1. NONAVALENT HPV VACCINE
GARDASILTM 9 an update
Kunter Yüce M.D
Hacettepe University Medical Faculty
Dept Obstetrics & Gynecology
Prof and Head of Gynecologic Oncology Unit
President of Turkish Society for Colposcopy and Cervical Pathology

2. Disclosure statement
No conflict of interests to declare 2 2

3. safe Bivalent and Quadrivalent vaccines effective
beneficial effect at the population level as early as 3 years after introduction of an HPV vaccination program:
prevalence of vaccine HPV types
incidence of CIN 2+ lesions 
incidence of ano-genital warts 
safe
local symptoms at site of injection
(pain, swelling. erythema)
senkop after vaccination
new onset chronic and autoimmune disease none
Joura EA NEJM Arnheim-Dahlström L BMJ Macartney KK Drug Saf 2013 Tabrizi S, J Infect Dis Block SL Pediatr Infect Dis J 2010

4. Prevention against Cx cancer with bHPV and qHPV vaccines ~70 %
cross-protection against nonvaccine HPV types partial ?
duration and clinical significance uncertain ?
Percentage of cervical cancer cases attributed to the most frequent HPV types in all world regions combined,as estimated from: B: meta-analysis of more than cases

5. Cross-protection bivalent vaccine:
cross-protection against the non-vaccine HPV oncogenic types,
with 31.5% efficacy in preventing associated CIN2 lesions
In the Costa Rica study, cross-protection at 4-year follow-up was demonstrated against HPV 31, 33 and 45 infection, with efficacy of 51.3% in HPV-naĩve women and 45.2% in all women regardless of initial HPV infection status.
At 9.4-year follow-up, the bivalent vaccine continued to demonstrate efficacy against incident HPV 45 but not against other non-vaccine HPV types
quadrivalent vaccine an independent meta-analysis
cross-protection is limited to HPV 31,
however, this protection is not significant when lesions co-infected with HPV 16 or 18 are excluded.
Schiller JT, Vaccine Luckett R,Feldman S Hum Vacc Immunothr 2016;6:1332

6. More oncogenic HPV antigens More protective effects
A new vaccine ?
More oncogenic HPV antigens
More protective effects

7. HPV Types in cytology
Serrano B et al. Potential Impact of a nine valent vaccines. Infectious Agent and Cancer 2012

8. HPV Types in histology
Serrano B et al. Potential Impact of a nine valent vaccines. Infectious Agent and Cancer 2012

9. ADSCC: adeno squamous carcinoma SCC: squamous cell carcinoma
ADC: adenocarcinoma
ADSCC: adeno squamous carcinoma
SCC: squamous cell carcinoma
Serrano B et al Potential Impact of a nine valent vaccines. Infectious Agent and Cancer 2012

10. Relative contribution of HPV 16,18,31,33,45,52,58 in cases of ICC HPV-positive, by region
Serrano B et al. Potential Impact of a nine valent vaccines. Infectious Agent and Cancer 2012

11. Most common HPV Types in Turkey
Cytology
Histology
HPV Type % 16
44.0 31
7.7 18
7.5 45
3.9 33
3.5
HPV Type % 16
64.7 18
9.9 45 31
3.0 33
2.2
Usubutun A, Int J Gynecol Pathol, 2009

12. The place of HPV genotypes in cervical cancer etiology
Serrano et al., Infect Agent Cancer, Sanjose et al., Lancet Oncol, 2010

13. Serrano B, Infect Agent Cancer 2012
HPV types in invasive cervical cancer
8.977 cervix Ca
18.5 % type 31/33/45/52/58
89.4 % type 16/18/31/33/45/52/58
in SCC %
in AdenoCa %
Estimated new cases related to 7 types: in in
Serrano B, Infect Agent Cancer 2012

14. GardasilTM9 HPV 6-11-16-18 31, 33, 45, 52, 58 Merck & Co
NONA VALENT (9 VALENT) VACCINE Serrano B et al Potential Impact of a nine valent vaccines. Infectious Agent and Cancer 2012
HPV
31, 33, 45, 52, 58
Merck & Co
GardasilTM9

