1) A large study in India found that two doses of the HPV vaccine, administered 6 months apart, were as effective at preventing HPV infection as three doses in girls aged 10-18 years. 2) The two-dose schedule produced similar antibody levels and no cases of persistent infection with HPV types 16 and 18 were found over an average follow up of 4.7 years. 3) Based on these results, the study supports the WHO recommendation of a two-dose schedule of the HPV vaccine for young girls.

1. Cervical Cancer Vaccine
Latest Updates
Dr. Gaurav Gupta
5th Feb, 2017

2. Conflict of Interest
• Received grants from various vaccine
manufacturers including

3. WIIFY ?
• Is Cervical Cancer Vaccine Important?
• Latest schedules? When & Why?
• Does it work – real world effectiveness?
• Comparing vaccines?
• Safety
• Improving coverage
• The Future

7. Quiz
• What are the serotypes in Gardasil 4?

8. Latest schedules – When & Why

9. Why to vaccinate early with HPV
vaccine?

10. Increased Risk of HPV Infection in Young Females:
Progression of the Transformation Zone
 Adolescent females may have
increased susceptibility to HPV
infection, compared with adults.
 During and after puberty, the
transformation zone is
particularly vulnerable to
infection and carcinogenesis.1,2
 ~99% of HPV-related genital
cancers arise within the
transformation zone of the
cervix.1
1. Castle PE. J Low Genit Tract Dis. 2004;8:224–230.
2. 2. ACOG Committee on Adolescent Health Care. Obstet Gynecol. 2004;104:891–898.
SCJ = squamocolumnar junction.

11. Exposure to HPV at a Young Age Increases the Risk of
Cervical Lesions and Cancer in Women[1]
1
2
3
4
5
6
7
CIN Invasive Cervical Cancer
RelativeRiskEstimatesa
≤17
18–22
aMantle-Haenszel estimates adjusted for age only.
1. La Vecchia C et al. Cancer. 1986;58:935–941.
Relative risks for CIN and invasive cancer increase with decreasing age of first
sexual intercourse.
Age at First
Intercourse (Years)
(n=206) (n=327)
Reference Population: First intercourse 23 years of age or never
5 times higher risk
of Invasive cancers

12. 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Age at Enrollment (Years)
500
700
900
1100
1300
1500
1600
SerumcLIAGMTWith
95%CI,mMU/mL
Adolescent Females Young Adult Females
Serum anti-HPV 6 responses 1
month after completion of
vaccination regimen
Per-protocol immunogenicity
population (ages 9–26)a
aInclusive of protocols 007, 013, 015, 016 and 018; all GMTs measured using competitive Luminex® immunoassay;
women 24–26 years of age were omitted in the figure because of small numbers. Similar results were observed for HPV 11, 16, and 18.
GMT = geometric mean titer.
1. Giuliano AR et al. J Infect Dis. 2007;196:1153–1162.
Higher Immune Response in
Adolescents Versus Young Adults1

13. SAGE = Strategic Advisory Committee of Experts; WHO = World Health Organization.
1. World Health Organization. Wkly Epidemiol Rec. 2009;84:1–16.
Vaccination is most effective when given to females naïve to
infection with vaccine-related HPV types
Primary target population is likely to be girls 9 or 10 through
13 years of age
WHO SAGE Recommendations:
Primary Target Population for
Vaccination1

14. Evidence supporting 2-Dose
study of Gardasil

15. Sankaranarayanan et al, Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a
multicentre prospective cohort study Published online December 1, 2015 www.thelancet.com/oncology

16. Salient features of the study
• Large,multicentre,prospective study.
• Indian data
• Comparison of 2D vs 3D
Sankaranarayanan et al, Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a
multicentre prospective cohort study Published online December 1, 2015 www.thelancet.com/oncology

17. Global Investigators List
• IARC, Lyon, France: Dr Rengaswamy
Sankaranarayanan, Dr Richard Muwonge, Mr Eric
Lucas, Dr Tarik Gheit, Dr Massimo Tommasino, Dr
Catherine Sauvaget
• DKFZ, Heidelberg, Germany: Dr Michael Pawlita,
Julia Butt, Dr Angelika Michel, Dr Tim Waterboer,
Dr Martina Willhauck-Fleckenstein, Dr Martin
Müller, Ute Koch,
• Monika Oppenländer EMBL, Heidelberg,
Germany: Dr Peter Sehr
Sankaranarayanan et al, Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a
multicentre prospective cohort study Published online December 1, 2015 www.thelancet.com/oncology

