Cervical cancer is one of the commonest cancers in women. As it affects young women it has grave personal, social and economic consequences. It is unfortunate that despite cancer cervix being a preventable disease, we have failed to reduce the number of deaths related to it. Recent developments in the understanding of the disease process and its link to the oncogenic strains of Human Papilloma Virus (HPV) has opened new avenues in the way of prevention of cervical cancer.

1. HPV Vaccine: A Breakthrough In Prevention of Cervical Cancer

2. HPV vaccine: A breakthrough in prevention of cervical cancer
R. Sharma*
ABSTRACT
Background: Cervical cancer is one of the commonest cancers in women. As it affects young women it has grave
personal, social and economic consequences. It is unfortunate that despite cancer cervix being a preventable
disease, we have failed to reduce the number of deaths related to it. Recent developments in the understanding of the
disease process and its link to the oncogenic strains of Human Papilloma Virus (HPV) has opened new avenues in
the way of prevention of cervical cancer.
Method: The information was collected through literature search using the key words HPV, cancer cervix and
prevention.
Result: It is now well established that almost all cervival cancers are caused by oncogenic Human Papilloma Viruses
(HPV), with types 16 and 18 being responsible for almost 70%. This fact has led to the development of a vaccine with
great potential of preventing the disease by preventing the causative infection in the target population.
Conclusion: A prophylactic vaccine to prevent HPV-related precancerous lesions and cancers would save lives,
reduce the need for costly medical procedures and provide both women and communities throughout the world, with
substantial benefits. The reduction in the incidence of cervical cancer and mortality is expected to be greatest in low
and middle-income countries where there is no or only limited screening for cervical cancer.
Copyright © 2012, Indraprastha Medical Corporation Ltd. All rights reserved.
Keywords: Cervical cancer, HPV, Prevention
INTRODUCTION
Cervical cancer is one of the commonest cancers in women
worldwide, second only to breast cancer.1
As it affects
young women it has grave personal, social and economic
consequences. In India it is still the commonest cancer in
women accounting for about 130,000 new cases and
80,000 deaths annually.2
Unfortunately, prevention of
cervical cancer is not yet among the top ten National health
priorities in India and a comprehensive National Health
Strategy for cervical cancer prevention is still lacking. As
a result, despite cancer cervix being a preventable disease,
we fail to reduce the number of deaths related to it.
The long pre-cancerous stage of cancer cervix provides
a great opportunity to treat a cervical lesion before it turns
malignant. The resourceful countries that managed to run
an organized screening programme using Pap smear as
a screening test, achieved about 70% reduction in the
disease related mortality.3
Screening by Pap smear cytology has certain limitations,
especially in resource-poor countries. In addition to having
low sensitivity, the laboratory based infrastructure and
skilled health care professionals for taking, making, trans-
porting and interpreting smears, are hard to find even in
urban health care facilities in India. Communicating the
results to women, and providing confirmatory diagnostic
tests in the form of colposcopy and directed biopsy, and
treatment of precancer (CIN) are other limitations in low
resourceful countries.4
Some recent developments over the last few years have
the potential to change the way we address the problem of
cervical cancer prevention. One such significant develop-
ment is the availability of two very effective vaccines
against human papilloma virus (HPV).
Senior Consultant, Department of Obstetrics and Gynaecology, Indraprastha Apollo Hospitals, Mathura Road, Sarita Vihar, New Delhi 110076, India.
*
Tel.: þ91 11 26925858, 26925801, email: rnj_sharma@yahoo.com
Received: 1.5.2012; Accepted: 2.5.2012; Available online: 9.5.2012
Copyright Ó 2012, Indraprastha Medical Corporation Ltd. All rights reserved.
doi:10.1016/j.apme.2012.05.005
Apollo Medicine 2012 June
Volume 9, Number 2; pp. 87e90
Original Article