15. December 11, 2014 Approval Date FDA
Nonavalent vaccine (GardasilTM 9)
December 11, Approval Date FDA
years old girl & years old boy
March application recommendation by US-ACIP
Advisory Committee on Immunization Practices
girls: routine years old (earliest 9 years old))
catch-up years old
boys: routine years old (earliest 9 years old)
catch-up years old
MSM and immune deficiency: years old
February 2015 in Canada
June 2015 in European Union and Australia
Type 6, 11, 16, 18, 31, 33, 45, 52, 58 vaccine
has the potential to prevent ~90 % of cervical cancer and the other HPV related diseases
Pils S, Clin Microbiol Infect Sankaranarayanan R, Int J Gynecol Obstet Castle PE, Epidemiol Infect Petrosky E, MMWR Morb Mortal Wkly Rep Garland SM, Vaccine 2015

16. April Turkey
Gardasil®
MERCK SHARP & DOHME

17. March Turkey
Cervarix® GSK

18. Turkey ?????
Merck & Co
GardasilTM9

19. Composition of Gardasil: 20 μg HPV 6 VLP 40 μg HPV 11 VLP
225 µg AAHS
500 μg AAHS
Adjuvant:
Amorphous
Aluminum Hydroxyphosphate Sulphate
Joura EA, NEJM 2015

20. Joura EA, Cancer Epidemiol Biomarkers Prev 2014
HPV types in CIN and AIS
15-45 years old women
Type 16/18/31/33/45/52/58
CIN %
CIN %
CIN %
AIS %
responsible !!!!
Joura EA, Cancer Epidemiol Biomarkers Prev 2014

21. Quadrivalent vaccine + type 31/33/45/52/58
(nonavalent vaccine Gardasil 9)
if effective as much as first two vaccines (Gardasil 4 & Cervarix)
anogenital warts %
CIN %
CIN %
AIS %
invasive cancer %
Prevention potential
Significant decrease of invasive and preinvasive disease incidence
Joura EA, Cancer Epidemiol Biomarkers Prev Serrano B, Infect Agent Cancer 2012

22. The role of HPV genotypes in Gardasil9
in the other anogenital woman cancer
gardasil9
87.1 % vulvar Ca
85.3 % vaginal Ca
95.9 % woman anal Ca
94.1 % VIN 2-3
78.7 % VaIN 2-3
86.2 % woman AIN 2-3
90 % of HPV (+) woman anogenital cancer
88 % of whole woman anogenital cancer
prevention potential
Serrano B, Eur J Cancer 2015

23. Double-blind randomized phase II-III study
16-26 years old patients
0,2 and 6. month vHPV vs qHPV vaccine
Antibody response in serum
(seronegativity against 9 types)
HPV-DNA test
(PCR negativity for 9 types at the end of 7th month)
Liquid-based cytology
HPV in biopsy-LEEP tissue
Joura EA et al, A 9-Valent HPV Vaccine against Infection and Intraepithelial Neoplasia in Women N Eng J Med 2015

24. High grade preinvasive lesions
Primary end points:
High grade preinvasive lesions
High grade CIN
AIS
High grade VIN
High grade VaIN
Invasive lesions
Cervical cancer
Vaginal cancer
Vulvar cancer
Follow up:
1. day, 7, 12, 18, 24, 30, 36, 42, 48, 54. months
Labial, vulvar, perineal, perianal, endocervical, ectocervical swabs (14 HR-HPV)
Pap test
Joura EA et al, NEJM 2015

25. ≥ CIN 2 cases related to HPV 31, 33, 45, 52, 58
48 months follow-up in group 9vHPV vaccine (n=5948) 1 case in group 4vHPV vaccine (n=5943) 27 cases
Joura EA et al, A 9-Valent HPV Vaccine against Infection and Intraepithelial Neoplasia in Women, N Eng J Med, 2015

26. ≥ CIN 2 cases among participants not HPV-infected on Day 1
48 month follow-up in group 9vHPV vaccine 26 cases in group 4vHPV vaccine 40 cases
Joura EA et al, A 9-Valent HPV Vaccine against Infection and Intraepithelial Neoplasia in Women, N Eng J Med, 2015

