Vaccine 40 (2022) 3802–3811

Contents lists available at ScienceDirect

Vaccine
journal homepage: www.elsevier.com/locate/vaccine

The cost-effectiveness of human papillomavirus vaccination in the

Philippines
Cecilia L. Llave a,b, Maria Esterlita V. Uy a, Hilton Y. Lam c, Josephine G. Aldaba a, Clarence C. Yacapin a,
Michelle B. Miranda a, Haidee A. Valverde c, Wilda T. Silva d, Saira Nawaz e, Rose C. Slavkovsky e,
Jessica Mooney e, Elisabeth L. Vodicka e,⇑
a
Institute of Child Health and Human Development, University of the Philippines Manila-National Institutes of Health, Manila, Philippines
b
Department of Obstetrics and Gynecology, University of the Philippines Manila-Philippine General Hospital, Philippines
c
Institute of Health Policy and Development Studies, University of the Philippines Manila-National Institutes of Health, Manila, Philippines
d
Disease Prevention and Control Bureau, Department of Health, Manila, Philippines
e
Center for Vaccine Innovation and Access, PATH, Seattle, WA, USA

a r t i c l e i n f o a b s t r a c t

Article history: Cervical cancer is the second most common cancer among women in the Philippines. Human papillo-
Received 18 March 2022 mavirus (HPV) vaccination provides protection from the most common cancer-causing HPV types. This
Received in revised form 5 May 2022 analysis used a proportionate outcomes model to estimate the potential cost-effectiveness of four differ-
Accepted 8 May 2022
ent HPV vaccine products—CervarixTM, CecolinÒ, GARDASILÒ, and GARDASILÒ9—for routine HPV vaccina-
Available online 20 May 2022
tion of 10 cohorts of 9-year-old girls from the government and societal perspectives. Model parameters
included cervical cancer burden, healthcare and program costs, vaccine efficacy with and without poten-
Keywords:
tial cross-protection, and vaccination coverage. Univariate and probabilistic sensitivity analyses evalu-
Cost-effectiveness
Cervical cancer
ated the impact of uncertainty on model results. Compared to no vaccination, HPV programs with
Human papillomavirus CecolinÒ, CervarixTM, and GARDASILÒ are projected to be cost-effective at US$1,210, US$1,300, and US
HPV vaccination $2,043 per DALY averted, respectively, from the government perspective, and at US$173, US$263, and
Philippines US$1,006 per DALY averted, respectively, from the societal perspective when cross-protection was con-
sidered. When direct comparisons were made across vaccines, GARDASILÒ was dominated by
CervarixTM and CecolinÒ. In a scenario where cross-protection was not considered, results were similar
except that CervarixTM and GARDASILÒ were both dominated by CecolinÒ. GARDASILÒ9 was not cost-
effective under any of the modeled scenarios.
Ó 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).

1. Introduction
Human papillomavirus (HPV) is a sexually transmitted, small
non-enveloped deoxyribonucleic acid (DNA) virus with specific
types known to cause cervical cancer [1]. Two high-risk oncogenic
HPV serotypes, 16 and 18, cause about 70% of all cervical cancers
[2]. Cervical cancer is the fourth most frequent cancer among
women worldwide, and more than 85% of the global cervical can-
cer burden occurs in low- and middle-income countries (LMICs)
[2,3]. In 2020, it was estimated there were 604,000 new cases
worldwide and 91.5% of the 342,000 deaths occurred in LMICs [2].
In the Philippines, cervical cancer is the second most frequent
cancer among women, with about 8,000 new cases diagnosed each
year [4]. As of 2020, the age-standardized annual incidence rate is
⇑ Corresponding author.
E-mail address: evodicka@path.org (E.L. Vodicka).
15.2 per 100,000 women, while the mortality rate is 7.9 per
100,000 women [2]. About 2.9% of women with normal cervical
cytology are estimated to be infected with HPV 16 and/or HPV
18 at a given time [4]. Infection with HPV types 16 and 18 is preva-
lent in 58.6% of invasive cervical cancer cases, while infection with
HPV types 45, 52, 58, 59, 51, 31, 39, and 66 is prevalent in 32% of
cases [4].
Three prophylactic HPV vaccines are currently available and
marketed worldwide: bivalent CervarixTM, quadrivalent GARDA-
SILÒ, and nonavalent GARDASILÒ9. All three vaccines are safe and
highly efficacious against infection with HPV types 16 and 18
and associated diseases [5,6,7]. GARDASILÒ and GARDASILÒ9 pre-
vent infection with HPV types 6 and 11, which cause 90% of genital
warts. GARDASILÒ9 protects against five additional oncogenic
types (31, 33, 45, 52, and 58) that together account for an addi-
tional 10% to 20% of all cervical cancers [8]. In addition to the three
vaccines currently available on the global market, the bivalent HPV

