Complete update on HPV vaccine.

1. D R . S U K H W I N D E R S I N G H
HPV VACCINES: AN
UPDATE

2. OUTLINE
• Global burden of HPV related cancers
• Human papilloma virus
• HPV life cycle in cervix
• Types of HPV
• Association between Human Papillomavirus and Malignant Diseases
• Clinical manifestations
• HPV disease prevention
• History of HPV vaccine
• Vaccine profile
• Mechanism of action HPV vaccines
• Natural history of HPV infection & carcinoma cervix
• Whome to vaccinate
• Possible HPV vaccination target groups and special populations
• Vaccination recommendations for HPV
• Adverse effect of HPV vaccine
• HPV vaccine delivery strategy
• Progress in HPV vaccine implementation
• Hpv vaccination in India
• Other way to prevent cervical cancer
• Therapeutic HPV vaccines

3. GLOBAL BURDEN OF HPV RELATED
CANCERS
Cervical cancer
• 2,784 million women aged 15 years and older worldwide are at risk
of developing cervical cancer
• 4th most common cancer among women in the World
• 2nd most common cancer among women aged 15-44 years
Worldwide

4. CERVICAL CANCER
New annual
cervical cases
• India – 122,844
• World – 527,624
Annual deaths due to
cervical cancer
• India –67,477
• World – 265,672
23%
77%
India
World
27%
73%
India
World

5. ANOGENITAL CANCERS OTHER THAN THE
CERVIX
• Anal cancer:
• average worldwide incidence of 1 per 100,000
• 27,000 new cases every year
• Vulvar cancer:
• 4% of all gynaecologic cancers
• Vaginal cancer:
• 2% of all gynaecologic cancers
• Penile cancer:
• 22,000 new cases every year
de Martel C et al. Lancet Oncol 2012;13(6):607-15

6. HUMAN PAPILLOMA VIRUS
• Papillomavirus genus
• Papillomaviridae family
• Non-enveloped virus
• 55 nm in diameter
• Icosahedral capsid composed of 72 capsomeres enclosing
a ds circular DNA genome

7. HUMAN PAPILLOMA VIRUS
• genome - 7900 base pairs
• the genome encodes several early genes (E1, E2, E4, E5,
E6, and E7)
• structural late genes (L1 and L2)
• 200 HPV types known

8. GENE
CATEGORY
GENE FUNCTION
Early genes
E1 Viral DNA replication
E2 • viral transcription
• DNA replication
• segregation of viral genomes
E4 • HPV genome amplification
• virus maturation
• release of virions
E5 • se activity of E6 and E7
• Generate aneuploidy and chromosomal instability
E6 • Bind and degrade the tumor-suppressor protein p53
• inhibit apoptosis
E7 Bind and degrade the tumor-suppressor protein pRB
Late genes L1 • Major capsid protein
• attachment to cell surface receptors
• highly immunogenic & induce the production of neutralizing
type-specific antibodies against the virus
L2 • Minor capsid protein
• helps packaging of viral DNA into capsids

9. HPV LIFE CYCLE IN CERVIX

11. • Non-oncogenic HPV:
• 6,11,32,40,42,43,44,54,55,57,61,62,64,71,72,74,81,84,87,89,
90,91
• Oncogenic HPV types:
• High risk oncogenic virus
• 16,18,31,33,35,39,45,51,52,56,58,59
• Probable/possible carcinogen
• 26,30,34,53,66,67,68,69,70,73,82,85,97
TYPES OF HPV

12. ASSOCIATION BETWEEN HUMAN
PAPILLOMAVIRUS AND MALIGNANT DISEASES
Worldwide India
Human Papillomavirus and Related Diseases Report April 2017

13. ASSOCIATION BETWEEN HUMAN
PAPILLOMAVIRUS AND MALIGNANT DISEASES
Forman D et al. Vaccine 30s 2012
Lacey CJ et al 2006

14. CLINICAL MANIFESTATIONS
• Cutaneous warts
• deep plantar warts
• common warts
• plane or flat warts
• Epidermodysplasia Verruciformis
• Anogenital Warts
• Recurrent Respiratory Papillomatosis
• Cancers
• Cervical
• Anal
• Vaginal
• Vulvar
• Penile
• Oro-pharyngeal cancer

15. TYPES OF HPV

16. HPV DISEASE PREVENTION

17. THE NEED FOR VACCINATION
AGAINST CERVICAL CANCER
• Natural HPV infection induces a weak immune response
• Vaccination induces higher antibodies in blood and site of
infection which neutralizes virus.

18. WHY VACCINATION IS THE BEST FORM
OF PREVENTION
• All genital HPV infections can’t be prevented except by
abstinence and lifetime mutual monogamy
• Barrier methods of contraception confer a protection
against HPV infection – still questionable
• Asymptomatic infection except for genital warts
• In developing country like India, large-scale routine
screening is difficult to achieve.

