Abstract

The Human Papillomavirus (HPV) vaccines have been widely introduced in the national
immunization programs in most of the medium and high income countries following
endorsement from national and international advisory bodies. HPV vaccine is unique and its
introduction is challenging in many ways – it is the first vaccine developed to prevent any
cancer, the vaccine is gender specific, it targets adolescent females who are difficult to reach by
any health intervention programs. It is not unusual for such a vaccine to face scepticism and
reservations not only from lay public but also from professionals in spite of the clinical trial
results convincingly and consistently proving their efficacy and safety. Over the last few years
millions of doses of the HPV vaccine have been administered round the world and the efficacy
and safety data have started coming from the real life programs. A comprehensive cervical
cancer control program involving HPV vaccination of the adolescent girls and screening of the
adult women has been proved to be the most cost-effective approach to reduce the burden of
cervical cancer. The present article discusses the justification of HPV vaccination in the
backdrop of natural history of cervical cancer, the mechanism of action of the vaccines, efficacy
and safety data from phase III randomized controlled trials as well as from the national
immunization programs of various countries.

Keywords: Human Papillomavirus vaccine, efficacy, safety, Phase III randomized trials,
national immunization programs
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Introduction
The International Agency for Research on Cancer (Lyon, France) recognized Human
Papillomavirus (HPV) as the ‘necessary’ cause of cervical cancer and HPV types 16 and 18 as
carcinogenic agents for humans based on the strong and consistent associations between the
infections and the disease.[1] The recognition of the etiologic role of carcinogenic HPV types
paved the way for a novel primary prevention strategy against cervical cancer through vaccines
targeting the virus. India ranking number one globally in terms of cervical cancer burden has an
estimated 134,420 new cases of cervical cancer every year and 72,825 deaths from the
disease.[2] In spite of some reduction in incidence in recent years in the urban population,
possibly owing to raised average age at marriage, reduction in number of child births and high
number of hysterectomies, the fact remains that the disease is the leading cancer killer of Indian
women of reproductive age. A comprehensive approach to cervical cancer prevention and
control involving health education, vaccinating girls before initiation of sexual activity,
screening women for precancerous lesions and treatment before progression to invasive disease
can significantly reduce the morbidity and mortality from the disease.

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HPV in Natural History of Cervical Carcinogenesis
HPV is the most common sexually transmitted infection (STI). Women are at highest risk of
acquiring HPV when they initiate their sexual life. Peak prevalence of infection is observed
between 20 and 25 years and the prevalence comes down drastically after 30 years of age since
most of the infected women clear the infection due to natural immunity. More than 90 percent of
the immune-competent women have been found to clear the HPV 16 infection within 5 years
without any treatment.[3] Women who cannot clear the infection and have persistently infected
cervix are at the highest risk of developing cervical cancer.

The papillomavirus infects the basal keratinocytes through micro-abrasions present in the
cervical epithelium. If there is persistent infection, the viral genome gets integrated to the host
genome that over-expresses two onco-proteins, E6 and E7. The E6 proteins degrade p53 genes
resulting in genetic instability and accumulation of mutated deoxyribonucleic acid (DNA) that
trigger uncontrolled cellular multiplication.[4] The E7 protein degrades the active form of
retinoblastoma protein leading to the progression of the cell into the S-phase of the cell cycle
with subsequent unregulated cell replication.[5] Thus unregulated cellular proliferation in the
affected epithelium leads to development of cervical neoplasia.

Cervical cancer is preceded by HPV induced premalignant condition known as cervical

intraepithelial neoplasia (CIN), graded from CIN 1 to CIN 3 depending on the severity. While
majority of CIN 1 lesions are self-limiting, CIN 2 and CIN 3 are considered true pre-malignant
lesions. Given adequate follow up time, specially the CIN3 lesions, 30 percent to 50 percent of
them will progress to invasive cancers.[6] Cervical cancer screening detects the disease at the
CIN 2/3 stage when appropriate interventions prevent further progression to invasive cervical
cancer (ICC). The vaccines prevent even the development of CIN 2/3 by preventing persistent
infection of certain high risk HPVs, thus eliminating the chance of development of invasive
cancer in the future by those HPV types.