18. Indian Investigators List
Sankaranarayanan et al, Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a
multicentre prospective cohort study Published online December 1, 2015 www.thelancet.com/oncology

19. Study sites-9
Hyderabad, Osmanabad, Dindigul
Pune, Mumbai
Ahmedabad
Delhi
Gangtok ,Aizwal
Sankaranarayanan et al, Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a
multicentre prospective cohort study Published online December 1, 2015 www.thelancet.com/oncology

20. Aim
• To compare the immunogenicity and frequency of
persistent infection and cervical precancerous lesions
caused by vaccine-targeted HPV after vaccination with:
• two doses of quadrivalent vaccine on days 1 and 180 or later
• with three doses on days 1, 60, and 180 or later, in a cluster-
randomised trial.
• Study was designed to be done in nine locations (188
clusters) in India.
Sankaranarayanan et al, Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a
multicentre prospective cohort study Published online December 1, 2015 www.thelancet.com/oncology

21. Study design and Participants
• Participants were unmarried girls aged 10–18
years vaccinated in four cohorts:
• girls who received three doses of vaccine on days 1, 60, and
180 or later,
• two doses on days 1 and 180 or later,
• two doses on days 1 and 60 by default, and
• one dose by default.
• a multicentre, cluster-randomised trial in India
from Sept 1, 2009-Apr 2010 and median FU
was 4.7yr.
Sankaranarayanan et al, Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a
multicentre prospective cohort study Published online December 1, 2015 www.thelancet.com/oncology

22. Primary outcomes
• Immunogenicity outcomes:
– HPV-L1 genotype-specific binding Ab
concentrations (Geometric mean MFI)
– Antibody avidity (Geometric mean avidity index)
– Ab concentrations specific for neutralising
epitopes in HPV-L1 using GMTs
• Infection outcomes:
– first incident and persistent infections of vaccine
targeted HPV types during follow-up.
Sankaranarayanan et al, Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a
multicentre prospective cohort study Published online December 1, 2015 www.thelancet.com/oncology

23. Assessments done
• Ab titres: Blood samples obtained by nurses during
the vaccination session at a clinic or during
household visits on day 1 and months
7,12,18,24,36,48,60 from a cohort.
• Cervical samples: Pelvic examination done at 18
months after marriage or 6 months after delivery of
their first child, whichever was earlier and every year
thereafter for 3 years.
Sankaranarayanan et al, Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a
multicentre prospective cohort study Published online December 1, 2015 www.thelancet.com/oncology

24. Results:Subject recruitment
17729 girls
(10-18yr)
1D default (n=4950) (28%)
Day1
2D default (n=3452) (19%)
Days 1 & 60
2D (n=4979) (28%)
Days1,180
3 D (n=4348) (25%)
Days 1,60,180
Sankaranarayanan et al, Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a
multicentre prospective cohort study Published online December 1, 2015 www.thelancet.com/oncology

25. Results:Mean MFI
HPV types 16, 18, 6, and 11 L1 antibodies
Dashed lines show the threshold (cutoff ) values for seroconversion. MFI=median fluorescence intensity. *MFI values for month 7 were used for
the three-dose and two-dose vaccine groups, whereas MFI values for month 12 were used for the two-dose default and one-dose default groups.

26. Results: Persistent infection
• In 838 women for whom two or more samples were
available for analysis, there were no persistent HPV
16 and 18 infections in any of the four study groups
at a median follow-up of 4·7 years
Sankaranarayanan et al, Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a
multicentre prospective cohort study Published online December 1, 2015 www.thelancet.com/oncology

27. Adverse events• Median follow-up was 4·7 years (IQR 4·2–5·1).
• Local and systemic reactions within 15 days of
administering 34856 vaccine doses in the study included:
injection-site pain (number of reactions; n=1092),
low-grade fever (n=293),
injection-site swelling (n=124),
dizziness (n=64),
Headache (n=49),
nausea (n=30),
skin rash (n=15),
diarrhoea (n=13),
abdominal cramps (n=13), and
fainting attacks (n=10).
• No serious adverse events were attributable to the
vaccine.
Sankaranarayanan et al, Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a
multicentre prospective cohort study Published online December 1, 2015 www.thelancet.com/oncology

