CERVICAL CANCER AWARENESS

1. Changing the HPV Landscape with
an Indigenous Vaccine – CERVAVAC
Dr. Poonam Taneja

2. 1. Basics of HPV
2. Classification of HPV types
3. HPV & Cervical cancer
4. CERVAVAC
5. Clinical Data Summary

3. Basics of HPV

4. What is Human Papilloma virus (HPV)?
• Human papilloma virus is the most common sexually transmitted infection (STI)
• Most sexually active men & women being exposed to the virus at some point during their lifetime
• Increased risk of HPV at younger age
• Highest prevalence occurs amongst adolescent & young adults between age 15-25 years
• More than 200 types have been identified
• Around 30-40 of them cause genital HPV infections
• HPV can cause several type of cancer – Cervical, Oral, Penile, Vaginal, Vulvar & Anal

5. How does HPV spread?
• 2 individuals + sexual activity could result in HPV infection
• Can spread through vaginal, anal, or oral sex with someone who has the virus.
• It is most commonly spread during vaginal or anal sex
• It also spreads through close skin-to-skin touching during sex.
• A person with HPV can pass the infection to someone even when they have no signs or symptoms
• If person is sexually active, he/she can get HPV, even if he/she have had sex with only one person
• Symptoms can be developed years after having sex with someone who has the infection. This
makes it hard to know when the person first got infected

6. HPV evades the immune system
1. Muñoz N, Castellsague X, de Gonzalez AB, Gissmann L. Vaccine 2006;24 Suppl 3:S1–10
2. Stanley M. Vaccine. 2006;24Suppl 1:S16-22.
The HPV virus does not cause cell death, which means
that the immune system is not alerted2
In the cell, the HPV virus hides while multiplying1-2
HPV infection occurs locally at the cervix therefore
no presence of the virus in the bloodstream1-2

7. HPV evades the Immune System
1.Stanley M. Vaccine 2006;24: S106-13,2.Tindle, Nat Rev Cancer 2002;2, 59, 3.Stanley M.
Vaccine 2006;24:S16-22,4. Stanley M. HPV Today 2007;11: 1-16
No inflammation, no attraction of immune cells
Local immunosuppression
No viremia
Poor exposure to antigen presenting cells
For Internal Training Purpose Only

8. HPV lifecycle in the Cervix
Basement membrane
Normal
epithelium
Cervical canal
Mature
squamous
layer
Squamous
layer
Parabasal
cells
Basal (stem)
cells
Infected
epithelium

9. Classification of HPV types

10. Classification – HPV types
• HPV types are classified on basis of potential to cause cancer
• At least 30 HPV types target genital mucosa classified as High risk (Oncogenic) and low risk types
16,18, 31, 33, 45, 52, & 58
Low-risk types
Cause high/low grade
cervical lesions & cancers
of
• Cervix
• Anal
• Vaginal
• Vulvar
• Penile
• Oropharyngeal
Genital warts
High-risk types
6, 11 & others (42,43,44)
H
I
G
H
R
I
S
K
L
O
W
R
I
S
K

11. Classification
type 6,11 & others (42,43,44)
types 16, 18, 31, 33, 35, 39,
45, 51, 52, 56, 58, 59
HPV Type
Lesions Region
Genital
Warts
Cancer
……………………………………………………………………………
……………………………………………………………………………
……………………………………………………………………………
Low risk types
High risk types

12. Oncogenic and low-risk HPV types
• High risk oncogenic types
• Of 30 types, 12 types are classified as oncogenic (WHO)
• 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59
• Globally, types 16 and 18 together account for 71% of Cervical Cancer cases
• In India, it accounts for 83.32% of cases of cervical cancer
• Other oncogenic HPV types (in descending order of global prevalence) include 45 (6%), 31 (4%),
33 (4%), 52 (3%), 58 (2%), 35, 59, 56, 51, 39, 68, 73 and 82 (WHO)
• Low-risk types cause benign genital warts/lesions
• 90% of genital warts are due to types HPV 6 and 11
• Other low-risk types include 42, 43, and 44

13. HPV 16
HPV 18
HPV 6
HPV 11
Cancer causing Types Non-cancer causing types
• 83.2% of Cervical Cancer in India 90% of Anogenital warts (WHO)
HPV is a necessary cause of cervical cancer – 99.7%
HPV
HPV & Cervical cancer
- ICO/IARC HPV Information Centre 2022