19. HISTORY OF HPV VACCINE
• 1977 - Dr.Harald zur Hausen detected HPV in warts and cervical
cancer
• 2006 – US FDA approved Gardasil vaccine
• 2008 - Dr. Hausen received Nobel Prize for his work on HPV
• 2009 - FDA approved Cervarix vaccine
• 2014 - FDA approved 9-valent HPV vaccine
• 2016 - U.S. FDA approved adding a 2-dose schedule for 9-valent
HPV vaccine (Gardasil 9) for adolescents ages 9 -14 years

20. VACCINE PROFILE
• 2 licensed prophylactic HPV vaccines
• Bivalent (16,18)
• Quadrivalent (6,11,16,18)
• Both produced by recombinant technology

21. VACCINE PROFILE
• Virus-like particles (VLP)
• Purified L1 protein
• form empty shells
• do not contain viral genetic material or live biological product
• non infectious.

23. no

24. MECHANISM OF ACTION HPV VACCINES
Bind to viral particles
Transudate from capillaries to basal stem cells in the
genital epithelial mucosa
L1- Neutralizing serum IgG 1–4logs > natural infection
Anti-L2 antibodies cross-neutralizing
VLP(L1 & L2)-based HPV vaccination

25. NATURAL HISTORY OF HPV INFECTION
& CARCINOMA CERVIX
• In natural infection, antibodies against L1 appear 6–8
months following infection
• In 50–70% of infected individuals
• Other viral proteins (E1, E2 and E6) do not elicit antibody
responses
• IgM response occurs first and decays early
• IgG response appears late

26. CROSS-TYPE PROTECTION
• Gardasil – HPV 31
• Cervarix - HPVs 31,33,52,45 and 51

27. WHOME TO VACCINATE
• Girls aged 9 to 14 years prior becoming sexually active
• Catch-up vaccination till 45 year old females
• Males

28. EVALUATION BEFORE VACCINATION
• Contraindicated :
• Known hypersensitivity to any vaccine components
• Serious bleeding disorders
• Pregnancy
• Delay vaccination - severe febrile illness
• HPV serologic or DNA testing or cervical cytology are not
recommended before vaccination

29. POSSIBLE HPV VACCINATION TARGET GROUPS
AND SPECIAL POPULATIONS
Primary target group of females:
• Girls 9–14 years of age
• HPV vaccines are most efficacious-
• before onset of sexual activity
• females naive to vaccine-related types
• Primary vaccine target group depend on
• country’s vaccine licensing indications
• age of initiation of sexual activity of females

30. POSSIBLE HPV VACCINATION TARGET GROUPS
AND SPECIAL POPULATIONS
Secondary or “catch-up” populations of females:
• females 15 years and older
• May decrease impact of vaccination on cervical cancer-
shorter interval between vaccination and sexual
exposure to vaccine related HPV types

31. SPECIAL POPULATIONS
Pregnant and lactating females:
• HPV vaccination not recommended in pregnant females
• If pregnant women vaccinated, vaccination be
discontinued until completion of the pregnancy

32. SPECIAL POPULATIONS
Immunocompromised individuals:
• Limited Data
• HPV vaccination of target group before onset of sexual
activity reduces risk of administering HPV vaccines to
HIV-infected individuals
• Countries with HPV vaccines in national immunization
programmes do not vaccinate females whose HIV status
is unknown

33. ACIP-RECOMMENDATIONS FOR HPV
• On 19 October 2016, CDC and ACIP recommended :
Females < 15 years should receive 2
doses of HPV vaccine at least 6
months apart rather than the
previously recommended 3 doses.

34. ACIP-RECOMMENDATIONS FOR HPV
4vHPV & 2vHPV vaccine:
• <15 years (Target group) – 2 doses (0, 6-12 months)
• If interval between doses is <5 months - 3rd dose given at least 6
months after the 1st dose
• 16-26 years (Catch-up group):
• 3 doses ( 0, 2, 6 month)
• Interval between 1st & 2nd dose - 6–12 weeks
• Interval between the 2nd & 3rd dose - 12–23 weeks
• >26 years- geometric mean titres lower than 16-26 years
• Concomitant Administration with Other Vaccines:
• meningococcal conjugate vaccine, tetanus, diphtheria, and acellular pertussis
vaccine; inactivated polio vaccine and hepatitis B vaccine
• No effect on seroconversion rates and geometric mean titres
• Pregnancy - Category B

35. ACIP-RECOMMENDATIONS FOR HPV
4vHPV & 2vHPV vaccine:
• Interchangeability of HPV Vaccine Products
• Vaccination completed with same HPV vaccine product
• if providers don’t have same HPV vaccine product either HPV vaccine
product may be used to continue or complete the series for females to
provide protection against HPV 16 & 18.
• Only 4vHPV used in males.

