HPV vaccination

Dr Kanika Gupta
Gynae-Oncologist
 Cervical cancer worldwide

• 500,000 women diagnosed per year1

• Worldwide, every 2 minutes a woman dies of cervical
cancer1
– 270,000 deaths (data from GLOBOCAN 2002)1
– In less developed regions, cervical cancer remains the
leading cause of cancer deaths in women
– Projections indicate by 2050 > 1 million new cases of
cervical cancer each year2
• Despite the impact of screening in a large number of
countries, women continue to be at risk 3

1. Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004;
2. Parkin DM, et al. Eur J Cancer 2001; 37(Suppl 8):S4-S66.
2. Kitchener HC, et al. Vaccine 2006; 24(Suppl 3):S63–S70.
 100% of cervical cancers are caused
by HPV
Global total HPV-attributable cancers in 2002
Attributable Attributable to HPV
to HPV % all 16/18
HPV
Total cancer
Site % Cases % Cases
cancers
Cervix 492,800 100 492,800 93.5 70+ 344,900
Vulva, vagina 40,000 40* 16,000 3 80 12,800
Anus 15,900 90* 14,300 2.7 92 13,100
Oropharynx 9,600 12* 1,100 0.2 91 1,000
Mouth 98,400 3* 2,900 0.5 97 2,800
Total 527,100 374,600

Adapted from Parkin DM & Bray F. Vaccine 2006; 24(Suppl 3):S11.

Walboomers JMM, et al. J Pathol 1999; 189:12–19.
 The Human Papillomavirus

100 HPV Types Have Been Identified

30 HPV Types are Transmitted by Genital

skin to skin Contact

15 HPV Types are Oncogenic

80% of Cervical Cancers are Caused

by 4 HPV Types:
HPV16, HPV18, HPV45, HPV31
Munoz N et al. N Engl J Med 2003; 348(6):518-527
 HPV types associated with the development of
cervical cancer (SCC)
• The 5 most common HPV types associated with squamous cell
carcinoma by region (ICO survey 2007, preliminary results)
World Africa Asia Europe1 L. America2 Oceania
(n=7733) (n=616) (n=1130) (n=2618) (n=3236) (n=133)
HPV % HPV % HPV % HPV % HPV % HPV %

HPV16 61.6 HPV16 46.8 HPV16 66.6 HPV16 63.9 HPV16 60.1 HPV16 64.8

HPV18 8.2 HPV18 18.9 HPV18 7.2 HPV18 6.7 HPV18 7.5 HPV18 14.1

HPV45 5.5 HPV45 10.8 HPV58 4.7 HPV33 5.7 HPV45 6.0 HPV45 5.5

HPV31 4.5 HPV35 5.3 HPV33 4.5 HPV45 4.7 HPV31 5.8 HPV33 3.1

HPV33 4.3 HPV52 4.4 HPV52 3.1 HPV31 4.0 HPV33 3.7 HPV35 2.3

1 Europe + North America

2 Latin America: Central and South America
Data updated July 2007.
Multiple infections are proportionally distributed by the number of types infected Professor Xavier Bosch.
 HPV types associated with the development of
cervical cancer (Adenocarcinoma)
• The 5 most common HPV types associated with adenocarcinoma by
region (ICO survey 2007, preliminary results)

World Africa Asia Europe1 L. America2 Oceania

(n=816) (n=72) (n=54) (n=315) (n=355) (n=20)
HPV % HPV % HPV % HPV % HPV % HPV %

HPV16 47.8 HPV18 47.6 HPV18 46.0 HPV16 53.2 HPV16 48.8 HPV16 37.5

HPV18 29.0 HPV16 36.9 HPV16 32.4 HPV18 27.4 HPV18 23.5 HPV18 34.7

HPV45 12.3 HPV45 9.5 HPV45 10.1 HPV45 11.8 HPV45 13.5 HPV45 16.7

HPV31 1.2 HPV35 2.4 HPV59 5.4 HPV33 1.2 HPV31 2.4 HPV11 4.6

HPV33 1.1 HPV51 2.4 HPV66 3.4 HPV35 1.2 HPV39 1.7 HPV54 3.2

1 Europe + North America

2 Latin America: Central and South America
Data updated July 2007.
Multiple infections are proportionally distributed by the number of types infected Professor Xavier Bosch.
Cervical adenocarcinoma