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Mechanism of Action of the HPV Vaccines
The HPV vaccines currently available are – the bivalent vaccine (Cervarix™, GlaxoSmithKline
Biologicals) and the quadrivalent vaccine (Gardasil™, Merck). These vaccines aim to prevent
infection from HPV types 16 and 18, since these two types are most carcinogenic and are
responsible for majority of cervical cancers. The risk of developing squamous cell carcinoma of
cervix is 435 times higher if someone is infected by HPV 16 and 248 times higher if someone is
infected by HPV 18, compared to a non-infected individuals.[7] The proportion of cervical
cancers attributed to HPV 16/18 ranges from 66.8 percent in sub-saharan Africa to 84.3 percent
in Europe and America.[8] In an Indian study encompassing four different zones, type 16 alone
was detected in 57.5 percent of cervical cancers, type 18 alone in 10.4 percent, and both types
were detected in additional 7.3 percent.[9] The fact that nearly 70 percent of all cervical cancers
in India are attributed to HPV 16/18 signifies that, if the vaccines are 100 percent effective in
preventing HPV 16/18 infections and if administered prior to exposure to HPV infections, the
maximum quantum of protection that can be expected is around 70 percent. The vaccinated girls
are still at risk of developing cervical cancer from the HPV types other than types 16/18, though
such risk is much lower.

The antigens for both the vaccines are virus like particles (VLP) derived from the L1 surface
protein of the respective types of the virus. The VLPs are non-pathogenic and cannot infect cells,
since they do not have viral genome. The vaccines induce high titer of serum immunoglobulin G
antibody against respective HPV types, which is secreted in the cervico-vaginal secretion and is
also exuded from the micro-abrasions in the epithelium. Presence of the antibodies at the point of
viral entry ensures the neutralization of the virus before it gets an opportunity to bind to infect
the basal keratinocytes.[10]

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Efficacy of the HPV Vaccines in Phase III trials
Both bivalent and the quadrivalent vaccines have been rigorously evaluated through phase III
randomized placebo controlled trials (RCT). The primary efficacy end point for these studies was
prevention of CIN 2 or worse disease. An advisory committee of the World Health Organization
(WHO) (in which the pharmaceutical agencies had no role to play) agreed upon such endpoint as
surrogate for cervical cancer, since it is not ethically acceptable to allow any subject of a study to
be followed up until she develops ICC.[11] The secondary efficacy end point was prevention of
type-specific persistent infection, which is an obligate precursor of cervical neoplasia.

Till date two phase III RCTs have evaluated the bivalent vaccine and three phase III RCTs have
evaluated the quadrivalent vaccine.[12] In the phase III trials there were subjects without any
evidence of HPV infection or cytological abnormality and also subjects with active or past HPV
infection and even cytological abnormalities. To compensate for the expected difference in
outcomes in these two major subgroups, the trials analyzed the vaccine efficacy in two different
efficacy cohorts - per-protocol population and the intention-to-treat population. The per-protocol
population included those who neither had positive serology (indicative of past infection) nor
DNA in cervix (indicates active infection) for the target HPV types and received three doses of
the vaccines within one year. This population in real life represents young sexually naïve
subjects receiving full doses of the vaccines. The Intention to treat analysis included subjects
who might or might not have evidence of past or active HPV infection and received at least one
dose of the vaccine. Some of them even had abnormal cytology at the time of entry in the
studies. This cohort represents a mixed population of sexually naïve and sexually active girls or
women who may or may not receive complete dose of the vaccines. The efficacies of the
vaccines observed in the RCTs should be judged in the light of these two efficacy cohorts
reflecting two different real life scenarios. The summary of the efficacies of the vaccines for
various endpoints from the phase III trials is given in Table 1.

Table 1

Vaccine efficacy against various end-points in per-protocol and intention to treat cohorts from
phase III RCTs-Risk ratio of zero indicates 100percent efficacy, whereas one indicates no
difference with controls[12]
As per the WHO guidelines the primary target for the HPV vaccine for the national
immunization programs should be girls aged between 9 years and 13 years.[13] The efficacy of
the vaccines will be similar to the per-protocol analysis population rather than the intention-to-
treat population in this sexually naïve population if they receive three doses of the vaccine. There
is an exciting possibility that even two doses of the vaccine may be as protective as three doses,
going by the initial results of the Costa Rican phase III trial.[14]

Concerns have been expressed about the possible increase in the risk of cervical neoplasias in the
women with HPV infection (past or present) from quadrivalent vaccination.[15] As discussed
earlier, in the phase III quadrivalent vaccine trials at the study entry nearly 1 percent women in
vaccine and placebo group had high grade squamous intra-epithelial lesions (HSIL) or atypical
squamous cells – cannot exclude high grade squamous intra-epithelial lesions (ASC-H) on
cytology and more than 5 percent had low grade squamous intra-epithelial lesions (LSIL) on
cytology. They were included in the intention-to-treat analysis and obviously some of them in
either group went on to develop CIN 2 or CIN 3 lesions. The vaccinated group did have higher
incidence of CIN 2/3 (though the difference was not significant as evident by wide confidence
intervals) compared with the placebo group. The baseline demographic analysis showed that the
vaccinated group had higher prevalence of other risk factors like current smokers, other STIs and
most importantly HSIL cytology at baseline (6.5 percent vs 3.7 percent). This imbalance in
baseline demographic characteristics and the small number of events was responsible for the
observed discrepancy in the sub-group analysis. In subsequent studies of quadrivalent vaccines
and all studies with bivalent vaccines where the subgroups were more balanced in terms of the
other risk factors, no such increase in risk of neoplasias was observed. All these information was
presented to Food and Drug Administration (FDA) prior to obtaining the license and are still
available in the public domain.[16]