36. ADMINISTRATION
• HPV vaccine shaken well before administration
• Dose of vaccine - 0.5 ml
• Intramuscularly, preferably deltoid muscle or antero-
lateral thigh

37. INTERRUPTED SCHEDULE (0,2,6M)
• Interrupted after 1st dose:
• 2nd dose to be given as soon as possible and 2nd & 3rd dose be
separated by at least 12 weeks
• Interrupted after 2nd dose:
• 3rd dose to be given as soon as possible

38. INCORRECTLY VACCINATED (0,2,6M)
• Average interval between :
• 1st & 2nd dose - 6–12 weeks
• 2nd & 3rd dose - 12–23 weeks
• Minimum interval:
• 1st & 2nd dose - 4 weeks
• 2nd & 3rd dose - 12weeks
Inadequate doses and shorter intervals – vaccines
schedule readministered

39. SPECIAL SITUATIONS
Abnormal Pap Test, Known HPV Infection, Anogenital
Warts, or HPV-Associated Lesions:
• Protection against vaccine HPV types only
• Might not be infected by any of the vaccine HPV type
• Vaccination also recommended for:
 females regardless of abnormal Pap test result
 Females/males regardless of known HPV infection, HPV-associated
precancer lesions, or anogenital warts
 Females with abnormal cervical cancer screening

40. SPECIAL SITUATIONS
Immuno-compromised Persons :
• Vaccine efficacy between immuno-compromised and immuno-
competent persons – unclear
• ACIP recommends same vaccination schedule for immuno-
compromised
Men Who Have Sex with Men:
• Higher risk of HPV infection
• ACIP recommends routine vaccination with 4vHPV

41. SPECIAL SITUATIONS
Lactating Women:
• Can receive HPV vaccine
History of Sexual Abuse or Assault:
• Risk of HPV infection
• ACIP recommends HPV vaccination beginning at age 9 years
with 2-dose series
• Older females & males victims should receive HPV vaccine
through the recommended ages

42. HPV VACCINES SHOULD
NOT BE GIVEN TO…
• History of allergies to any vaccine component
• 4vHPV & 9vHPV - hypersensitivity to yeast
(Saccharomyces cerevisiae)
• 2vHPV - anaphylaxis caused by latex
• Moderate or severe acute illnesses
• Pregnant women

43. DURATION OF VACCINE PROTECTION
• HPV vaccines offer long-lasting protection
• Studies followed vaccinated individuals for around ten
years - no evidence of protection decreasing over time

44. ADVERSE EFFECT OF HPV VACCINE
Common HPV vaccine reactions which resolve
spontaneously and rarely require treatment are:
• Redness, pain, swelling, or induration at injection site
• Fever
• Headache, myalgia, arthralgia
• Nausea, vomiting, diarrhea, abdominal pain
• Pruritis, rash, urticaria
• Syncope, dizziness

45. SHOULD BOYS BE VACCINATED??
• Benefits:
• protection against HPV-associated diseases in men
• enhanced herd immunity with consequent reduction in HPV
transmission in populations
• Can countries attain sufficiently high male vaccination
coverage rates?----Most promising question

46. HPV VACCINE DELIVERY STRATEGY
Ideal HPV vaccine delivery strategy outlined by WHO in
2013:
• compatible with existing vaccine-delivery infrastructure and cold
chain capacity
• affordable, cost-effective and sustainable
• able to achieve the highest possible coverage
HPV vaccine delivery strategies:
• Vaccine delivery at health-care facilities
• Vaccine delivery through outreach:
• School-based outreach
• Other outreach
• Vaccine delivery through campaigns

47. PROGRESS OF HPV VACCINE
IMPLEMENTATION
• January 2008, 13 countries had recommended catch-up
vaccination of older adolescent females or young women
• 2009 – 1st WHO paper on HPV vaccines published
• Both 4vHPV & 2vHPV vaccine licensed in > 100
countries
• July 2009 – HPV vaccines were WHO pre-qualified
• May 2011 – 32 countries worldwide introduced HPV
vaccine in their national immunization program
• 2015 – 65 countries worldwide introduced HPV vaccine
in their national immunization program

48. HPV VACCINE- INDIA
• HPV vaccines introduced under pilot projects in 2006
• GAVI states- a coverage of 25-70% over 10 years in a
country like India can save > 1 million lives.
• Pap testing & HPV DNA testing or HPV antibody before
vaccination is not needed
• Prevention of cervical cancer continues to be largely
neglected in India

49. AVAILABILITY OF VACCINE IN INDIA
• GlaxoSmithKline and Merck & Corp sell in India
• No manufacturing facility in India
• No Indian company selling HPV vaccines
• But some Indian companies have HPV vaccines in their
pipeline
• Cervarix and Gardasil have India import license of validity up
to December 2016 and June 2018 respectively.