• Adenocarcinomas account for approximately 15–

25% of all invasive cancers2
• Up to 30% diagnosed in women < 35 years2
• Greater likelihood of recurring compared with
squamous cell carcinomas3
• It is more likely to metastasize (spread to other
parts of the body) early2

1. Cancer Research UK 2008. Accessed at http://www.cancerhelp.org.uk/help/default.asp?page=2758;

2. Parkin DM, et al. Vaccine 2006; 24(Suppl 3):11-25;
3. Smith HO, et al. Gynecol Oncol 2000; 78:97-105;
4. Altekruse SF, et al. Am J Obstet Gynecol 2003; 188:657–663;
5. Smith JS, et al. Int J Cancer 2007; 121:621–632;
6. Bosch XF, et al. J Nat Cancer Inst 1995; 87:796–802;
7. de Sanjose S, et al. 24th International Papillomavirus Conference and Clinical Workshop; Beijing, 2007.
Risk of HPV infection

• HPV infections are very common

• The cumulative risk of acquiring cervical HPV infection
in women with only one sexual partner is 46% (3 years
after first sexual encounter)1
• The risk of oncogenic HPV infection is high even after
first intercourse and continues throughout a woman’s
sexually active lifetime2–4
• Up to 80% of women will acquire an HPV infection in
their lifetime5–7
– While most infections are cleared, women are less likely to
clear infections as they get older8

1. Collins S, et al. Br J Obstet Gynaecol 2002; 109:96–98; 2. Schiffman M, et al. J Natl Cancer Inst 2003; 31:14–19;
3. Sellors JW, et al. CMAJ 2003; 168:421–425; 4. Dunne EF, et al. JAMA 2007; 297:813–819;
5. Brown DR, et al. J Infect Dis 2005; 191:182–192; 6. Koutsky L, et al. Am J Med 1997; 102:3–8;
7. Bosch FX, et al. J Natl Cancer Inst Monogr 2003; 31:3–13; 8. Castle PE, et al. J Infect Dis 2005; 19:1808–1816.
 HPV Lifecycle in the Cervix
Shedding of virus-
laden epithelial cells

Cervical canal Viral assembly

(L1, L2, E4)
Mature
squamous
layer
Viral DNA replication
Squamous (E6 & E7)
layer

Episomal viral DNA

Parabasal in cell nucleus
cells (E1 & E2, E6 & E7)

Basal (stem) Infection of basal

cells cells (E1 & E2)

Basement membrane
Normal Infected
epithelium epithelium Frazer IH. Nat Rev Immunol 2004; 4:46–54.
 Progression of Cervical Disease

Progression*
Months Years
Time

Normal HPV infection CIN1 CIN2 CIN3 Invasive

epithelium koilocytosis carcinoma

Low-grade squamous High-grade squamous

intraepithelial lesion intraepithelial lesion (HSIL)
(ASCUS/LSIL)
Regression
* With increasing probability of viral DNA integration
CIN=cervical intraepithelial neoplasia; Burd EM. Clin Microbiol Rev 2003; 16:1–17;
ASCUS=atypical squamous cells of undetermined significance Solomon D, et al. JAMA 2002; 287:2114–2119
Risk of HPV infection

• HPV infections are very common

• The cumulative risk of acquiring cervical HPV infection
in women with only one sexual partner is 46% (3 years
after first sexual encounter)1
• The risk of oncogenic HPV infection is high even after
first intercourse and continues throughout a woman’s
sexually active lifetime2–4
• Up to 80% of women will acquire an HPV infection in
their lifetime5–7
– While most infections are cleared, women are less likely to
clear infections as they get older8