28. Summary
• Two doses of quadrivalent HPV vaccine (10-18yr),
administered with an interval of 180 days or more
between doses are:
immunologically non-inferior to the three-dose schedule
and
afford protection against incident and persistent HPV 16, 18,
6, and 11 infections
similar to that afforded by three doses
– The findings support the WHO recommendation to use
two doses separated by 6 months or more for vaccination
of young girls.
Sankaranarayanan et al, Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a
multicentre prospective cohort study Published online December 1, 2015 www.thelancet.com/oncology

29. Recommendations: Gardasil 2-dose
IAP Recommendations
• Only 2 doses of either of the 2 HPV vaccines for adolescent/pre-adolescent girls
aged 9-14 years.
• For girls 15 years and older and immunocompromised individuals 3 doses are
recommended
• For 2 –dose schedule, the minimum interval between doses should be 6
months
• For 3 dose schedule, the doses can be administered at 0, 1-2 (depending on
brands) and 6 months.
VASHISHTHA et al, Indian Academy of Pediatrics (IAP) Recommended Immunization Schedule for Children Aged 0 through 18 years – India, 2014 and Updates
on Immunization VOLUME 51__OCTOBER 15, 2014

30. Current Global Experience: Countries Currently Implementing
Alternate Dosing Schedules
Canada
Quebec &
BC
Mexico Switzerland Colombia South Africa Brazil Austria
Schedule
Quebec
0-6 months
0-6-60 months 0-4 or 0-6 months 0-6 months 0-6 months 0-6-60 months 0-6 months
BC
0-6-36 months
Starting
age
Quebec
9 y.o girls
(4th grade)
9 years old 11-14 y.o. girls
(First dose before
15th birthday)
9-18 y.o. girls
(4th grade –
12th grade)
9 -10 y.o. girls 11-13 y.o. girls in
2014
9-11 y.o. girls in
2015
9 y.o boys &
girls
BC
11 to 12 y.o.
girls
(6th grade)
3rd dose
Quebec: No 3rd
D
BC: 14 to 15 y.o.
(9th grade)
Third dose if
proven necessary
Third dose
being
considered
(at month 60)
Third dose if
proven necessary
Third dose being
considered
(at month 60)
Brand
Choice
2013/2014
100% Gardasil
Since Launch
2013 MOH:
100% Cervarix
Previously GRD
90% Gardasil
Since Launch
100% Gardasil
Since Launch
100% Cervarix 100% Gardasil
Most probably
Gardasil
3
0

31. 31
Gardasil® 2-Dose: Global Regulatory Status (73)
7 NORTH AMERICA
Canada Jamaica
Mexico El Salvador
Costa Rica Honduras
Dominican Republic
ASIA PACIFIC
Hong Kong Thailand
Korea Philippines
Taiwan Sri Lanka
Malaysia Pakistan
Singapore Indonesia
Kazakhstan
SOUTH AMERICA
Brazil Venezuela
Colombia
Argentina
Peru
Ecuador
Trinidad & Tobago
MIDDLE EAST &
AFRICA
Brunei Turkey
Israel
South Africa
EUROPE
Austria
Belgium
Bulgaria
Croatia
Cyprus
Czech Republic
Denmark
Estonia
Finland
France
Serbia
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Lithuania
Luxembourg
Malta
Macedonia
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Bosnia &
Herzegovina
Merck Regulatory Affairs, February 2016
33
7
11
CIS Countries
Armenia Georgia
Aruba Moldova
Azerbaijan Ukraine
Turkmenistan Uzbekistan
Belarus Russian Federation
10
4

32. QUIZ
• Arshnoor, 24 years, Female, has just
completed 3 doses of HPV vaccine. She wants
to know if she needs PAP smear testing, as she
is protected?