3. HPV AND CANCER CERVIX
Nearly all cervical cancers (99.7%) are preceded by persis-
tent infection with one or more of the oncogenic types of
HPV.5
establishing that HPV infection is the cause of
cervical precancer and cancer. This association provides
a tremendous opportunity for cervical cancer prevention
through vaccination against oncogenic HPV viruses espe-
cially in medium and low resourceful countries.
THE HPV VIRUS
HPVs are double stranded, circular, non-enveloped DNA
viruses of Papovaviridae family. As it is non-enveloped,
it is more resistant to the environment and prescription
medication. Out of more than 100 known HPV genotypes
only a few are associated with carcinogenesis. Of these,
at least 13 may cause cervical cancer or are associated
with other anogenital and oropharyngeal cancers. HPV
types 16 and 18 cause about 70% of all cases of invasive
cervical cancer worldwide, with type 16 having the greatest
oncogenic potential.6
The distribution of HPV types varies
among geographical regions, but the dominant oncogenic
type in all regions is HPV-16.
THE HPV INFECTION
Human papilloma virus (HPV) is the most prevalent sexu-
ally transmitted infection in the world, occurring in up to
75% of sexually active women at some stage in their
life.7
However, few are aware of the infection. HPVs are
highly transmissible via close skin-to-skin contact, predom-
inantly, not exclusively through penetrative intercourse.
Most HPV infections are acquired in young age, are short
lived and are due to non-oncogenic strains. When an active
infection becomes dormant it is not possible to predict
whether or when the virus will become active again.
Currently there is no treatment for HPV infection, therefore
once infected, a person may remain infected for life. Persis-
tent genital infection with oncogenic strains can lead to the
development of anogenital precancers and cancers over
10e20 years. Occasionally, early lesions can become
malignant within a year or two.
The infections are restricted to the intraepithelial layer of
the mucosa and do not induce a vigorous immune response.
Only half of all infected women develop detectable serum
antibodies that do not necessarily provide protection against
subsequent infection by the same HPV type. The median
time from infection to seroconversion is approximately
8e12 months, although immunological response varies by
individual and HPV type.
HOW HPV INDUCES CANCER
All types of HPV have an affinity to epithelial cells of skin
and mucous membranes, and infect the keratinocytes in the
basal layers of a stratified squamous epithelium. The virus
replicates and assembles exclusively in the nucleus. In
humans, cell division is regulated largely by two proteins e
Rb and p53. These proteins are responsible for the cell’s death
if it becomes diseased or its DNA is damaged. Two genes in
HPV, E6 and E7, produce proteins that can attach themselves
to Rb and p53 and block their effect on regulating cell divi-
sion.8
When this happens, the infected cells reproduce
without any control and tumours are created from unregulated
proliferation. However, a large amount of evidence suggests
the existence of p53-independent functions of E6 that are also
necessary and important for transformation. While the virus
serves only as the initiating event, over time some of the
wildly growing cells develop permanent changes in their
genetic structure that cannot be repaired. Once this happens,
some may eventually turn into cancer cells.
THE HPV VACCINE
The facts that HPV infection with oncogenic strains is
necessary for the development of cervical cancer and that
more than 70 per cent of the cervical cancers are attributed
to types 16/18 led to the development of the HPV vaccines
directed to HPV-16/18. Both the vaccines have been found
to be very effective in preventing persistent infection with
HPV-16/18 and consequent high grade CIN attributed to
these two subtypes. This is likely to be translated into
high protection against cervical cancer in the vaccinated
population. One mathematical model suggested that
a vaccine with 98 per cent efficacy against 16 and 18 could
reduce cervical cancer incidence by 51 per cent, if all
adolescent girls were vaccinated before sexual debut.9
The two vaccines GardasilÒ
-quadrivalent (Merck), and
CervarixÔ-bivalent (GlaxoSmithKline) that got FDA
approval are against the two most prevalent oncogenic
strains of HPV in cancer cervix i.e.16 and 18 responsible
for about 70% of cancer cervix worldwide,9
leaving other
less common ones responsible for the remaining 30% of
cervical cancers. Vaccinating girls and women before their
sexual debut or those who are naïve to these two strains has
potential to reduce the disease burden by 70%.
Using recombinant technology the vaccines are prepared
from purified L1 structural proteins that form HPV type-
specific virus-like particles (VLPs). Neither vaccine
contains live biological products or viral DNA, so they
are non-infectious. HPV vaccines are designed for prophy-
lactic use only, they do not clear existing HPV infection or
88 Apollo Medicine 2012 June; Vol. 9, No. 2 Sharma