1. Collins S, et al. Br J Obstet Gynaecol 2002; 109:96–98; 2. Schiffman M, et al. J Natl Cancer Inst 2003; 31:14–19;
3. Sellors JW, et al. CMAJ 2003; 168:421–425; 4. Dunne EF, et al. JAMA 2007; 297:813–819;
5. Brown DR, et al. J Infect Dis 2005; 191:182–192; 6. Koutsky L, et al. Am J Med 1997; 102:3–8;
7. Bosch FX, et al. J Natl Cancer Inst Monogr 2003; 31:3–13; 8. Castle PE, et al. J Infect Dis 2005; 19:1808–1816.
HPV infections continue to occur in women
over 25 years of age
• The risk starts from sexual debut1 and continues throughout
life2
• Incident infection of oncogenic types is estimated to be 5.3%
(range: 5–10%) in women 25–55 years of age3
• Although new infections decrease with age, risk of
persistence increases with age4
• Immune function declines with age resulting in decreased
capacity to respond to both new and previously encountered
infections5

1. Collins S, et al. Br J Obstet Gynaecol 2002; 109:96–98;

2. Schiffman M & Krüger Kjaer S. J Natl Inst Cancer 2003; 31:14–19;
3. Bory JP, et al. Int J Cancer 2002; 102:519–525;
4. Castle PE, et al. J Infect Dis 2005; 191:808–816;
5. Graham JE, et al. J Behav Med 2006; 29:389–400.
Disease progression

• For every 1 million women infected with HPV1:

– 100,000 will develop precancerous changes (cervical
dysplasia)*
– 8,000 will develop carcinoma in situ (CIS)*
– 1,600 will develop invasive cervical cancer if dysplasia and
CIS are not detected or treated*
• Cervical cancer is a relatively rare outcome of a
common oncogenic HPV infection2
• Over 80% of HPV infections are transient,
asymptomatic and resolve spontaneously3–6

* Highest estimate based on model without screening.

1. McIntosh N. Jhpiego strategy paper 8. May 2000. Accessed at
http://www.jhpiego.jhu.edu/scripts/pubs/category_detail.asp?category_id=4;
2. Bosch FX, et al. J Clin Pathol 2002; 55:244–265;
3. Ho GY, et al. N Engl J Med 1998; 338:423–428; 4. Moscicki AB, et al. J Pediatr 1998; 132:277–284;
5. Giuliano AR, et al. J Infect Dis 2002; 186:462–469; 6. Franco EL, et al. J Infect Dis 1999; 180:1415–1423.
How is the Virus
Transmitted ?
Mechanism of HPV Transmission & Acquisition

Sexual contact

– Through sexual intercourse

– Genital–genital, manual–genital, oral–genital

Proper condom use may help reduce the risk, but is not fully
protective against infection.

Nonsexual routes

– Mother to newborn (vertical transmission)

– Fomites (eg, undergarments, surgical gloves, biopsy forceps)

• Hypothesized but not well documented; would be rare
 Hence Teenagers
Who Experiment in
Non-Penetrative Sex

May be at Risk Of HPV Infn

Risk of Acquiring HPV After Sexual
Intercourse

• 60% of Girls with One Sexual Partner will have HPV

Infection within 5 years of beginning sexual intercourse.
• 80% of females get infected with HPV by the age of 50
years.
BUT Do You Know ?
90% of females will clear off the infection naturally within
2 years.
Prevention of cervical cancer –
primary prevention
• Vaccination provides primary prevention against cervical HPV
infection – a necessary cause of cervical cancer1,2
• Because vaccination does not protect against all oncogenic HPV
types,3 screening must be continued
• Optimum time to vaccinate is prior to risk of HPV exposure3 (onset
of sexual activity); however:
– women remain at risk of infection throughout their sexually
active lives4 and can therefore benefit from vaccination
– this continued risk is demonstrated by the prevalence of
oncogenic HPV infections in women of all ages4