50. COST OF HPV VACCINE-INDIA

51. HPV VACCINATION IN INDIA
Indian Academy of Pediatrics Committee
on Immunisation (IAPCOI) recommends
offering HPV vaccine to all females who
can afford the vaccine.
• Schedule same as given by ACIP

52. HPV VACCINATION IN INDIA

53. HPV VACCINE-RESEARCH
• Research carried out in India:
• Capsomere vaccines –
• more cheap
• manufactured in E.coli
• require no cold-chain.
• Monovalent vaccines (based on the L2 protein)-
• Broader protection
• Needle free delivery systems

54. PIPELINE VACCINES
Market assesment of newer vaccines, 2015

55. OTHER WAYS TO PREVENT CERVICAL
CANCER
• Reduce high-risk sexual behaviours
• Condom use
• Avoid or reduce tobacco use and smoking
• Seek prompt treatment of sexually transmitted infections

56. THERAPEUTIC HPV VACCINE????
• Several types developed and tested in preclinical and
clinical trial
• Types :
• live vector
• protein or peptide
• nucleic acid
• cell-based vaccines
• Whole cell based type
• Tumour cell based type
• Majority target HPV onco-proteins E6 and E7

57. THERAPEUTIC HPV VACCINES
RECENTLY USED IN CLINICAL TRIALS
TYPE VACCINE ANTIGEN CONSTRUCT
Bacterial Vector
Based
Lm-LLo-E7
(ADXS11-001;
ADXS-HPV)
HPV-16 E7 prfA-
defective
Listeria
monocytogenes
strain
GLBL101c HPV16-E7
expressing
modified
version of HPV16-E7
Recombinant
Lactobacillus
casei
Viral Vector Based TA-HPV HPV-16/18 E6/E7 Recombinant
Vaccinia virus
TG4001 HPV-16
E6/E7
Recombinant
modified
Vaccinia Ankara-
expressing
HPV-16 E6, E7, and
IL-2
MVA E2 HPV-16 E2 Recombinant
Modified
Vaccinia Ankara
virus

58. THERAPEUTIC HPV VACCINES
RECENTLY USED IN CLINICAL TRIALS
TYPE VACCINE ANTIGEN CONSTRUCT
Peptide/Protein
Based
HPV16-SLP HPV-16 Combination of nine
HPV-16 E6 and four
HPV-16 E7
E6/E7 synthetic
peptides with incomplete
Freund’s adjuvant
GL-0810 HPV-16 antigen HPV-16 immunomodulatory
peptide with adjuvant
Montanide and GM-CSF
Pepcan + Candin HPV-16 E6 HPV16 E6 peptides
combined with Candida
skin testing reagent
candin
GTL001
(ProCervix)
HPV-16 and
HPV-18
Recombinant HPV16 and
HPV18 E7 proteins fused
to catalytically inactive
Bordetella pertussis CyaA
expressed in E. coli

59. THERAPEUTIC HPV VACCINES
RECENTLY USED IN CLINICAL TRIALS
TYPE VACCINE ANTIGEN CONSTRUCT
Peptide/Protein
Based
TA-CIN HPV-16 E6/E7/L2 HPV16 E6E7L2 fusion
protein
TA-CIN + TA HPV HPV-16/18 E6/
E7/L2
HPV16 E6E7L2 fusion protein and
vaccinia virus with HPV16/18 E6/E7
Nucleotide Based pNGVL4a-sig/
E7(detox)/
HSP70 + TAHPV
HPV-16/18 E6/E7 Plasmid encoding mutated form of
HPV16-E7 linked to sig and HSP70
and vaccinia virus with
HPV16/18 E6/E7
pNGVL4a-CRT/
E7(detox)
HPV-16 E7 Plasmid encoding mutated form of
HPV16-E7 linked to CRT
GX-188E HPV-16/18 E6/E7 Plasmid encoding fusion protein of
HPV 16/18 E6/E7 linked to Flt3L and
tpa
VGX-3100 HPV-16/18 E6/E7 Mixture of two plasmids
encoding optimized consensus of E6
and E7
antigen of HPV 16 and 18

60. THERAPEUTIC HPV VACCINES
RECENTLY USED IN CLINICAL TRIALS
TYPE VACCINE ANTIGEN CONSTRUCT
Whole Cell
Based
DC + KLH HPV-16 and
HPV-18 E7
Dendritic Cells pulsed
with HPV-16 and HPV-18
E7 and keyhole limpet
hemocyanin
DC HPV antigens DC pulsed with HPV+
tumor lysate

61. THANK YOU