14. HPV & Cervical cancer

15. HPV & Cervical cancer deaths in India
- ICO/IARC HPV Information Centre 2022
77,348
Deaths
Annually
1,23,907
Deaths
Annually
Annual no. of
cervical cancer
cases
Annual no. of
cervical cancer
Deaths
51.15
Crore
Women at risk for
cervical cancer >=15
yrs
Contributes 17% of Globe
Contributes 21% of Globe
Contributes 23% of Globe

16. Confidential
•It is cancer that begins on the cervix, which is the mouth of the uterus
What is Cervical cancer?

17. Signs & Symptoms of Cerival cancer
• Early on, there are usually no symptoms of cervical cancer. The longer a person has cervical cancer
without treatment, the more likely they will have symptoms.
Some of the symptoms of advanced cervical cancer can include:
• Abnormal vaginal bleeding
• Unusually heavy vaginal discharge
• Painful intercourse
• Painful urination
• Bleeding after intercourse, between periods or after a pelvic exam
• The interval between the acquisition of HPV infection and progression to invasive carcinoma is
usually 15–20 years or longer

18. Warts
• Genital warts may appear as a small
bump, cluster of bump, or stem like protrusions
• They commonly affect vulva in women, or
cervix and penis or scrotum in males. They may
also appear around the anus.
• They can range in size, appearances and be
large, small, flat or cauliflower shaped
• Genital warts appear 6 week to 8 months
after sexual contact with HPV infected person
• HPV types 6 & 11 are common causes of
genital warts

19. Warts
Genital Warts in female Genital Warts in male
Global estimates: the overall reported annual incidence
of anogenital warts ranged from 160 to 289 per 100 000.
*in men and women combined
* including new and recurrent cases

20. Can Cervical Cancer be prevented?
• Yes, cervical cancer can be prevented by
Educate & Aware
Screening
Vaccination

21. Cervical Cancer Awareness Level
• People are not aware about tremendous disease burden caused by
cervical cancer.
• People may lack accurate information on its natural history, detection
& treatment.
• Many women/parent have not heard of cervical cancer & do not
recognize early signs & symptoms when they occur.
• Women at risk may not be aware of the need to be tested, even when
they do not have any symptoms.
WHO Book - Comprehensive cervical cancer control : a guide to essential practice.

22. Cervical cancer screening
• Cervical cancer is most often found in women who have not been screened with the Pap test in
more than five years or have never been screened at all.
• There are two screening tests that can help prevent cervical cancer or find it early:
Pap test or Pap Smear
Cells are taken from the cervix & looked at under a microscope. The Pap test results show
cells that are not normal & may become cancer.
High Risk (HR) HPV test
The HR HPV test looks for the high-risk types of this virus that cause most cases of cervical
cancer. The HPV test can be done at the same time as the Pap test using either the same sample of
cervical cells or a second sample taken right after the Pap test.

23. Cervical cancer screening
Cervical Cancer Screening Recommendations for Women at Average Risk
•Cervical cancer screening should start at 21 years of age
•Pap test every three years between 21 and 29 years old
•Pap test and HPV test (co-testing) every five years between 30 and 65 years old or a Pap test every
three years.

24. Vaccination
• HPV vaccines are highly effective at preventing the infection of
susceptible women with the HPV types covered by the vaccine.
• HPV vaccine should be given to females before they reach an age
when the risk of HPV infection increases & they are at subsequent risk
of cervical cancer.
• HPV vaccine should be ideally given from 9-26 year old girls as per the
recommendation.
• HPV vaccine is given as 2/3 doses (depending on the age of recipient)
over a period of 6 months.