27. Incidence of disease related to HPV 6, 11, 16, 18
similar in the two vaccine group (9vHPV & qHPV vaccine) 40 month follow-up 1 case / case /5832
Joura EA et al, A 9-Valent HPV Vaccine against Infection and Intraepithelial Neoplasia in Women, N Eng J Med, 2015

28. immunogenicity analyses in per-protocol population:
~ 100 % seroconversion to the 9vHPV vaccine types within 1 month after dose 3
According to the GMT, the noninferiority of the response to the 9vHPV vaccine as compared with the response to the qHPV vaccine for HPV 6,11,16,18
The number of cases of infection and disease associated with HPV 6,11,16,18 was similar in the 9vHPV group and qHPV vaccine group
Joura EA et al, NEJM 2015

29. in the per-protocol efficacy population analyses:
incidence rate of High Grade cervical, vulvar, vaginal disease related to 5 added types :
in qHPV group 1.6/1000 person-years
in 9vHPV group 0.1/1000 person-years
9vHPV efficacy %
efficacy against disease related to 5 types
96.3 %
efficacy against persistent infection related to 5 types %
Joura EA et al, NEJM 2015

30. Adverse events
Joura EA et al NEJM 2015

31. Adverse events 9vHPV (n=7071) n % 4vHPV (n=7078) n % ≥ 1 adverse event
Injection-site event
(pain,swelling,erythema,pruritis)
*within 1 to 5 days after any vaccination
Systemic event
(Headache,Pyrexia,Nausea,Dizziness,Fatigue)
*within 1 to 15 days after any vaccination
Serious event
(death)
Joura EA et al, A 9-Valent HPV Vaccine against Infection and Intraepithelial Neoplasia in Women, N Eng J Med, 2015

32. Safety Profile of the 9-Valent HPV Vaccine: A Combined Analysis of 7 Phase III Clinical Trials Moreira ED, Block SL et al Pediatrics 2016
>15000 male & female

33. Safety Profile of the 9-Valent HPV Vaccine: A Combined Analysis of 7 Phase III Clinical Trials Moreira ED, Block SL et al Pediatrics 2016
The incidences of AEs were similar
in younger (9–15 years) and older (16–26 years) females
In study 001 in female subjects 16 to 26 years of age,
the most common injection-site AEs (incidence ≥5%):
pain, swelling, and erythema
89.9%, 40.0%, and 34.0% after 9vHPV
83.5%, 28.8%, and 25.6% after qHPV vaccinations
these AEs were more frequent with 9vHPV vaccine; the difference was statistically significant (P < .001) for the 3 AEs.
In study 009 in female subjects 9 to 15 years of age,
the most common injection-site AEs (incidence ≥5%)
also pain, swelling, and erythema
89.3%, 47.8%, and 34.1% after 9vHPV
88.3%, 36.0%, and 29.3% after qHPV vaccinations
These AEs were more frequent with 9vHPV vaccine
but was statistically significant (P = .003) only for swelling.

34. increased with subsequent doses for both vaccines.
Safety Profile of the 9-Valent HPV Vaccine: A Combined Analysis of 7 Phase III Clinical Trials Moreira ED, Block SL et al Pediatrics 2016
In both studies, most injection-site AEs were mild to moderate in intensity and
increased with subsequent doses for both vaccines.
Severe injection site AEs increased with subsequent doses
(in study 001,
severe injection site pain increased
from 0.7% or 0.4% after dose 1
to 2.6% or 1.7% after dose 3
with 9vHPV and qHPVvaccines, respectively).

35. Safety Profile of the 9-Valent HPV Vaccine: A Combined Analysis of 7 Phase III Clinical Trials Moreira ED, Block SL et al Pediatrics 2016
The most common vaccine-related systemic AEs (incidence ≥5%)
for 9vHPV vaccine were headache and pyrexia
in study 001
14.6% and 5.0% of subjects for 9vHPV
13.7% and 4.3% of subjects for qHPV
in study 009
11.4% and 5.0% of subjects for 9vHPV
11.3% and 2.7% of subjects for qHPV
within the ranges previously reported in the qHPV vaccine and placebo arms of the qHPV vaccine clinical program
(eg, headache and pyrexia in 18.7% and 10.1% of subjects for qHPV vaccine, and 19.9% and 8.4% for placebo, respectively).
The frequencies of systemic AEs generally decreased with subsequent doses for both vaccines.