1. Schiffman M. Lancet 2007; 370:890–907; 2. Walboomers JMM et al. J Pathol 1999; 189:12–19;
3. Stanley M. Vaccine 2006; 24(Suppl 3):S106–113; 4. Dunne EF, et al. JAMA 2007; 297:813–819.
Natural HPV infection induces a weak immune response1-4

Uncertain whether HPV infection will recall

Poor exposure to antigen presenting cells
memory in vaccinated women

Uses the natural life cycle of epithelial cells to release new viruses 1-4
No
Does not cause cellinflammation,
death1-4 no danger signals

Enters basal epithelial cell, integrates DNA in host cell 1-4

Replicates inLocal
the cellsimmunosuppression
and remains entirely intraepithelial 1-4

Local infection1-4
No viremia
Infects the epithelium through micro abrasions 1-4

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
 Neutralizing antibodies prevent HPV infection

• HPV vaccination focuses on HPV infects target cells in basal

preventing HPV infection through layer of the cervical epithelium
generation of high levels of
Infection
‘neutralizing’ antibodies
• Neutralizing antibodies bind to viral
capsid and thereby prevent the Basal cell layer
of cervical epithelium
infection of host cells1
• The time from exposure to Neutralizing antibodies prevent HPV
attachment of the virus to the target from infecting basal epithelial cells
cell is 15 min to 48 h2
No infection

The likely mediator of protection is X

neutralizing antibody
WHO 20063
1. Stanley M et al. Vaccine 2006;24 Suppl 3:S106–S113;
2. Schwarz TF et al. Gynecol Oncol 2008; 110(Suppl 3): S1-S10.
3. WHO Expert Committee on Biological Standardization, 2006.
 Why do we need high antibody levels?

• 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

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.
 What makes a good cervical cancer
vaccine?
• Antigens (virus-like particles) that closely mimic the virus
structure
• Generation of neutralizing antibodies – the major basis
of protection
• High levels of antibodies in the serum that can transude
to the site of infection resulting in:
– An immune response that improves on natural immunity, as natural
immunity does not guarantee protection
– The greatest possible protection against cervical cancer-causing
HPV types
– Durable protection afforded by sustained protective immune
responses
Development of virus-like particles as HPV
vaccine antigens

HPV-containing double ‘Empty’ non-infectious

stranded DNA virus-like particle mimics
the virus

Stanley M, et al. Vaccine 2006; 24(suppl 3):S3/106–113.

 Composition of the two licenced HPV vaccines

Antigens AS04 Adjuvant system

CervarixTM
+ Aluminium
salt
(Al(OH)3)
+ MPL
Immunostimulant

HPV 16 VLPs HPV 18 VLPs

AS04-containing vaccine

Antigens Adjuvant

Gardasil® + Aluminium salt

(amorphous aluminium
hydroxyphosphate
sulphate)
HPV 16 VLPs HPV 18 VLPs HPV 6 VLPs HPV 11 VLPs

AAHS-containing vaccine
HPV Vaccines: Cross-protective
Efficacy
Papillomavirus phylogenetic tree

40 39 70 59
7 32
44 55 42
PCV1 18 27
13 45 61 2a
11 57
6
73 3
34 28
10
RhPV1 29
58
33 51
52 26 30
16
35 53
56
31 66

• The alpha-papillomavirus genus of the papillomavirus phylogenetic tree

is shown*
• Oncogenic types closely related to HPV 16 and 18 are highlighted
• HPV 16 is most closely related to HPV 31
• HPV 18 is most closely related to HPV 45
*Selected species and types are shown
Adapted from de Villiers E, et al. Virology. 2004; 324:17–27.
 HPV vaccines and cross protection

• Antibodies generated in response to vaccine antigens may provide

protection against other closely-related antigens
• HPV 16 & 31 and 18 & 45 are phylogenetically closely-related
– A strong immune response to HPV vaccine types may lead to cross-
protective efficacy against infection with other non-vaccine types
• This is particularly important for prevention of adenocarcinoma
- >90% of adenocarcinomas result from these 4 HPV types

Cumulative presence of HPV types in cervical adenocarcinoma

HPV types Cumulative %

16 47.8
16 + 18 76.8
16 + 18 + 45 89.1
16 + 18 + 45 + 31 90.3

Bosch FX, International Papillomavirus Conference, Beijing; 2007.

