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Review Article
Indian J Med Res 144, August 2016, pp 169-180
DOI: 10.4103/0971-5916.195023

Current global status & impact of human papillomavirus vaccination:

Implications for India
Rengaswamy Sankaranarayanan1, Neerja Bhatla2 & Partha Basu1

Screening Group, Early Detection and Prevention Section, International Agency for Research
on Cancer (IARC-WHO), Lyon, France & 2Department of Obstetrics and Gynaecology,
All India Institute of Medical Sciences, New Delhi, India
1

Received May 17, 2016

This review addresses the effectiveness and safety of human papillomavirus (HPV) vaccines, the
current status of its introduction in the National Immunization Programmes (NIPs) and its relevance to
India, which contributes a fifth of the global burden of cervical cancer. The vast literature on efficacy,
acceptability and safety of HPV vaccination and its impact after population level introduction was
reviewed and discussed. The efficacy of HPV vaccines in preventing high-grade precancerous lesions
caused by vaccine-targeted HPV infections was 90 per cent or higher in HPV nave women in randomized
clinical trials. Two doses at 6 or 12 months apart are recommended for 9-14 yr old girls and three doses
over six months to one year period for those aged above 15 yr. More than 80 countries or territories have
introduced HPV vaccination in their NIPs, of which 33 are low- and middle-income countries (LMICs);
in addition, 25 LMICs have introduced pilot programmes before a phased national expansion. Significant
reductions in the frequency of HPV 16 and 18 infections, genital warts and cervical premalignant lesions
in vaccinated cohorts and herd immunity in general populations have been reported from countries
that introduced vaccination in NIPs as early as 2007. More than 280 million doses of HPV vaccines have
been administered worldwide with the excellent safety profile with no serious adverse events linked
to it. The high burden of cervical cancer and the high efficacy and safety of HPV vaccination justify
its introduction in the Indian NIP at the earliest possibility to substantially reduce the cervical cancer
burden in future.
Key words Cervix cancer - control - efficacy - human papillomavirus vaccination - India - national programmes - prevention - safety

Human papillomavirus-related cervical cancer

burden

effective population-based cervical cancer screening

programmes. In most Asian countries including India,
cervical cancer is the second most common cancer in
women1. Cervical cancer accounts for 528,000 cases in
the world (445,000 cases in LMICs); it causes 265,700
estimated deaths annually globally, with 230,200

Cervical cancer is the fourth leading cancer in

women globally, but its major burden is felt in the
low- and middle-income countries (LMICs) with
very limited resources to introduce and sustain
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INDIAN J MED RES, AUGUST 2016

(86.6%) deaths in the LMICs2. The age-standardized

incidence rate of cervical cancer varies between 5.6
and 24.3 per 100,000 women in different regions of
India3. India accounts for an estimated 122,800 new
cases and 67,500 deaths annually due to cervical
cancer2. Although a declining trend in the cervical
cancer incidence, with annual percentage change
ranging between -1.1 and -3.4, has been observed in
different regions of India over the last two decades, the
rates remain significantly higher than in other countries
in Asia and the absolute numbers of cervical cancer
cases and deaths are on the increase due to population
growth and advanced clinical stages at presentation3,4.
The knowledge that persistent infection with
one of the oncogenic, high-risk types of human
papillomaviruses (HPVs) is the necessary cause
of cervical cancer, implying that the infection is
obligatory to initiate the carcinogenic process, has
opened up an exciting and effective means of primary
prevention using vaccination5,6. HPV is the most
common infection of the genital tract epithelium,
with the highest risk of acquiring the infection after
sexual debut. Most of the infections are cleared over
six months to two years. In a small proportion (5-10%)
of infected women, the infections persist for reasons
not yet well understood, and they are at high-risk of
developing cervical precancerous lesions and cancer.
More than 200 types of HPV have been identified
and are classified into low- and high-risk types based
on their potential to cause malignancy. The high-risk
(carcinogenic) types include HPV 16, 18, 31, 33, 35,
39, 45, 51, 52, 56, 58 and 59. Types 66, 68 and 73 are
considered as probably carcinogenic. Among these
types, HPV types 16 and 18 are the most carcinogenic
and are responsible for approximately 70 per cent of
the cervical malignancies; HPV types 31, 33, 35, 45,
52 and 58 account for an additional 20 per cent of the
cervical cancers worldwide7-9. In India, 80 per cent of
cervical cancers and 63 per cent of high-grade cervical
precancerous lesions are attributed to HPV types 16
and 18; an effective vaccine targeting these two types
with high coverage of the population will have a huge
impact in the country10-12. High-risk HPV infection is
responsible for 43 per cent of the vulvar cancers and
70 per cent of vaginal cancers in women, 50 per cent of
penile cancers in men and 30 per cent of oropharyngeal
cancers and 88 per cent of anal cancers in both sexes13.
The low-risk HPV types 6 and 11 are responsible for
more than 90 per cent of genital warts14, a distressing
condition in young men and women.