25. 1. Parr EL et al. J Virol 1997;71(11):8109-15,2. Nardelli-Haefliger D et al. J Natl Cancer Inst 2003;95(15):1128-37,3. Schiller JT et al. Nat Rev Microbiol 2004;2(4):343-7,4. Poncelet et al. ESPID,Porto, Portugal 2007;
Abstract 37, session ES2, 5. Stanley M. HPV Today 2007;11: 1-16, 6. Einstein M, Cancer Immunol Immunother 2007;57(4):443-51.
• Vaccination induces antibodies
in the blood
•Data show that vaccine-induced antibodies in the
blood can reach to the site of infection1-3
•Higher antibody levels in the blood mean higher
antibody levels at the site of infection4
•Antibodies neutralize the virus and prevent entry
into cells5,6
Why do we need high antibody levels?
For Internal Training Purpose Only

26. HPV VLP Vaccines
Source : Berzofsky JA, Ahlers JD, Janik J, Morris J, Oh S, Terabe M, Belyakov IM. Progress on new vaccine strategies against chronic viral infections. J Clin Invest. 2004 Aug;114(4):450-62.

27. India’s 1st Indigenous qHPV Vaccine

28. qHPV vaccine and Cancer prevention:
Real world data
Risk of cervical cancer who were vaccinated before
the age of 17 years was 88% lower than among those
who un-vaccinated.
- N Engl J Med. 2020 Oct;383(14):1340-1348
87% reduction in cervical cancer for age 12–13 years,
compared to unvaccinated cohort
- Lancet. 2021 Dec 4;398(10316):2084-2092.
Anal cancer - Relative to 2001 to 2008 period,
incidence significantly decreased among aged
20 to 44 years.
- JAMA Oncol. 2022 Apr 1;8(4):1-3.
28
The Younger, the Better

29. WHO global strategy to eliminate
cervical cancer
90%
70%
90%
• of girls fully vaccinated with
HPV vaccine by age 15
years.
• of women are screened
with a high-performance
test by 35 years of age and
again by 45 years of age
• of women identified with
cervical disease receive
treatment
Source: https://www.who.int/publications/i/item/9789240014107
29

30. Inequity in access to HPV vaccination
 High burden of Cervical cancer:
 Low awareness
 Insufficient availability and access to vaccines
 Screening and vaccine reluctance
30
Bruni L et al. Prev Med. 2021;144:106399.

31. Serum Institute’s goal - Affordable
HPV vaccine
 The driving force behind the development of Quadrivalent (6,11,16 & 18) HPV
vaccine was to produce an effective, safe and affordable vaccine for reach out to
Immunization program/Private market, thereby reducing the local and global burden of
cervical cancer.
 SIIPL’s motto of supplying life saving vaccines cost effectively, is supported by its
huge manufacturing capacities.
31

32. CERVAVAC Development Roadmap
Phase 1
Completion
Phase 2
Enrollment
initiation
Clinical Study
Report
availability
CT–Clinical Trial
CSR- Clinical Study Report
DCG(I)
–Drug Control General of India
MA–Marketing Authorization
SEC–Subject Expert Committee
May 2018
Jul 2017
Feb 2016 Sep 2018 Jan 2020 Feb 2020 Mar 2022
MA
Dossier
submissio
n to
DCG(I)
May 2022
SEC
Meeting
Grant of
Marketing
Authorizatio
n India
Jun 2022 Jun 2022 July 2022
2010
R & D
R & D- Research and Development
Phase 2/3
Results
Phase 2 Completion and
DSMB Recommendation
Phase 3
Enrollment
initiation
Phase 2/3
CT
approval
Completion of
Non-Clinical
Studies
32

33. Brief Study Design - Phase 2/3
33
 Partially Double-blind, Multi-centre, Randomized, Active Controlled.
 Gardasil® as a active comparator Vs CERVAVAC.
 Two age cohorts
 Cohort 1- Aged 9-14 yrs (2 dose – 0 and 6 M)
 Cohort 2- Aged 15-26 yrs (3 dose – 0, 2 and 6M)
 3 Arms in each age cohort
 CERVAVAC (6, 11, 16, 18) – Male
 CERVAVAC (6, 11, 16, 18) - Female
 Gardasil (6, 11, 16, 18) – Female
 Multicentric study carried out in 12 premier institutes/hospitals in India.