https://doi.org/10.1016/j.vaccine.2022.05.025
0264-410X/Ó 2022 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
C.L. Llave, Maria Esterlita V. Uy, H.Y. Lam et al.
vaccine CecolinÒ (Xiamen Innovax Biotech Co. Limited, China) tar-
gets HPV 16 and 18, has been available in China since 2020, and
was prequalified by the World Health Organization (WHO) in Octo-
ber 2021 [9,10]. Cross-protection offered against non-vaccine HPV
types varies by product. CervarixTM confers protection against HPV
types 31, 33, and 45; GARDASILÒ against HPV type 31 [11,12,13].
The phase 3 pivotal efficacy trial for CecolinÒ reported no statisti-
cally significant cross-protection [14].
The WHO recommends HPV vaccination for all girls 9 to 14 years
old, ideally administered before sexual debut (i.e., before risk of
first exposure to HPV infection) [15]. The primary target age and
delivery strategy vary by country, with most using a two-dose
schedule through school-based, health facility-based, and/or com-
munity outreach delivery strategies [16].
In the Philippines, HPV vaccination was first introduced into the
national immunization program (NIP) in 2013 through a school-
based demonstration program targeting girls aged 10 to 14 years
in two regions of the country [17]. This strategy saw high coverage,
with about 90% of the target population of 8,000 being immunized.
In 2015, the NIP began a phased scale-up of HPV vaccination in 20
provinces throughout the country that targeted 9- to 14-year-old
girls through a health facility-based approach [18], which was sub-
sequently changed back to a school-based approach. According to
the Department of Health (DOH), average HPV vaccination cover-
age between 2015 and early 2020 was 64% for the first dose and
27% for the second dose. This decline in coverage was in line with
a decline in rates for all vaccination programs in the Philippines,
due in large part to increased vaccine hesitancy after a 2017
national controversy surrounding the country’s school-based vac-
cination campaign against dengue fever using Dengvaxia [19].
Since 2020, due to school closures from the SARS-CoV-2 pandemic,
HPV vaccination shifted back to a health facility-based approach
and is being given in 48 provinces and 57 cities, representing
59% and 39% of provinces and cities, respectively, in the country.
While studies exploring cost-effectiveness of HPV vaccination
in the Philippines have shown that HPV vaccination is cost-
effective, budget implications and affordability remain significant
challenges—a common challenge in middle-income countries that
are not eligible for subsidized vaccine prices provided by Gavi,
the Vaccine Alliance [20,21,22]. As new vaccines with varying pro-
duct profiles and prices enter the market, Filipino healthcare lead-
ers and policymakers will face decisions about which vaccine
product is most appropriate and sustainable. Estimating the long-
term health, economic, and financial impacts with updated data
provides local decision-makers with evidence regarding the poten-
tial value of different vaccine product choices and long-term deliv-
ery strategies.
The purpose of this study is to estimate the cost-effectiveness of
different HPV vaccines to assist policymakers in the Philippines
and other countries on decision-making for the HPV immunization
program.
2. Methodology
2.1. Study design
We assessed and compared different costs and health outcome
scenarios of various HPV vaccination choices (i.e., CervarixTM, Ceco-
linÒ, GARDASILÒ, and GARDASILÒ9) as compared to no vaccination
in 9-year-old Filipino girls over a ten-year routine immunization
period from 2021 to 2030. We analyzed the costs based on two
perspectives: (1) government, which includes vaccination program
costs and net treatment costs for cervical cancer cases with the
government as payer; and (2) societal, which includes vaccination
program costs and net direct and indirect treatment costs for cer-
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Vaccine 40 (2022) 3802–3811
vical cancer regardless of payer. First, the potential health impact
of estimated cervical cancer cases, disability-adjusted life years
(DALYs), and deaths averted from vaccination was compared to
no vaccination. Then, the incremental cost-effectiveness ratio
(ICER) was calculated using the following formula:
v accination program costs cer v ical cancer treatment cost sav erted
DALYs av erted
The main results of this study are the cost per DALYs averted by