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Efficacy of HPV Vaccine in National Immunization
Programs
WHO recommended in 2007 that HPV vaccination of 9-13 year old girls should be considered as
part of comprehensive cervical cancer control through effective, affordable and equitable
delivery strategies.[17] Until February 2013 the vaccine is part of the National Immunization
Programs of 55 countries that include almost all countries in North America and Europe,
Australia, New Zealand, Argentina, Chile, Mexico and Peru in Latin America, Singapore,
Bhutan, Japan and Malaysia in Asia.[18] Actual population impact of HPV vaccination on the
incidence of HPV-related diseases is currently available from many of these country programs.

Australia was the first country in the world to provide free quadrivalent HPV vaccines
(protecting against genital warts as well as cervical cancer) to 12 to 18 year old girls starting
from mid-2007. The earliest effect of the HPV vaccination is evident from the protection from
genital warts since the natural history of the warts is much shorter compared to cervical
neoplasias. The very first report of reduction of incidence of genital wart in the vaccinated
population was from the sexual health clinics in Melbourne, Australia.[19] In the vaccinated
cohort of women below 21 years there was drastic reduction in the incidence of genital warts
compared to the older non-vaccinated cohort. Data from the Victoria Cervical Cytology Registry,
Australia showed that within 3 years after the introduction of the vaccination program, the
incidence of high grade abnormalities in young women became nearly half of that reported
before the introduction of the vaccine.[20] The first effectiveness study of the quadrivalent
vaccine from an entire country was reported from Sweden in 2013.[21] The efficacy against
genital warts in the subjects vaccinated before the age of 14 years (93 percent) in Sweden was in
fact higher than the efficacy among HPV-naive subjects reported in the quadrivalent HPV
vaccine clinical trials (83 percent).

The most robust evidence of the effectiveness of the vaccine in cervical cancer prevention was
obtained from Finland.[22] The participants of the FUTURE II and FUTURE III studies (to
evaluate the quadrivalent vaccines) from Finland were followed up after completion of the trials
in 2007 through the well-organized Finnish cancer Registry over the next five years. The study
participants were unblinded, and the placebo recipients were offered the quadrivalent vaccine.
Nearly half of the placebo recipients were vaccinated at this stage. An age-matched reference
unvaccinated cohort was linked with the cancer registry as the control group to identify all cases
of CIN3 and ICC during the follow up. During the follow up no CIN3 or cervical cancer was
detected in the vaccinated cohort, three CIN3 cases but no cancers were detected in the original
placebo cohort (nearly 50 percent were vaccinated). In the unvaccinated reference cohort 59
CIN3 and three cervical cancers were detected. CIN3+ incidence rates of 0/100,000 person years
in the original vaccinated cohort was in stark contrast to the incidence rate of 93.8/100,000
person years in the unvaccinated reference cohorts, thus proving the long term (nearly 10 years)
protection offered by the HPV vaccine against the most valid end point of CIN3 and invasive
cancers.

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Safety Data from Phase III trials
All RCTs reported serious and non-serious adverse events (AE) in similar fashions following
standard good clinical practice guidelines from more than 20,000 trial participants. Pain at the
injection site, headache and fatigue were the most frequently reported vaccine related AEs. The
serious adverse events (SAE) were reported in similar frequency in both the vaccine and control
arms (pooled relative Risk for participants having SAE = 1.00; 95 percent CI 0.91-1.09)
suggesting no additional risk of SAE due to HPV vaccination.[12] SAEs that were considered to
be vaccine related were rare.