Human papillomavirus vaccines Principles and

mechanism of action
Globally, three types of HPV vaccines are
currently available bivalent vaccine (CervarixTM;
GSK Biologicals, Belgium) targeting HPV types 16
and 18; quadrivalent vaccine (GardasilTM, Merck,
USA) targeting HPV 16, 18, 6 and 11; and 9-valent
vaccine (Gardasil 9TM; Merck, USA) targeting HPV
31, 33, 45, 52 and 58 in addition to HPV 16, 18, 6
and 11. The first two are available in India. The L1
surface proteins of the targeted HPV types are used
as the antigen. The L1 protein undergoes conformal
changes to self-assemble into virus-like particles
(VLPs) in artificial production systems. The VLPs are
non-infective and non-pathogenic as these are devoid
of the viral DNA essential to initiate the carcinogenic
process. Adjuvants used to ensure robust and longlasting immunogenicity include aluminium phosphate
and monophosphoryl lipid A combination (ASO4)
in the bivalent vaccine and aluminium hydroxylphosphate sulphate in the quadrivalent and the 9-valent
vaccine. Two intramuscular doses at six months interval
are recommended for girls below 15 yr of age. For
those 15 yr and above and for immune-compromised
girls/women, three doses over a 6-month period are
recommended15.
The HPV vaccines are highly immunogenic
leading to seroconversion in more than 99 per cent
of the vaccinated girls and women16-19. Following
vaccination, L1 proteins are recognized by the immune
system in the regional lymph nodes to generate strong
antibody response (IgG), and its concentration is 1-4
logs higher than the antibody levels induced by the
natural HPV infections. The IgG is exuded at the
possible sites of infection (mucosa of genital tract, oral
cavity, etc.), neutralizes the virus and prevents its entry
into the cells. The vaccine-induced immune memory
in the form of circulating plasma cells and memory
B-cells allows generation and exudation of protecting
IgG each time the body is challenged by exposure to
HPV infection.
Efficacy of vaccines in randomized clinical
trials (RCTs)
The HPV vaccines have been evaluated in
randomized, double-blind, placebo-controlled RCTs
to assess their efficacy to protect against persistent
vaccine-targeted HPV infections and high-grade
cervical intraepithelial neoplasia [cervical intraepithelial
neoplasia grade 2 (CIN2), CIN3 and adenocarcinoma

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SANKARANARAYANAN et al: IMPLICATIONS OF HPV VACCINE FOR INDIA

in situ (AIS)] in young adult women. An advisory

committee of the World Health Organization (WHO)
recommended in 2003 that the prevention of high-grade
precancerous lesions would be adequate evidence of
the efficacy of the vaccines to protect against invasive
cervical cancers20. The pre-licensure Phase III RCT for
the bivalent vaccine was the PApilloma TRIal against
Cancer In young Adults (PATRICIA) trial21-23 and the
Costa Rica HPV Vaccine Trial was the first publically
funded RCT24,25. The pre-licensure Phase III RCTs
to evaluate the quadrivalent vaccine were Females
United to Unilaterally Reduce Endo/Ectocervical
Disease (FUTURE) I and FUTURE II trials26,27. The
characteristics of the participants of the Phase III trials
and the vaccine efficacies observed are described in
Table I. The bivalent vaccine was administered on
days 1, 30 and 180 while the quadrivalent vaccine was
administered on days 1, 60 and 180. Both vaccines were

171

highly efficacious in preventing CIN2, CIN3 or AIS

caused by the vaccine-targeted HPV types in young
women who were not infected with the respective
HPV types either in the past (seronegative to the HPV
types) or at the time of enrollment (cervical sample
negative for HPV DNA) and received all three doses
of the vaccine (according to protocol: ATP cohort).
The intention to treat (ITT) cohort included all the
randomized women receiving at least a single dose
irrespective of the HPV infection status. The efficacy
of both vaccines in preventing high-grade CIN caused
by vaccine-targeted HPV infections was 90 per cent
or higher in the ATP cohorts (Table I). The efficacy
of both vaccines was demonstrated in the ITT cohort
also though considerably less than that observed in the
ATP cohort. This signifies that the vaccines will have
maximum benefit in the young sexually nave girls who
resemble the population in the ATP cohort. In addition,