 Whom To
Vaccinate ?
Whom to Vaccinate?

• Most countries Recommend Vaccination in all girls in

the Primary age group from 9-12 years.

• Catch-up Vaccination till 26 years, some countries

recommend till 45 years of age also.

• Australia Recommends Vaccination in Males also.

Why 9-26 years?
Why 9-26 years?

• Peak of HPV Infection occurs at 19-24 years

• Median Age of Sexual Debut In India is 18 years
• Immunogenecity Higher in 10-15 years old Girls
Age-Specific Rates of HPV Infection &Cancer*

25 Peak of cervical cancer

25
HPV infection
Peak of HPV infection

Cancer Incidence Rate (×105)

Cervical Cancer
20 (n=3752) 20
HPV Prevalence (%)

15
15

10 10

5 5

0 0
20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64

Age for vaccination Age Group (Years)

9 – 26 years
Lag Phase btw Infn & CA Cx – 10- 20 yrs

* Two different cohorts (cross-sectional study) followed during the same time span to measure the rate of high-risk HPV infection in one and the rate of cervical cancer in the other.
1. Adapted from Bosch FX, Lorincz A, Muñoz N, Meijer CJLM, Shah KV. J Clin Pathol. 2002;55:244–265, with permission from the BMJ Publishing Group.
Median age (in years) sexual debut and gender

At the national level median age at sexual debut was 18 years in both rural and urban areas.
National Behavioural Surveillance Survey (BSS) 2006, NACO
What to do if patient is between 26-45 years
of age ?
• Present recommendation in India is from 9-26 years
• Some countries recommend up to age of 45 years
• Chance of patients getting all 4 strains is one in a
thousand , so some benefit is likely for all patients.
• It may protect against further re-infections if the
infection is cleared of naturally
• Some cross protection to other strains may also be
there.
• To be decided on a case to case basis after discussion
with patients
WHO position on HPV vaccines

• Routine HPV vaccination should be included in national

immunization programmes
• HPV vaccines are most efficacious in females who are naive to
vaccine-related HPV types
• Primary target population should be selected based on data on
the age of initiation of sexual activity and the feasibility of
reaching young adolescent girls through schools, health-care
facilities or community-based settings.
• The primary target population is likely to be girls within the age
range of 9 or 10 years through to 13 years
• HPV vaccination of males is not recommended

WHO position paper, WEEKLY EPIDEMIOLOGICAL RECORD, NO. 15, 10 APRIL 2009
Recommendations of the Indian Academy of Pediatrics
Committee on Immunisation (IAPCOI)

• The currently available vaccines are safe and efficacious.

• Recommends offering HPV vaccine to all females who can
afford the vaccine (Category 2)
• The vaccine should preferably be given prior to sexual debut.
• The vaccine should preferably be introduced to parents as a
cervical cancer preventing vaccine and not as a vaccine
against a sexually transmitted infection (STI).
• Need for boosters and potential for serotype replacement
would be known in future.

http://www.iapcoi.com/hpv.htm
Recommendations of the Indian Academy of Pediatrics
Committee on Immunisation (IAPCOI)
• The recommended age for initiation of vaccination is 10-
12 years.
• HPV vaccines can be given simultaneously with other
vaccines such as hepatitis B and Tdap.
• As a precaution against syncope following any vaccine in
adolescents, the vaccinee should be counseled prior to
vaccination, vaccine be administered in a sitting/lying
down position and the patient observed for 15 minutes
post vaccination.

http://www.iapcoi.com/hpv.htm
The Association of Physicians of India (API)
Guidelines

• Age for initiation for vaccination to be 10 - 12 years

(Level Ib, Grade A).
• Catch-up vaccination can be advised up to the age of
26 years for Gardasil vaccine and 45 years for Cervarix
vaccine.
• The HPV vaccines can be given simultaneously with
other vaccines e.g., Hepatitis B, Tdap.
• The vaccine can be administered to
immunosuppressed individuals. However, the
immunogenicity and efficacy may be lower (Level IV,
Grade C).