34. Study Sites & Principal Investigators
34
Clinical Study Sites & Principal Investigators
All India Institute of Medical Sciences, New Delhi (Dr. Neerja Bhatla)
Tata Memorial Hospital & Cancer Research Institute, Mumbai (Dr. Sharmila Pimple)
KEM Hospital & Research Centre, Pune (Dr Anand Kawade)
Postgraduate Institute of Medical Education & Research, Chandigarh (Dr. Vanita Suri)
Christian Medical College, Vellore (Dr. Anitha Thomas)
Chittaranjan National Cancer Institute, Kolkata (Dr. Ranajit Mandal)
Grant Medical Foundation (Ruby Hall Clinic), Pune (Dr. Smita Joshi)
MNJ Institute of Oncology & Regional Cancer Centre, Hyderabad (Dr. A Rajeswar)
G. Kuppuswamy Naidu Memorial Hospital, Coimbatore (Dr. Latha Balasubramani)
M. S. Ramaiah Medical College & Hospital, Bangalore (Dr. Rajini Uday)
Kasturba Medical College and TMA Pai Hospital, Manipal (Dr Veena Kamath)
Bharati Vidyapeeth Medical College & Hospital, Pune (Dr. Sanjay Lalwani)

35. Phase II overview
35
Objectives
To assess the safety of SIIPL qHPV and Gardasil vaccines in 9-14 years cohort (2
doses) and 15-26 years (3 doses) of the vaccine.
Determination of assay method for immunogenicity testing for Phase-III part.
 All subjects enrolled in Phase-II part of the study were included in Primary
immunogenicity analysis in Phase-III part.
Age Cohort
SIIPL qHPV SIIPL qHPV Gardasil
Male Female Female
Cohort 1 (9-14 yrs) 100 100 100
Cohort 2 (15-26 yrs) 100 100 100
Total in each arm 200 200 200
Total 600

36. Phase II – Summary of safety
36
 Safety data was analysed by performing group level unblinding.
 Overall, Pain or Tenderness was the most common solicited local AE (41.50%); followed by
Induration or Swelling (2.50%) and Pruritus (2.67%).
 Headache was the most frequently reported solicited systemic AE (14.17%) followed by Pain in the
Extremity (8.33%) and Dizziness (6.00%).
 The AEs reported in the Phase-II part of the study were predominantly mild to moderate in
intensity, non-serious and recovered completely.
 No solicited reactogenicity with severity of Grade 3 or more was reported during the study.
 None of the SAE was causally related to the study vaccine.
 The overall incidence of the AEs was in line with the product label of the comparator & DSMB
unanimously recommended that study had met primary end points of safety and it should
be moved to Phase-III part.

37. Phase II – Immunogenicity objective
37
 Phase II clinical samples were tested by three different assays
1. Multiplexed ELISA on MSD platform
2. ELISA
3. Pseudovirion Based Neutralization Assay (PBNA).
 The total number of subjects required for the primary immunogenicity analysis
was calculated based on SD of the finalized assay.
 Both assays ELISA & ELISA-MSD had shown a high Correlation (>0.9) with the
PBNA Assay
 Multiplex ELISA on MSD platform was finalized for the immunogenicity testing of
Phase III samples as it is more sensitive assay, has high throughput capacity
and tests more samples in parallel for different HPV types simultaneously.

38. Study Population and Allocation
38
Phase II/III Study
Cohort I : 9-14 yrs
(2 dose schedule)
SIIPL-qHPV
(Male)
Phase 2 + 3
(n = 366)
[100 + 266]
SIIPL-qHPV
(Female)
Phase 2 + 3
(n = 366)
[100 + 266]
Gardasil
(Female)
Phase 2 + 3
(n = 366)
[100 + 266]
Cohort II : 15-26 yrs
(3 dose schedule)
SIIPL-qHPV
(Male)
Phase 2 + 3
(n = 366)
[100 + 266]
SIIPL-qHPV
(Female)
Phase 2 + 3
(n = 366)
[100 + 266]
Gardasil
(Female)
Phase 2 + 3
(n = 366)
[100 + 266]
• Total sample size planned for the study (Phase-II / III) : 2196 [Phase-II : 600; Phase-III: 1596]
• Due to COVID-19 pandemic some subjects were unable to receive all doses as per vaccination schedule.
• Additional subjects were enrolled with DCGI permission. Final number of total subjects was 2307.