Table I. Characteristics of the participants and the key vaccine efficacy results from the randomized clinical trials
Characteristics

RCTs for bivalent vaccine (PATRICIA &

CVT)

RCTs quadrivalent vaccine

(FUTURE I & FUTURE II)

Eligible age (yr)

15-25 (PATRICIA)
18-25 (CVT)

16-24 (FUTURE I)
15-26 (FUTURE II)

Number of participants

18,644 (PATRICIA)
7466 (CVT)

5455 (FUTURE I)
12,167 (FUTURE II)

Median follow up (months)

48

42

Characteristics of the ATP analysis cohort

Received 3 doses as per protocol

Vaccine efficacy in ATP cohort against CIN2/3

or AIS (CIN2+) related to HPV 16 and/or 18

PATRICIA: 94.9 (95% CI: 87.7-98.4)

CVT: 88.7% (95% CI: 31.3-99.5)

98.2% (95% CI: 93.3-99.8)

Vaccine efficacy in ATP cohort against CIN2+

related to non-vaccine oncogenic types

PATRICIA: 46.8% (95% CI: 30.7-59.4)

CVT: 78.7% (95% CI: 47.1-92.8)

32.5% (95% CI: 6.0-51.9)

Characteristics of the ITT cohort

All randomized women receiving at least

one dose; case counting from 1 day after
dose 1

All randomized women receiving at

least one dose; case counting from 1
day after dose 1

Vaccine efficacy in ITT cohort against CIN2+

related to HPV 16 and/or 18

PATRICIA: Against CIN2+ 60.7% (95%

CI: 49.6-69.5)
CVT: 89.8% (95% CI: 39.5-99.5)

CIN2: 54.8 (95% CI: 40.8-65.7)

CIN 3: 45.1 (95% CI: 29.8-57.3)

Received all 3 vaccine doses within

1 year
Seronegative to HPV 16/18 at baseline (for Seronegative and DNA negative for
PATRICIA only)
relevant HPV types at enrollment
DNA-negative to HPV16/18 at baseline and Remained HPV-negative at 1 month
through dose 3
after dose 3
Normal or low-grade cervical cytology at
baseline
Case counting started 1 month after dose 3
Case counting started 1 month after
dose 3

CIN2, cervical intraepithelial neoplasia Grade 2; CIN 3, cervical intraepithelial neoplasia Grade 3; AIS, adenocarcinoma in situ, CVT:
Costa Rica Vaccine Trial; ITT, intention to treat; ATP, according to protocol; CI, confidence interval; RCTs, randomized clinical trials;
PATRICIA, PApilloma TRIal against Cancer In young Adults; FUTURE, Females United to Unilaterally Reduce Endo/Ectocervical
Disease; HPV, human papillomavirus
Source: Ref 20-26

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INDIAN J MED RES, AUGUST 2016

the quadrivalent vaccine was highly protective against

genital warts caused by types 6 and 11 with vaccine
efficacy of 98.9 per cent [95% confidence interval (CI)
96.1-99.9] in the ATP cohort and 79.3 per cent (95% CI
72.7-84.5) in the ITT cohort26.
Since pre-adolescents were not included in the
efficacy trials, immunobridging studies were used to
extend the use of currently licensed vaccines to preadolescents. The protective roles of the vaccines in
9-14 yr old girls were confirmed through these studies
as efficacy studies are not feasible and are unethical
in this age group. In such studies the same vaccine
dosage schedule was used as in the efficacy trials
and induction of non-inferior serum antibody titres
was used as the outcome measure. Both vaccines
demonstrated high immunogenicity in girls aged 9-14
yr, and the post-vaccination antibody titres in the
young girls were 1.7-2.0-fold higher than that in the
15-26 yr old women in whom the protective efficacy
of the vaccine against infection and disease were
already established28.
The immunogenicity of both vaccines remains
unaltered when administered concomitantly with
diphtheria, tetanus, and acellular pertussis (Tdap)
vaccine, meningococcal conjugate vaccine, hepatitis A
vaccine, hepatitis B vaccine and combined hepatitis A
and B vaccine and inactivated poliovirus vaccine; there
was no increase in the frequency of adverse events29.
Neither of the HPV vaccines had any impact on the
clearance or progression of infection in women who
were infected with HPV 16 or 18 (HPV DNA positive)
at enrollment, implying the absence of any therapeutic
effect of the vaccines on existing HPV infections21-26,30.
Studies have evaluated the efficacy of less than
three doses of the vaccine, efficacy of a new vaccine
similar to a licensed vaccine or efficacy of a novel
vaccine developed from the L2 viral capsid protein to
induce neutralizing antibodies. A polyvalent vaccine
has been developed by including VLPs for additional
HPV types (9-valent vaccine by Merck) and has
been evaluated. Recently, a Working Group at the
International Agency for Research on Cancer (IARC)
and United States National Cancer Institute (NCI)
recommended that a virological end-point such as
persistent HPV infection of six months or longer, rather
than a disease end-point such as CIN2 or worse lesions,
might be used as the primary end-point for future
clinical efficacy trials31. The reduction in disease can be
verified by post-licensure monitoring31. The Working