JAPI, APRIL 2009, 57: 345

FOGSI Recommendations for Vaccination against
HPV Infection For the prevention of Cervical Cancer (i)

• The bivalent vaccine has been approved for use in females aged
10 to 45 years
• The Quadrivalent vaccine has been approved for use in females
aged 9 to 26 years
• Vaccination is not recommended in males, at present
• The HPV vaccine is not therapeutic. It does not treat existing HPV
infection or cervical intraepithelial neoplasia
• Women who have been vaccinated with the HPV vaccine should
continue with the cervical cancer screening
• For the quadrivalent vaccine three doses at 0, 2 and 6 months
• For bivalent vaccine three doses at 0,1 and 6 months
• At present there are no data to support the use of boosters.
FOGSI Oncology Committee, www.fogsi.org, HPV vaccine
FOGSI Recommendations for Vaccination against HPV
Infection For the prevention of Cervical Cancer (ii)

• Testing for HPV is not recommended before vaccination

• The vaccine can be given to patients with previous CIN, but the
benefits may be limited to the protection against infection of HPV
genotypes (and related CIN) with which they have not been
infected.
• The use of the vaccine in pregnancy is not recommended
• Women who become pregnant before completion of vaccination
are advised to postpone the remaining dose until after the
pregnancy.
• Lactating women can receive the HPV vaccine and still continue
breastfeeding because it is a vaccine without live viral DNA.

FOGSI Oncology Committee, www.fogsi.org, HPV vaccine

Prevention of cervical cancer – primary
prevention
• Vaccination provides primary prevention against cervical HPV
infection – a necessary cause of cervical cancer1,2
• Because vaccination does not protect against all oncogenic HPV
types,3 screening must be continued
• Optimum time to vaccinate is prior to risk of HPV exposure3 (onset
of sexual activity); however:
– women remain at risk of infection throughout their sexually
active lives4 and can therefore benefit from vaccination
– this continued risk is demonstrated by the prevalence of
oncogenic HPV infections in women of all ages4

1. Schiffman M. Lancet 2007; 370:890–907; 2. Walboomers JMM et al. J Pathol 1999; 189:12–19;
3. Stanley M. Vaccine 2006; 24(Suppl 3):S106–113; 4. Dunne EF, et al. JAMA 2007; 297:813–819.
 Prevention of cervical cancer – secondary
prevention
• Cervical cancer screening has greatly reduced morbidity and
mortality, but has limitations
– It does not prevent infection or development of precursors
of cervical cancer1
– Lesions which progress quickly may not be detected in
time2
– Early stages of adenocarcinoma are difficult to detect3
– Cervical cancer screening is not widely available in all
countries4

1. Cancer Research UK 2008. Available at: http://info.cancerresearchuk.org/healthyliving/screening/cervicalcancerscreening/

2. Holowaty P, et al. J Natl Cancer Inst 1999; 91:252–258; 3. Krüger Kjaer S, et al. Epidemiol Rev 1993; 15:486–498
4. Gakidou E, et al. PLoS Med 2008; 5:e132. doi:10.1371/journal.pmed.0050132.
Conclusion

The goal of vaccination is

• Safe and continued protection from persistent infections and CIN2/3
as a surrogate of cancer
– Large-scale monitoring of efficacy, tolerability and safety in large
ongoing studies continue to investigate this
• To provide long-lasting protection against cervical cancer

The most effective HPV vaccine would induce

high and sustained levels of neutralising
antibodies at the site of infection throughout
a sexually active lifetime