine Delivery: This will become an important
issue in the public health scenario as this is an
injectable vaccine.

41.  Social and cultural values: Our social values will
make it difficult to give a vaccine to young girls against
a sexually transmitted disease though its main aim is
to prevent cancer in women.
 Religious issues: Giving of the vaccine is questioned
by many who may feel that vaccination against an STI
will “give permission” for their children to become
sexually promiscuous. They may also think that
religion will protect their children from premarital sex
and hence do no need the vaccine.

42. HPV Vaccine
IS’NT THIS A
REVOLUTION