39. Phase III - Primary Objectives
39
• To demonstrate immunogenic non-inferiority one month after the last dose i.e. at 7 month
Sr.
No.
SIIPL qHPV Gardasil
1
Girls (9-14 yrs)
2 doses
Women (15-26 yrs)
3 doses
2
Boys (9-14 yrs)
2 doses
Women (15-26 yrs)
3 doses
3
Women (15-26 yrs)
3 doses
Women (15-26 yrs)
3 doses
4
Men (15-26 yrs)
3 doses
Women (15-26 yrs)
3 doses

40. Assessment of Non-inferioroity as per
WHO
40
 SIIPL qHPV vaccine was compared with Gardasil (Efficacy proven vaccine), with Non-inferiority margin of 0.5
WHO Technical Report Series, No. 1004, 2017 WHO Technical Report Series, No. 999, 2016

41. 41
Immunogenicity Summary

42. Seroconversion at 7 months
42
Serotypes HPV 6 HPV 11 HPV 16 HPV 18
Cut-off Values 0.197 AU/mL 0.152 AU/mL 0.333 IU/mL 0.695 IU/mL
Ref : Use Of Children’s Sera To Establish Negative Cut-off Values For Hpv Serology Assays .Gitika Panicker, et al. Division of High-
Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, USA

43. Robust immune response is assuring
43
 WHO International Agency for Research on Cancer study in India has shown that even 2 to 4
fold higher antibody titres (as compared to that in unvaccinated women following natural
infections) correlate well with the high vaccine efficacy observed with single dose at 10 years.
Joshi S et al. Vaccine 41 (2023) 236–245.
 >1000 fold rise observed with CERVAVAC
 It reassures long term protection against all vaccine HPV types i.e
6, 11, 16 & 18.

44. Overall Summary
 CERVAVAC has demonstrated a robust antibody response.
 100% seroconversion was reported across all 4 vaccine types (Serotypes 6, 11, 16, 18).
 Geometric Mean Fold Rise for all 4 HPV serotypes is > 1000 fold across all the age cohorts
and gender.
 AEs reported were predominantly mild to moderate in intensity and recovered completely.
 No vaccine related SAE or solicited reactogenicity with severity of Grade 3 or more was
reported
 Overall incidence of AEs with CERVAVAC is within acceptable limits and in line with the
product label of the comparator viz., Gardasil.
44

45. CERVAVAC - Product Information
Target Population
CERVAVAC is indicated in 9 through 26 years of age (girls/women and boys/men) for the prevention of the diseases caused by Human
Papillomavirus (HPV) types 6,11,16 and 18.
Name of the ingredient Quantity Function
Active Ingredients
Human Papillomavirus type 6 L1 protein ≥ 20 µg
Immunogen
Human Papillomavirus type 11 L1 protein ≥ 40 µg
Human Papillomavirus type 16 L1 protein ≥ 40 µg
Human Papillomavirus type 18 L1 protein ≥ 20 µg
Inactive ingredients
Aluminium hydroxide (as Al+++) ≤ 1.25 mg Adjuvant
Name of the ingredient Quantity Function
Residuals from DS
L-Histidine 0.78 mg Stabilizer
Polysorbate 80 50 mcg Stabilizer
Sodium Chloride 9.56 mg Tonicity Modifier
Water for Injection (WFI) q.s. Vehicle
Note: Tris base and Glacial Acetic acid are used for pH adjustment.
Mode of Administration, Presentation and Storage condition
 The vaccine is administered by an intramuscular injection.
 Presentation: 1-dose and 2-dose vial (without preservative).
 Dose: 0.5 mL
 Vaccination Schedule :
• Aged 9-14 years (2 dose) - 0 and 6 months
• Aged 15-26 years (3 dose) - 0, 2 and 6 months
 Store in refrigerator (2º C to 8º C), Do not freeze.
Once opened, multi-dose vials should be used as soon as
practically possible and within 6 hours when kept between
+2ºC and +8ºC.
 Shelf life : 36 months

46. Indication and Posology
Age at the time
of the first
injection
Immunization and schedule
9 to 14 years *
Two doses schedule
0.5 ml at 0, 6 months
CERVAVAC is suspension for injection. QHPV (Serotypes 6,11,16,18) vaccine (Recombinant)
Each dose is of 0.5 ml.
Indications:
Indicated in girls and women & boys and men 9 through 26 years of age for prevention of disease
caused by HPV types – 6,11,16,18
From 15 years to 26
years
Three doses schedule
0.5ml at 0, 2, 6 months

47. Method of administration
• Cervavac is for intramuscular injection in the deltoid region
• CERVAVAC should under no circumstances be administered intravascularly or
intradermally or subcutaneously
Shelf life- unopened vial 36 months
• Once opened, multi-dose vials should be used as soon as practically possible
and within 6 hours when kept between +2ºC and +8ºC
• All opened multidose vials of CERVAVAC™ should be discarded at the end of
immunization session or within six hours, whichever comes first.