36. The AE profile following 9vHPV vaccination was similar
Safety Profile of the 9-Valent HPV Vaccine: A Combined Analysis of 7 Phase III Clinical Trials Moreira ED, Block SL et al Pediatrics 2016
The AE profile following 9vHPV vaccination was similar
between genders;
AE frequencies were generally lower in male than female subjects.
The 9vHPV vaccine AE profile was similar between races
AEs of syncope in 36 of the vHPV vaccine recipients (0.2%), Of the 36 cases, 20 occurred on the same day as vaccination. Events occurred mostly in female subjects (94%)
Among 9vHPV vaccine recipients
7 subjects (<0.1%) experienced serious vaccine-related AEs,
7 subjects died during the studies.
None of the deaths were considered vaccine related.
Twenty subjects (0.1%) discontinued vaccination because of an AE

37. Safety Profile of the 9-Valent HPV Vaccine: A Combined Analysis of 7 Phase III Clinical Trials Moreira ED, Block SL et al Pediatrics 2016
In study 001, new medical conditions (incident medical conditions occurring outside of the period of day 1 to 15 postvaccination and not considered serious AEs) generally comparable between subjects who received 9vHPV or qHPV vaccines; frequencies of new medical conditions for each system organ class were similar between the 2 vaccines In study 001 and among all 9vHPV vaccine recipients, the most frequent new medical conditions (incidence ≥5%): infections arthralgia (9vHPV: 1.8%; qHPV: 1.7%) thyroid conditions (9vHPV: 1.2%; qHPV: 1.0%)

38. Conclusion 9vHPV vaccine:
prevents (associated with HPV 31,33,45,52,58)
Cervical, vulvar, vaginal disease
Persistant infections
Antibody responses to HPV 6, 11, 16 and 18 among participants who received the 9vHPV vaccine are noninferior to those among participants who received the qHPV vaccine
The incidence of disease related to HPV 6,11,16,18 is similar in the two vaccine group
The rate of clinical adverse events are similar in the two vaccine groups
Local side efects are higher in 9vHPV vaccine (more antigen and more adjuvant)
JJoura EA et al , N Eng J Med, 2015

39. Limitations of study Lack of a placebo control group (not ethical !!)
No minimum protective anti-HPV antibody titer has been identified
Follow-up was limited in duration
Cost effectiveness ??
2 doses ?
JJoura EA et al , N Eng J Med, 2015

40. Pediatrics 2015
the median age of sexual debut is in the late teens (15-19 years) in most countries
Wellings K et al Lancet 2006
But, Virginal adolescents (≤15 years old) were not included in HPV vaccine efficacy evaluations because of low HPV exposure and ethical constraints
Is qHPV vaccine efficacy findings in subjects aged 16 to 26 years same in subjects aged 9 to 15 years on the basis of the demonstration of noninferior immunogenicity ?

41. Efficacy high: Side effects low: 9-15 years old: Results:
(ideal prophylactic HPV vaccination population)
1935 girls
669 boys
16-26 years old:
470 young women
at day 1 and month 7 immunogenicity
in older group at day 1 and month 7 HPV-DNA PCR
Results:
Efficacy high:
The antibody responses in 9-15 year-old boys and girls is shown to be noninferior to those observed in 16-to-26- year-old young women
Seroconversion for all 9 HPV vaccine types are achieved in >99 % of participants
Side effects low:
Discontinuations n=1
Serious adverse event n=2
Local and systemic adverse events lower in 9-15 year old
Van Damme P, Pediatrics 2015