Group recommended HPV 16/18-positive high-grade

vulvar intraepithelial neoplasia/vaginal intraepithelial
neoplasia as a disease end-point for vulvar/vaginal
protection, and a persistent HPV 16/18 infection endpoint for evaluating oral/oropharyngeal infection. The
Working Group recommended immunobridging studies
with immunological non-inferiority as the sufficient
end-point for extending licensure to other population
groups (e.g., those aged <16 yr), once a vaccine is
shown to be effective in other population group (e.g.,
individuals aged 16-26 yr), with reduction in disease
being verified by post-licensure monitoring31.
In a randomized, double-blind, Phase IIb-III study
of the 9-valent HPV vaccine in 14,215 women aged
16-26 yr, the 9-valent vaccine generated a non-inferior
antibody response to HPV-6, 11, 16 and 18 to that
by the quadrivalent HPV vaccine. In the ATP cohort
(receiving all three doses, nave to relevant HPV types
at enrollment and DNA negative for the relevant types
till 1 month post-dose 3), the efficacy of the 9-valent
vaccine in preventing the HPV 31-, 33-, 45-, 52- and
58-related CIN2 or worse disease was 96.3 per cent32.
The 9-valent vaccine was not effective in preventing
infection and disease related to non-vaccine targeted
HPV types.
Efficacy of less than three doses of HPV vaccination
Less than three doses of HPV vaccine, if found
effective, could substantially reduce costs, improve
compliance, ease logistics and facilitate scale up in the
national immunization programmes (NIPs). The high
immunogenicity of HPV vaccines in adolescent girls
prompted randomized trials comparing two doses of
the vaccine (administered at 6 months interval) in girls
below 15 yr of age to three doses in young women 15
yr or above33,34. These trials and a few non-randomized
studies19,35-38 confirmed that two doses of both bivalent
and quadrivalent HPV vaccines, administered at an
interval of six months or more between doses, are
immunologically non-inferior to three doses. Nonrandomized comparisons of less than three doses of
bivalent HPV vaccine in the Costa Rica Vaccine and
PATRICIA trials37,38 and of quadrivalent HPV vaccine
in an Indian study19 indicated that one or two doses by
default were as protective as three doses in preventing
persistent HPV 16 or HPV 18 infections, although one
dose was less immunogenic than three doses. However,
one dose generated detectable titres of neutralizing
antibodies and one-dose antibodies were as avid as
three-dose antibodies19,37,38. The above observations
and the fact that there is no known minimum threshold

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SANKARANARAYANAN et al: IMPLICATIONS OF HPV VACCINE FOR INDIA

concentration of antibodies that is protective prompted

the investigators to recommend that one-dose merits
further assessment19,37,38.
The WHO after reviewing the available evidence
on less than three-doses recommended a two-dose
schedule for girls (at an interval of 6 months, which
may be extended to 12 months to facilitate vaccination)
if vaccination is initiated prior to 15 yr of age and
a three-dose schedule (at 0, 1-2 and 6 months) if
vaccination is initiated after 15th birthday and for
immunocompromised individuals, including those
infected with HIV15.
Countries implementing HPV vaccination as part
of the national immunization programmes
The HPV vaccines have been licensed almost in
all the countries across the globe, with the notable
exception being Peoples Republic of China. More than
80 countries have introduced HPV vaccine in the NIPs,
of which 33 are LMICs; in addition, 25 LMICs have
introduced HPV vaccination in pilot demonstration
programmes as a prelude to national scaling up in
NIPs (Table II)39,40. Many Pacific Island nations have
implemented HPV vaccination41. In most programmes,
a school-based approach is predominantly used to
deliver the vaccine to the targeted adolescents with
additional efforts using field clinics, and primary health
centres to cover girls who missed vaccination and do
not attend schools. Almost all pilot demonstration
programmes are supported by Gavi - The Vaccine
Alliance and use a two-dose schedule39. With efforts by
Gavi the procurement price of both vaccines is reduced
to around US$5, the prospects of introducing HPV
vaccination in the low-income Gavi-eligible countries
has substantially improved.