For any new vaccine there are concerns about vaccine-induced medical conditions, especially
systemic autoimmune disorders and neurological disorders. The long term follow up of the
subjects participating in the RCTs did not have higher incidence of these conditions compared
with the control group.[23] The Center for Disease Control (CDC), Atlanta, USA observed that
the reported number of cases of Guillain-Barré syndrome was within the range expected by
chance alone in the population.[24] Of the few reported deaths in the studies, causes of death
were consistent with causes expected in the general adolescent and adult populations, and were
not judged to be vaccine-related, not only by the investigators but also by the Global Advisory
Committee on Vaccine Safety (GACVS) of WHO.[25]

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Safety Data from National Immunization Programs
In Australia millions of doses of the vaccine have been administered and the most serious
adverse event reported is anaphylactic and allergic reactions. The current estimated rate of
anaphylaxis based on doses given in Australia is 1.7 cases per million doses.[26] This rate is
comparable to the rates for anaphylaxis for other vaccines given to children and adolescents,
which range from 0 to 3.5 per million doses.[25]

As of September, 2011, approximately 40 million doses of Quadrivalent vaccine were distributed

in the USA and Vaccine Adverse Event Reporting System (VAERS) in the country received a
total of 20,096 reports of adverse events of which 8 percent were considered serious.[27]
Thorough analysis of the all these reports by regulatory bodies like FDA and CDC did not
observe any major or unexpected adverse events that could be ascribed to the vaccine nor did
they find any consistent pattern of such events to suggest a causal association. These included the
reported cases of Guillain-Barré syndrome, thrombo-embolism, and deaths.

In the United Kingdom, the Commission on Human Medicines (CHM) and the Medicines and
Healthcare Products Regulatory Agency (MHRA) reviewed the safety of Bivalent vaccine two
years after its introduction in the national program. They concluded that no serious new risks
have been identified during its extensive use over 2 years.[28]

A typical instance of the high alertness of the regulatory bodies was evident recently, when CDC
and FDA convened a Clinical Immunization Safety Assessment (CISA) working group to
investigate the deaths owing to suspected cerebral vasculitis following vaccination in USA
reported in 2012.[29] After a thorough review and discussion of the article published in a not so
highly rated journal, the working group identified substantial methodological concerns and lack
of evidence to support the authors’ conclusions that the patients had vasculitis due to
vaccination, or that HPV vaccine was causally associated with deaths from cerebral
vasculitis.[30] We need to understand that deaths due to various causes including accidents do
occur even in apparently healthy young females. To ascribe the deaths to any intervention (HPV
vaccination in this case) certain conditions need to be fulfilled – proportion of deaths should be
higher in the intervention group than that observed in non-intervention group, there should be a
consistent pattern and a biologically plausible explanation after ruling out other more apparent
causes. Following these criteria none of the deaths initially suspected due to vaccination (deaths
due to accidents, snakebites or suicides in India, due to the rupture of an intra-thoracic tumor in
UK etc.) could be linked to the vaccines.

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Cost Effectiveness of HPV Vaccines
The cost-effectiveness study of all possible options for cervical cancer prevention showed that
the most effective strategy with the lowest incremental cost-effectiveness ratio per quality
adjusted life year is one combining HPV vaccination at age 12 years with triennial conventional
cytologic screening beginning at age 25 years.[31] Cost-effectiveness should be looked at in the
context of the negotiated price of the vaccine specific for the country, subsidies obtained from
international agencies, financial cost of the delivery strategy vis-à-vis the treatment cost of
advanced cancer, social and financial loss owing to losing mothers and wives at their prime and
cost of disabilities resulting from advanced cancer. The prices at which the vaccines are sold in
the private market are being drastically reduced for national programs. Hard bargaining with the
manufactures can possibly reduce the cost of per dose for a huge market as in India to less the
1$, a price that is considered affordable for immunization program in the country. India can seek
support from Global Alliance for Vaccines and Immunization (GAVI Alliance) since the
Alliance has already committed to donate the vaccines to eligible countries. Other important
vaccines, e.g., hepatitis B vaccine, have been introduced in National Immunization Program in
India with donations from GAVI and subsequently could be sustained due to the drastic price
reduction through indigenous productions.

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Conclusions
WHO, United Nations Populations Fund (UNFPA), International Union Against Cancer (UICC),
International Federation of Gynecologists and Obstetricians (FIGO) and other organizations that
influence public health policies globally have unanimously endorsed HPV vaccines as an
effective cancer prevention option. The Strategic Advisory Group of Experts (SAGE) on
immunization, which reports to the Director-General of WHO on issues ranging from vaccine
research and development to immunization delivery, surmised that the introduction of vaccines is
likely to bring great benefits worldwide, particularly to those developing countries where
cervical cancer is a major cause of death, and screening programs are limited or absent.[32] It is
time that the health policy makers in the countries with high cervical cancer burden like India,
make an informed decision and seriously consider the introduction of both HPV vaccination and
organized screening as part of comprehensive cervical cancer control program.

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Footnotes
Source of Support: Nil.

Conflict of Interest: Declaration of Dr. Partha Basu has been a member of the advisory boards
of both GlaxoSmithKline and Merck. He has been principal investigators for two HPV vaccine
trials sponsored by GlaxoSmithKline.

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