42. Vaccine 2015

43. 16-26 years old
1106 HM (heterosexual men),
313 MSM (having sex with men), women
0, 2 and 6. month, 0.5 ml i.m Gardasil 9
at day 1 and month 7 serum antibody titer for 9 HPV
Results:
in all three group effective:
More than 99% of participants seroconverted by month 7
to all 9 HPV types in all 3 groups.
Month 7 GMTs in HM are higher than those in women or MSM
(In contrast, qHPV vaccine)
Month 7 GMTs are numerically lower in MSM than in HM.
(just like in qHPV vaccine)
The geometric mean titers (GMTs) for HPV types 6, 11, 16, 18, , 33, 45, 52, and 58 for HM are non-inferior to those of women at Month 7
well tolerated
There are no serious vaccine-related AEs.
No subject died
One injection-site or systemic AE lower among young men (HM and MSM) than among young women.
Discontinuations from study vaccination as a result of an AE are rare (5 total)
Castellsagué X, Vaccine 2015

44. Randomized, double-blind, placebo-controlled
VACCINE 2015
Randomized, double-blind, placebo-controlled
safety/tolerability and immunogenicity study
9vHPV vaccine in girls and women years of age who previously received a 3-dose regimen of qHPV vaccine

45. placebo (saline) (n=306))
Previously received qHPV vaccine
12-26 years of age, females
third dose of qHPV vaccine administated at least one year prior to enrollment in the study
9vHPV vaccine (n=618)
placebo (saline) (n=306))
at day 1, month 2 and month ml i.m
Serum collected at the day 1 (pre-dose 1), month 2 (pre-dose 2), month 7 (post-dose 3) for analysis of anti-HPV responses
Garland SM, Vaccine 2015

46. Results: immunogenicity assessment
Seroconversion for all nine vaccine HPV types was achieved in >98 % of study participants who received a 3-dose regimen of the 9vHPV vaccine
in females who previously received a 3-dose regimen of qHPV
Anti-HPV 6, 11, 16, 18 GMTs increased substantially following the first 9vHPV vaccine, but did not change much following further vaccine administration
consistent memory response
Anti-HPV 31, 33, 45, 52, 58 GMTs increased also,
but were lower
clinical importance ?? Lower immunogenicity cannot be interpreted as lower protective efficacy against HPV related disease because there is currently no established anti-HPV titer that defines a threshold for protection

47. Safety assessment Results: local AEs are more common in vaccine group
43.9 % vs 91.1 %
mild to modarate in intensity
Systemic AEs similar
25.9 % vs 30.6 %
most common headache, pyrexia, nausea
Discontinuations from study vaccination as a result of an AE are rare
(3 total %)
No subject died
Garland SM, Vaccine 2015

48. Result ?
Since the 9vHPV vaccine was generaly well tolerated in prior recipients of 3 doses of qHPV vaccine,
it is reasonable to assume that it would also be well tolerated in prior recipients of 1 or 2 doses of qHPV vaccine

49. Can 9vHPV vaccine be administrated with the other childhood vaccines ?
well tolerated
does not affect the antibody response of the other vaccines
decreases the number of visits for vaccinations
may be increase the administration rate of HPV vaccine
(in USA only %  >90 %)
Schilling A, Pediatrics 2015

50. Review
Vaccines against human papillomavirus infections: protection against cancer, genital warts or both?
E.A. Joura, S. Pils Dept Gynaecol Obstet, Comprehensive Cancer Centre, Medical University of Vienna, Austria Clinical Microbiology and Infection ;S125eS
All currently available HPV vaccines provide strong protection against infections and disease related to HPV types 16 and 18
Protection against other oncogenic types is different for the various vaccines. Cross-protection is not as reliable as type-spesific protection and is of short duration Hence the nonavalent HPV vaccine is expected to give the broadest protection against pre-cancer and invasive cancer related to HPV.
Early vaccination is most effective; however, clinical efficacy has been demonstrated up to the age of 45

51. E.A. Joura, S. Pils Clinical Microbiology and Infection 22 2016;S125eS127 2016
Even for women treated for HPV-related disease, a reduction of subsequent HPV-related disease has been demonstrated for the quadrivalent and bivalent vaccines
Genital warts cause a substantial burden of disease and can be effectively prevented by vaccines protecting against HPV 6 and 11. Currently available data suggest that effective protection against cancer and warts can be provided and is not a matter of choice. Gender-neutral HPV vaccination programmes prevent disease in both sexes and substantially improve the coverage.
National and school-based programmes are superior to opportunistic vaccination. Improvement of the coverage is key for most countries and all efforts have to focus on this