While Australia, Denmark, USA and Canada

were the first high-income countries to introduce HPV
vaccination in NIPs in 2007, Panama (2008) in Latin
America, Bhutan (2009) in Asia and Rwanda (2010)
in Africa were the first LMICs that introduced HPV
vaccination42-44. Currently, eight of 10 girls aged 9-13
yr in the Latin American region have access to HPV
vaccination through NIP thanks to the foresight, wisdom
and commitment on the part of the national governments
and the pooled, bulk, negotiated purchase of the vaccines
on behalf of these countries by the revolving fund of
the Pan American Health Organization. The largest
HPV vaccination programme in any LMIC is in Brazil
that targets five million 11-12 yr old girls annually with
two doses; Uganda targets 850,000 (11 yr old) girls and
Malaysia targets 250,000 (12 yr old) girls annually with
two doses45,46. Most LMICs including Brazil, Mexico,
Malaysia and South Africa currently use a two dose
schedule. HPV vaccination coverage in most LMIC
programmes and demonstration projects exceed 80
per cent, and thus participation in LMIC programmes
is much higher than in most high-income countries.
The governments in countries that have implemented
programmes are closely monitoring the implementation
and safety profile of the vaccine; for instance, Malaysia,
since 2010 has administered more than four million
doses of HPV vaccines with the excellent safety profile
and the Malaysian Government have defended the
safety of HPV vaccines from its own experience47.
Effectiveness of HPV vaccine in the national
immunization programmes
The early protection offered by the vaccine at
the population level against vaccine-targeted HPV
infections, genital warts and cervical premalignant

Table II. Low- and middle-income countries with ongoing human papillomavirus vaccination programmes in public health services
Type of programme

Low-income countries (n=18)

Middle-income countries (n=42)

National programmes
covering the entire
country/territory

Rwanda, Uganda

Bhutan, Malaysia, Uzbekistan, Cook Islands, Federated States of

Micronesia, New Caledonia, Fiji, Kiribati, Marshall Islands, Palau,
French territories of New Caledonia and Wallis and Futuna, US
territories of Guam and Northern Mariana Islands, Botswana, Lesotho,
South Africa, Mexico, Trinidad and Tobago, San Salvador, Honduras,
Nicaragua, Panama, Brazil, Suriname, Guyana, French Guyana,
Uruguay, Argentina, Chile, Paraguay, Peru, Colombia, Ecuador, Cuba

Pilot demonstration
programmes

Nepal, Bangladesh, Benin, The

Gambia, Liberia, Madagascar,
Malawi, Mali, Mozambique,
Niger, Senegal, Sierra Leone,
Tanzania, Togo, Zimbabwe, Haiti

Laos, Mongolia, Solomon Islands, Cameroon, Ivory Coast, Ghana,

Kenya, Senegal, Moldova

Source: Ref 39,40

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INDIAN J MED RES, AUGUST 2016

lesions has been reported from countries that introduced

the vaccine between 2007 and 201048-55. In Denmark, the
atypia or worse and CIN2 or worse lesions increased in
all age groups during 2000-2010, the incidence of such
lesions decreased significantly in women younger than
18 yr [estimated annual percentage change (EAPC)
- 33.4%; 95% CI -49.6; -12.0] and in 18-20 yr old
women (EAPC - 12.6%; 95% CI -19.3; -5.3), after the
introduction of HPV vaccination programme; however,
no significant decrease was seen in older age groups50.
In a pooled analysis of 20 eligible studies involving
140 million person years of follow up after vaccination,
HPV 16 and 18 infections decreased significantly
between the pre- and post-vaccination periods in
high-income countries with 50 per cent or more HPV
vaccination coverage by 68 per cent [relative risk (RR)
0.32, 95% CI 0.19-0.52]; anogenital warts decreased
significantly by 61 per cent (RR 0.39, 0.22-0.71) in
girls 13-19 yr of age; significant reductions in warts
were observed in boys younger than 20 yr of age (RR
0.66, 95% CI 0.47-0.91) and in women 20-39 yr of age
(RR 0.68, 95% CI 0.51-0.89), suggesting significant
herd immunity offered by vaccination53. Significant
reductions were also recorded in HPV types 31, 33 and
45 in girls (RR 0.72, 95% CI 0.54-0.96), suggesting
some level of cross-protection. In countries where
female vaccination coverage was lower than 50 per
cent, significant reductions in HPV types 16 and 18
infection (RR 0.50, 95% CI 0.34-0.74) and in warts
(RR 0.86, 95% CI 0.79-0.94) occurred in girls <20
yr of age. Sentinel surveillance to monitor the impact
of HPV vaccination in the US indicated a 72 per cent
decline in CIN2 or worse lesions in women who had
vaccination four or more years before the screening
test that led to the diagnosis of CIN2+ disease54.
An ecological analysis in British Columbia, Canada,
indicated 86 per cent (95% CI 53-96) reduction in CIN2
or worse lesions in young women aged 15-17 yr after
the introduction of the HPV vaccination; however, no
reduction was found in 18-22 yr old women during the
same period55. The above results are promising for the
long-term effects of HPV vaccination in reducing the
cervical cancer burden.
Human papillomavirus vaccine safety
Extensive data on the safety of HPV vaccines
are available from clinical trials and the population
programmes. Globally, more than 270 million doses
have been administered with no serious adverse event
linked to the HPV vaccine and with an excellent safety