4. treat HPV-related disease. The mechanisms by which these
vaccines induce protection have not been fully understood
but seem to involve both cellular immunity and neutralizing
immunoglobulin G antibodies.
WHO SHOULD BE VACCINATED?
The HPV vaccine is most effective before a woman is
infected with an HPV, which is why the vaccine has been
recommended for girls as young as nine. It’s also approved
for women up to the age of 26, and tests are under way to
see if it’s effective for women above that age. Most coun-
tries that have licenced these vaccines, recommend their
use in girls aged 10e14 years. Some national programmes
also recommend routine or temporary catch-up vaccination
of older adolescent females and young women.
SCHEDULE
The quadrivalent vaccine is given at baseline and again after
2 months and 6 months. A minimum interval of 4 weeks
between the first and second dose, and a minimum interval
of 12 weeks between the second and third dose, are recom-
mended by the manufacturer if flexibility in the schedule is
necessary. The bivalent vaccine is given at baseline and again
after 1 month and 6 months. If flexibility in the schedule is
necessary, the manufacturer recommends that the second
dose be administered between 1 and 2.5 months after the first
dose. Currently, the manufacturers do not recommend
a booster dose following completion of the primary series.
POST VACCINATION IMMUNOGENICITY AND
CLINICAL EFFICACY
With both vaccines, practically all adolescent and young
women who were initially naive to vaccine related HPV
types developed an antibody response to these antigens after
3 doses. Serum antibody titres from adolescents aged 10e15
years were higher than titres in sera from older females
(aged 15e25 years). The protective effect of the vaccine
has been maintained throughout its observation period,
currently extending to 6.4 years for bivalent vaccine and 5
years for quadrivalent vaccine.6
The vaccine appears to
have partial efficacy against infections caused by HPV types
31 and 45, which are genetically related to types 16 and 18.6
SAFETY
In June 2007, WHO’s Global Advisory Committee on
Vaccine Safety10
concluded that both vaccines had good
safety profile. Mild and transient local reactions at the
site of injection (erythema, pain or swelling) may occur
in 10e20% but no systemic or serious adverse reactions
were assessed to be causally associated with the HPV
immunization. Selecting target ages for HPV vaccination
that usually precede the onset of sexual activity reduces
the likelihood of inadvertently vaccinating pregnant or
lactating females.
CONTRAINDICATIONS AND PRECAUTIONS
HPV vaccines should not be given to people who have
experienced severe allergic reactions after a previous vaccine
dose or to a component of the vaccine. Several countries
recommend that HPV vaccination should be delayed for indi-
viduals who have severe acute illness. Findings support an
increased occurrence of post vaccination syncope among
adolescent girls. Observation for 15 min after the injection
is administered, is recommended. HPV vaccines are not rec-
ommended for use in pregnant females. The quadrivalent
vaccine may be administered to lactating females because
available data do not indicate any safety concerns.
WHO POSITION ON HPV VACCINES
WHO recognizes the importance of cervical cancer and
other HPV-related diseases as global public health prob-
lems and recommends that routine HPV vaccination should
be included in national immunization programmes.
SUMMARY
HPV vaccination programmes for young adolescent
females (10e13 years) have a potential to substantially
reduce the incidence of cervical cancers if coverage is
high (>70%) and vaccine induced protection lasts for
10 years. Considerable reduction in incidence may also
be expected for the less frequent cancers of the vagina,
vulva, anus, and head and neck associated with HPV-16
and HPV-18. The reduction in the incidence of cervical
cancer and mortality is expected to be greatest in low and
middle-income countries where there is no or only limited
screening for cervical cancer. Since HPV vaccines are
prophylactic, the largest impact of vaccination is expected
to result from high coverage of young adolescent girls
before first intercourse rather than from vaccinating older
girls, because a smaller proportion of older girls would be
naive to vaccine related types before vaccination.
HPV vaccination is a primary prevention tool and does
not eliminate the need for screening later in life, since
HPV vaccine: A breakthrough in prevention of cervical cancer Original Article 89

5. HPV types other than 16 and 18 cause up to 30% of all
cases of cervical cancer.
Educating women on high risk behaviour for acquiring
HPV infection and spreading awareness about the diagnosis
and treatment of cervical precancer have a great role to play
in prevention of cancer cervix. Messages should emphasize
that HPV vaccines do not cure cancer; they prevent some,
but not all, HPV-related cancers; they are most effective
when given before the onset of sexual activity; they require
3 doses; they are not recommended for pregnant females;
and they will not prevent HIV infection or other sexually
transmitted infections.
Thus a prophylactic vaccine to prevent HPV-related pre-
cancerous lesions and cancers would save lives, reduce the
need for costly medical procedures and provide both
women and communities throughout the world, with
substantial benefits.
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90 Apollo Medicine 2012 June; Vol. 9, No. 2 Sharma

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