52. HPV vaccination: The most pragmatic cervical cancer primary prevention strategy

53. REVIEW
Impact of 2-, 4- and 9-valent HPV vaccines on morbidity and mortality from cervical
Cancer Rebecca Lucketta and Sarah Feldmanb Harvard Boston,USA
HUMAN VACCINES & IMMUNOTHERAPEUTICS ;6:1332–1342
All three vaccines show high efficacy in prevention of vaccine-specific HPV-type infection and associated high-grade cervical dysplasia in HPV-naĭve women.
Early clinical effectiveness data for the bivalent and quadrivalent vaccine demonstrate reduced rates of HPV 16 and 18 prevalence in vaccinated cohorts; data evaluating cervical dysplasia and cervical procedures as outcomes will shed further light on the clinical effectiveness of both vaccines.
The bivalent vaccine has demonstrated cross-protection to nonvaccine HPV types, including the types in the 9vHPV vaccine.

54. REVIEW Impact of 2-, 4- and 9-valent HPV vaccines on morbidity and mortality from cervical Cancer Rebecca Lucketta and Sarah Feldmanb Harvard Boston,USA HUMAN VACCINES & IMMUNOTHERAPEUTICS ;6:1332–1342
No clinical effectiveness data is yet available for the 9vHPV vaccine.
While HPV vaccination has great promise to reduce cervical cancer morbidity and mortality, estimated benefits are largely theoretical at present.
Large population-based clinical effectiveness studies will provide long-term immunogenicity and effectiveness, as well as assessment of cervical cancer as an endpoint, particularly as young vaccinated women enter the appropriate age range to initiate screening for cervical cancer.
Strengthening screening and treatment programs will likely have the greatest impact in the short-term on cervical cancer morbidity and mortality

55. Gardasil 9 will have the largest clinical impact on women who do not have access to routine cervical screening and to subset of men who have sex with men
The impact of Gardasil 9 on women already participating in cervical cancer screening programs will be much smaller.
LaJoie AS. Fernandez LM. Pendleton ME, Harper DM
Future adoption of 9vHPV will depend on factors including market price, cost-effectiveness data, use of a two-dose schedule, and safety and efficacy monitoring in real-life programs
Mariani L, Preti M etal Int J Gynaecol Obstet 2017;136:258

56. Questions (1):
Do we recommend 9vHPV vaccine the patients who have already completed the HPV vaccine series with q-valent or b-valent HPV vaccine ?
no The ACIP did not address revaccination with 9v vaccine
Which vaccine should be recommend girls and boys not previously vaccinated with any HPV vaccine?
9vHPV Gardasil9
What is the ideal time for 9vHPV vaccine ?
ideally should be given before the onset of sexual activity
Is 9vHPV vaccine contraindicated if there is a history of abnormal Pap, genital wart, HPV infection or HPV related disease no
Should be Pap test or HPV DNA test performed before Gardasil9 ? Are they necessary ?
Does Gardasil9 have therapeutic effect ?

57. Questions (2):
Is Gardasil9 cost effective in men as much as in women ? no
In which situation, will 9vHPV vaccine be cost effective in men as much as in women ?
if coverage rate is low in women (for example: in USA)
if administration for women is not obligatory
What is priority for administration of Gardasil9 ?
girls boys adult women adult men
Can be administrated 2 doses instead of 3 doses ?
probably yes (should be wait on-going studies results)
What should be done with patients who started the HPV vaccine series with 2-valent HPV or 4-valent HPV vaccine?
ACIP recommends that any appropriate HPV vaccine
(2v,4v or 9v for females and 4v or 9v for males) can be used to continue or complete the HPV vaccine series

58. Questions (3):
Can 9vHPV vaccine be administered in pregnancy ? no (limited data: no teratogenic effect )
in incidental vaccination in pregnancy, is termination necessary ? no
If she becomes pregnant before the completion of vaccine 3 dose series, what should be done ?
cancel the series, complete after the delivery
Vaccination in lactation ?
yes
Does 9vHPV vaccination change the screening programmes ?
Not yet to reduce ICC incidence Vaccine should be protective at least 15 years
What is the duration of prevention ?
???

59. Thank You for Your Attention…
With us… for ever…
Thank You for Your Attention…