profile. The adverse events reported after the HPV

vaccine administration were generally mild in intensity
and were similar to those expected after any vaccination.
These included vaccination site pain, tenderness,
swelling, fever, headache, myalgia and gastrointestinal
symptoms. The adverse events are considered as
serious if the events occurring at any point of time
lead to hospitalization, prolongation of an existing
hospitalization, permanent disability, life-threatening
illness or death. A meta-analysis of the vaccine trials
concluded that the frequency of serious adverse events
[odds ratio (OR) 0.99; 95% CI 0.87-1.14] and death (OR
0.91, 95% CI 0.39-2.14) were similar in the vaccinated
and control groups56. The majority of deaths reported
were accidental in nature, and none was attributable to the
vaccines. A study from India reported no serious adverse
event attributable to the vaccine after administering
34,856 doses of the quadrivalent vaccine to 10-18 yr old
girls and following them over four years19.
The estimated 200 million doses of the quadrivalent
and 80 million doses of the bivalent vaccines have been
administered globally till June 201557. The vaccine
surveillance systems in countries regularly monitor
and report the serious and the non-serious adverse
events after HPV vaccination. Some of the national
monitoring authorities such as the Therapeutic Goods
Administration, Australia, Adverse Events Following
Immunization Surveillance System (Canadian Adverse
Events Following Immunization Surveillance System,
CAEFISS), Canada, Medicines and Healthcare
Products Regulatory Agency, United Kingdom and the
United States (US) Centers for Disease Control and
Prevention (CDC) have robust system of recording and
reviewing all the post-vaccination adverse events. The
mandates of these organizations include continuous
reviewing of the safety of the vaccines and informing
healthcare professionals as well as the public of the
latest safety updates. The International monitoring
agencies such as the Global Advisory Committee on
Vaccine Safety, the WHO and the European Medicines
Agency are also monitoring the vaccine safety and
critically evaluating all the serious adverse events. The
details of the latest published reports on HPV vaccine
safety by these agencies are provided in Table III. All
these have concluded that the vaccines are safe, there
are no undue safety concerns to withhold or stop the
vaccination and the benefits far outweigh the risks.
Syncope or fainting attack within 15 min of
vaccination has been associated with the HPV

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SANKARANARAYANAN et al: IMPLICATIONS OF HPV VACCINE FOR INDIA

vaccination though the event is related to the vaccination

process rather than the vaccine itself. Adolescent girls
are more prone to such fainting attacks after injections,
and similar attacks are also seen after administration of
other vaccines such as meningococcal vaccine (fourth
dose) and Tdap vaccines to the adolescent girls. The
girls should be vaccinated in a sitting or supine position
to prevent such fainting attacks and related injuries and
should be observed for 15-30 min after vaccination.
Recently, concerns have been expressed regarding
two conditions reported after HPV vaccination: the
complex regional pain syndrome, chronic pain affecting

175

the limbs; and the postural orthostatic tachycardia

syndrome, a condition where the heart rate increases
abnormally after sitting or standing up, causing
dizziness, weakness, palpitation, etc. The review by
the WHO Vaccine Advisory Committee found that the
overall rates of these syndromes in vaccinated girls were
not different from the expected rates in these age groups,
even after taking into account possible underreporting58.
Possible autoimmune disorders including the
neurological diseases such as Guillain-Barre syndrome
(GBS) and demyelinating disorders have been reported
among the recipients of HPV vaccine. The surveillance

Table III. Latest position documents of the international and selected national agencies monitoring the human papillomavirus vaccine
safety in the national immunization programmes
Monitoring agency

Latest published report on HPV vaccine safety

Conclusion regarding safety

GACVS, WHO

Report of GACVS meeting of December

2-3, 2015 was published in the WHO Weekly
Epidemiological Record of 22 January 2016
Available from: http://www.who.int/vaccine_
safety/committee/topics/hpv/Dec_2015/en/

The GACVS has systematically investigated

safety concerns raised about HPV vaccines and has
issued several reports in this regard to date, GACVS
has not found any safety issue that would alter its
recommendations for the use of the vaccine.