33. Dobson SRM et al.JAMA 2013;309 (17):1793-1802

34. Study Groups & Duration
• Gr 1 (n=259): 9-13yr-2 doses of Gardasil (0,6m)
• Gr 2 (n=261): 9-13yr-3 doses of Gardasil (0,2,6m)
• Gr 3 (n=310):16-25yr-3doses of Gardasil (0,2,6m)
• Duration of follow up=36m
Dobson SRM et al.JAMA 2013;309 (17):1793-1802

35. Summary
• Immunogenicity of a 2-dose schedule at 0 and 6 months in girls 9
through 13 years of age is statistically noninferior for HPV-16 and
HPV-18 to the immunogenicity in women receiving 3 doses,
assessed 1 month after the final dose.
• The GMTs in girls receiving a 2-dose schedule were between 1.77-
to 2.24-fold higher than those in women receiving a 3-dose
schedule, assessed 1 month after the final dose.
Dobson SRM et al.JAMA 2013;309 (17):1793-1802

36. CONCLUSION
Based on the:
 Clinical Trial data
 WHO Recommendation
 IAP Recommendation and
 Approval in key countries
Gardasil is now approved to be used in a 2-dose alternative
schedule, at 0 and 6 months, for children 9 to 14 years old, in
India.[1]
1. Gardasil PI India

37. Quiz
• We inadvertently gave HPV vaccine to a
woman who didn't know she was pregnant at
the time. How should we complete the
schedule?

38. Comparing Vaccines

40. Why Genital Wart data is Important?
A reduction in the incidence of GWs is one of the first
markers of the effectiveness of HPV vaccination at a
population level, as they develop over a few months,
whereas precancerous lesions and cancer usually
develop over several years.
1
1. Blomberg et al: Clinical Infectious Diseases 2013;57(7):929–34

41. Five Years Into qHPV Vaccination Program, Significant Declines in
Rates of Genital Warts in Australian Females <30 Years of Age1
aAnalyses included a total of 34,900 females.
Figure reproduced from BMJ, Ali H et al, 346, f2032, 2013, with permission from BMJ Publishing Group Ltd.
1. Ali H et al. BMJ. 2013;346:f2032.
Year
20
18
16
12
10
8
6
4
2
0
14
2004 2005 2006 2007 2008 2009 2010 2011
Prevaccine period Vaccination period
Ptrend <0.001
Ptrend <0.001
Patients(%)
–72.6%
–92.6%
qHPV vaccine introduced <21 years (n=9,405)a
21–30 years (n=15,228)
>30 years (n=10,246)
• Significant decline in proportion of females diagnosed with genital warts
at first visit seen during qHPV vaccination period, especially in those
<21 years of age.
Proportion of Australian-Born Women Diagnosed as Having Genital Warts at First
Visit, by Age Group, 2004 to 2011

42. 1. Oliphant J et al. N Z Med J. 2011;124:51–58.
New Zealand: Impact of qHPV Vaccine
on Genital Warts1
63%
reduction
%First-visitclients
withgenitalwarts
2010a

43. 0
10
20
30
40
50
60
70
80
90
100
10–13 14–16 17–19 20–22 23–26 ≥27
Vaccine Effectiveness Against Genital Warts Was Greatest
in Females Vaccinated at a Younger Age
qHPV Vaccine Effectiveness: A Swedish National Cohort Study1
aEstimated effectiveness for women 27 years of age and older was <0 (95%CI: <0–13).
Estimated Effectiveness of qHPV Vaccination on Incidence
Rates of Genital Warts, by Age Group
Age (years)
Estimatedeffectiveness(%)
• Maximum reduction in incidence decreased with increasing age.
• No reduction in incidence was seen for those ≥27 years of age.
a
Amy Leval, Eva Herweijer, Alexander Ploner et al Quadrivalent Human Papillomavirus Vaccine Effectiveness: A Swedish National Cohort Study J Natl Cancer
Vaccine effectiveness was highest in girls vaccinated before age 14 years
(effectiveness = 93%, 95% CI = 73% to 98%)

44. Improving Coverage
• Make it about Cervical Cancer
• Male vaccination
• Counsel about warts
• During routine f/u
• Post partum

45. Future
• Availability of 9v HPV
• Single dose !?
• NIP

47. Quiz
• Jasleen, 14y 9 mo age is brought for Cervical
Cancer Vaccine – what is your advice?

48. Quiz
• Kanwal, 13 yr girl, has been given 2 doses of
HPV vaccines at a gap of 2 months, what be
your advice regarding the third dose?

49. Thank You!
• Missed something ?
• Get complete presentations at
www.slideshare.net/gauravg
• Contact me docgaurav@gmail.com
• Acknowledgments:
• Dr Puneet Kalra, Medical Advisor, Merck
• Dr Sharda Jain, Slideshare