48. HPV Vaccines Licensed in India
48
Gardasil Cervarix Gardasil 9 CERVAVAC
Manufacturer MSD GSK MSD SIIPL
Type Prophylactic vaccine consisting of virus-like particles containing L1 capsid proteins
Antigens
Quadrivalent vaccine HPV
types 6,11 ,16 and 18
Bivalent vaccine: HPV
types 16 and 18
Nonavalent vaccine HPV
types 6 ,11,
16,18,31,33,45,52 and 58
Quadrivalent vaccine HPV
types 6 ,11 ,16 and 18
Antigen
Expression
system
Yeast Baculovirus Yeast Yeast
Adjuvant
Alum:Aluminium
hydroxyphosphate sulfate
ASO4: aluminium
hydroxide, 3-deacylated
monophosphoryl lipid A
Alum:Aluminium
hydroxyphosphate sulfate
Aluminum Hydroxide
Gender
Licensed in India only for
Females
Licensed in India for
Females
Licensed in India for
Female and male
Licensed in India for
Female and male
Vaccination
Schedule
Girls : 9-14 yrs - 2 Dose
(at 0 and 6M)
Women : 15 yrs and older –
3 Dose (at 0, 2 and 6 M)
Girls : 9-14 yrs - 2 Dose (at
0 and between 5 to 13M)
Women : 15-45 yrs– 3
Dose (at 0, 1 and 6 M)
Girls & Women : 9-26 yrs -
3 Dose ( at 0, 2 and 6M)
Boys - 9-14 yrs - 3 Dose (
at 0, 2 and 6M)
Girls/Boys : 9-14 yrs - 2
Dose (at 0 and 6M)
Women/Men : 15-26 yrs –
3 Dose (at 0, 2 and 6 M)

49. A “Silver Bullet” for Cervical Cancer
The Lancet Oncology; October, 2022
49

50. Worldwide Public Private Partnership for CERVAVAC
50

51.  CERVAVAC i.e Quadrivalent (6, 11, 16 & 18) HPV vaccine is the first indigenously
developed and manufactured vaccine in India.
 It is a sterile suspension for intramuscular administration and prepared from highly purified
virus-like particles (VLPs) of the recombinant major capsid (L1) structural proteins.
 HPV-vaccination elicits neutralizing antibodies in sera and cervicovaginal secretions and
protects uninfected individuals from persistent anogenital infection and associated diseases
caused by the vaccine-targeted HPV types.
 After the efforts of more than 10 years in R & D, animal studies (single dose, repeat dose,
reproductive tox), clinical trials (phase I, II and III) CERVAVAC was licensed by NRA, in July
2022.
CERVAVAC®

52. CERVAVAC
Quadrivalent
Vaccine
(6,11,16, 18)
Assured Supply
Cost Effective
World Class
Manufacturing
Facilities
Gender Neutral
• Boys and Men - 9 to 26 years
• Facilitate a more rapid reduction
in HPV prevalence.
CERVAVAC - Sustainable, High Volume, High Quality, Cost Effective HPV Vaccine
• India’s First Indigenous HPV
vaccine
• Licensed in Q2 2022
• Excellent Track Record for
Gov/WHO/UNICEF/GAVI supply
• Network & reach to 170+ countries
• Fully Automated close loop system
• Dedicated facilities & dedicated
manpower for HPV manufacturing
• Most Affordable
• Remove the inequity in
Access to HPV Vaccination

53.  CERVAVAC – 2 dose vial available in interim launch in selected cities
 Cervavac 1 dose would be available in few months
 2 Dose vial is priced at MRP of Rs. 4000 ie. Rs. 2000 per dose
 Dcotor’s landing price for 2 dose vial – Rs. 3200 all incl. ie 1600 per dose
CERVAVAC - Price

54. THANK
YOU