EMA; Pharmaco-vigilance
Risk Assessment Committee

Report date: November 2015

Available from: http://www.ema.europa.
eu/ema/index.jsp?curl=pages/medicines/
human/referrals/Human_papillomavirus_
vaccines/human_referral_prac_000053.
jsp&mid=WC0b01ac05805c516f

This review concluded that the evidence does

not support a causal link between the vaccines
(Cervarix, Gardasil/Silgard and Gardasil - 9) and
development of CRPS or POTS.

Therapeutic Goods
Administration, Australia
(HPV vaccine was introduced
in Australia in 2007)

Report date: May 2015

Available from: http://www.tga.gov.au/alert/
gardasil-quadrivalent-human-papillomavirusvaccine-update-2

No safety concerns either in males and females

identified.

CAEFISS (HPV vaccine

was introduced in Canada in
2008)

Report date: March 2015

Available from: http://healthycanadians.
gc.ca/publications/healthy-living-vie-saine/
immunization-adverse-events-2015-1immunisation-effets-secondaires/index-eng.php

No significant vaccine safety concerns were

identified.

MEDRA, United Kingdom

(HPV vaccine was
introduced in UK in 2008)

Report date: November 2012 (Modification was

not felt necessary since then; Last reviewed on
September 24, 2014)
Available from: https://www.gov.uk/drug-safetyupdate/human-papillomavirus-vaccine-cervarixbalance-of-risks-and-benefits-remains-clearlypositive

Balance of risks and benefits remains clearly

positive after 6 million doses in 4 years.

ACIP, Centers for Disease

Report date: August 2014
Control and Prevention, USA Available from: http://www.cdc.gov/mmwr/
(Quadrivalent vaccine was
preview/mmwrhtml/rr6305a1.htm
licensed in USA in 2006 and
the bivalent vaccine in 2009)

HPV vaccines are very safe. CDC has carefully

studied the risks of HPV vaccination. The benefits
of HPV vaccination, such as prevention of cancer,
far outweigh the risks of possible side effects.

CRPS, complex regional pain syndrome; CDC, Disease Control and Prevention; POTS, postural orthostatic tachycardia syndrome;
GACVS, Global Advisory Committee on Vaccine Safety; EMA, European Medicines Agency; CAEFISS, Canadian Adverse Events
Following Immunization Surveillance System; MEDRA, Medicines and Healthcare Products Regulatory Agency; ACIP, Advisory
Committee on Immunization Practices; WHO, World Health Organization; HPV, human papillomavirus

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176

INDIAN J MED RES, AUGUST 2016

of 9-26 yr old women in USA receiving 1,490,428

doses of quadrivalent vaccine (from 2006 till 2012) by
CDC using the Vaccine Safety Datalink did not observe
any increased risk of GBS. Not a single incident case of
GBS was detected in the medical records within 42 days
following vaccine administration59. A health registerbased linkage study in Sweden and Denmark for 23
different autoimmune and five neurologic conditions
among quadrivalent vaccine recipients (n = 296,826)
aged 10-17 yr did not find any consistent evidence of
causal association of these diseases with the vaccine60.
Recently, a retrospective cohort study by the French
National Agency for Medicines and Health Products
Safety involving more than two million girls observed
similar frequency of all autoimmune conditions in
vaccinated and unvaccinated girls except the GBS;
however, the risk of GBS within three months of
vaccination was very small (1/100,000 vaccinated girls)
though comparatively higher than the unvaccinated
girls61. GBS is more commonly observed in the
adolescent girls and young adult women, the target age
for the HPV vaccines. Till date, there is no evidence
that the incidence of GBS following HPV vaccination
is higher than the background rate observed in age- and
sex-matched unvaccinated populations. There was no
elevated risk of thromboembolism in a large national
register based study in Denmark involving 500,345
vaccinated women of 10-44 yr of age62-64.
The CDC and the US Food and Drug Administration
have extensively reviewed the 96 reports of deaths in
vaccinated girls/women between 2006 and 2014. A
detailed review of each death by these agencies did not
identify any pattern of occurrence of death with respect
to time after vaccination, vaccine doses or diagnosis at
death to suggest any causal association with the HPV
vaccine65.
The HPV vaccines are not recommended in
pregnancy. However, the analysis of the outcomes of
the inadvertent administration of the vaccine in pregnant
women in the trials did not document any higher rates
of spontaneous abortions, preterm births, birth defects or
other adverse consequences. No intervention other than
stopping further vaccinations is recommended if a woman
becomes pregnant after receiving incomplete doses of
the vaccine or receives the vaccine while pregnant66,67.
Is human papillomavirus vaccination relevant to
India?
India is the largest contributor to the global
burden of cervical cancer. The slow decline in cervical

cancer incidence rates seen in different populationbased cancer registries in the country is very much
debated about and has been mainly attributed to the
changing reproductive profile with fewer child births
and increasing age at marriage and first childbirth in
addition to improving socio-economic conditions and
womens empowerment. The declining incidence rates
have prompted some experts to question the need for
HPV vaccination as a primary prevention measure in
the Indian NIP and they instead suggest screening with
visual inspection with acetic acid (VIA) as the major
intervention for cervical cancer control in India68.
Some experts even went to the extent of suggesting
that efforts to improve basic hygiene and sanitation
are enough to tackle the burden of cervical cancer in
the country69. Unsubstantiated claims about the lack of
vaccine safety from some have led to further debates
as well.
However, several regions of India still have rates
higher than most Asian countries, and the absolute
number of cases is on the increase due to population
growth. Moreover, the falling incidence rates seem
to be reaching a plateau and unlikely to decline
further unless specific interventions are put in place.
Fewer than five per cent of the eligible women in
India have ever been screened and there are almost
no government-sponsored population-based cervix
screening programmes in the country, except in the
State of Tamil Nadu where one round of VIA screening
has been offered to women through the government
health services1. The impact of this programme on
the cervical cancer burden is not clear. Screening
typically requires repeated interventions at least every
five years with high coverage of targeted women and
involves a number of steps such as quality-assured
testing, diagnosis, treatment and follow up care
for it to be effective. Introducing such efficiently
organized population-based cervical cancer screening
programmes will require substantial resources
and could be a challenging task. Cervix screening
programmes in many Latin American countries
did not have any impact on cervical cancer burden
despite several rounds of intervention since the 1970s
and many of them have recently reorganized their
screening programmes70,71. Even in high-resourced
settings, a screening programme takes a minimum of
10-15 yr to evolve. However, the preventive potential
of HPV vaccination is substantially augmented by
accompanying effective screening programmes, and
these are, therefore, complementary strategies.

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SANKARANARAYANAN et al: IMPLICATIONS OF HPV VACCINE FOR INDIA

An HPV vaccination programme targeting a

single year cohort of 9-13 yr old girls is a two time
intervention at 6 or 12 months apart and will build up
a cohort of women at very low risk of HPV16 and 18
infection and, consequently, at a low risk for cervical
cancer. The direct impact of HPV vaccination and
the herd effects will prevent a substantial proportion
(>70%) of cervical cancers in these cohorts of women.
In such cohorts, if resources permit, introducing
even a low-intensity screening programme such as
one round of HPV screening when they reach 30 or
35 yr of age will contribute to further augmented
protection by detecting and treating any lesion caused
by vaccine non-targeted HPV types and lesions in
those who missed vaccination. The high burden of
cervical cancer and the high efficacy and safety of
HPV vaccination justify its introduction in the Indian
NIP at the earliest possibility to substantially reduce
the cervical cancer burden in future. Initial resistance
against any new vaccination has not been uncommon
in India, and only strong government efforts have
led to sustained vaccination programmes with such
important achievements such as small pox eradication
and polio elimination in the country. A study conducted
in 201272 indicated that routine vaccination of 12
yr old girls in Brazil could prevent approximately
118,825 cases of cervical cancer, 33,700 deaths from
cervical cancer, 1.8 million cases of CIN2/3 and 9.5
million cases of genital warts in the next 50 years,
and the Brazilian Government has initiated HPV
vaccination targeting 12 yr old girls since 2014. The
efforts by the New Delhi State government to launch
HPV vaccination in the National Capital Territory is a
welcome development in this context73.
To conclude, the HPV vaccines with their wellestablished efficacies in preventing high grade
cervical premalignant lesions in the clinical trials
as well as the real life programmes have created a
great opportunity for India to reduce the huge burden
of cervical cancers. Cervical cancer screening
implemented through population-based organized
approach is also an effective strategy to tackle the
disease; though logistically highly complex, resource
intensive and is non-existent or at its nascent stage
in India. The policy makers and the public health
administrators in India need to be aware of the
complementary roles of the two strategies and initiate
measures to implement both to reduce the burden of a
preventable cancer.
Conflicts of Interest: None.

177

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Reprint requests: Dr Rengaswamy Sankaranarayanan, Screening Group, Early Detection and Prevention Section,
International Agency for Research on Cancer, 150 Cours Albert Thomas,
69372 Lyon Cedex 08, France

e-mail: [email protected]