each vaccination product compared to no vaccination as viewed
from both the government and societal perspectives, as well as
the comparison of these results among the four HPV vaccines.
Additional outcomes including costs, cases, and deaths are also
presented.
2.2. Model
We used the UNIVAC model, a Microsoft Excel-based propor-
tional outcomes model developed by the Pan American Health
Organization (PAHO) and the London School of Hygiene and Trop-
ical Medicine with specific use for LMICs [23]. UNIVAC can be cus-
tomized to reflect the local HPV program and policy choices (e.g.,
age group of interest), and to incorporate local data for model input
parameters. The model projects a static representation of the nat-
ural history of cervical cancer over the lifetime horizon. The model
produces conservative health impact and cost-effectiveness esti-
mates to aid in national vaccination policy decisions and has been
applied to other countries for economic evaluations of HPV, rota-
virus, Haemophilus influenzae type B, and pneumococcal vaccines
[24,25,26].
2.3. Methods, data sources and expert input
To ensure relevance to local decision-making, we aligned our
methodology with recommended guidance set forth in the 2020
Philippine Reference Case for Health Economic Evaluation by the
Health Technology Assessment Council (HTAC) whenever possible
[27]. Model parameters included demographic information for the
target population, cervical cancer incidence and mortality by age
and stage (described as local, regional invasive, and distant inva-
sive), disability weights for cervical cancer, average duration of ill-
ness, cervical cancer treatment costs, vaccine immunization
coverage, vaccine efficacy, and vaccination program costs (includ-
ing vaccine price, commodities, and delivery costs).
We gathered data inputs from published articles, health agen-
cies, and public institutions (i.e., DOH), and cervical cancer-
related information from the national health insurance (Phil-
Health) database spanning from 2015 to 2018. Where possible,
we prioritized the use of local data for input parameters. In the
absence of locally available data, we used estimates from countries
similar to the Philippines in terms of economic status (based on
GDP per capita), HPV vaccine delivery strategy, geographical loca-
tion, and population density. Base case parameters were identified
as the ‘‘most likely” estimates for each data point. We also identi-
fied low and high range estimates for each parameter to capture
potential variation from our base case values. Formal estimates
of variance (e.g., 95% confidence intervals) were applied when
available; otherwise, we applied a proportional estimate of varia-
tion from the base case (e.g., ±50% of base case estimate).
Four consultative meetings with key stakeholders were held
between December 2020 and April 2021 to obtain expert opinion
on data inputs for the model, particularly for those data inputs
which did not have local sources or that required assumptions.
Local experts and policy-makers from multi-disciplinary fields
such as obstetrics-gynecology, infectious disease, gynecology-
C.L. Llave, Maria Esterlita V. Uy, H.Y. Lam et al.
oncology, public health, health economics, health policy, and
health program management reviewed and discussed the prelimi-
nary input values and came to a consensus on final input parame-
ters that would ensure the most locally representative and up-to-
date information was used in the model.
We performed univariate sensitivity analyses to assess individ-
ual parameter variation on estimates of cost-effectiveness and to
identify drivers of model outcomes. Probabilistic sensitivity analy-
sis (PSA) evaluated joint parameter uncertainty on outcomes and
estimated 95% credible ranges for results by running 1,000 Monte
Carlo simulations in which values were drawn from each parame-
ter’s uncertainty range simultaneously. We assumed a PERT-Beta
distribution for all parameters due to lack of information about
each distributional shape [28]. The PERT-Beta distribution is com-
monly used in simulations and is defined by a minimum possible
value, the most likely value and a maximum value. The following
parameters were varied over their low and high ranges: disease
rates, vaccine coverage rates, vaccine efficacy, vaccine program
costs, and healthcare costs of treating cervical cancer. Due to wide
and heavily skewed ranges around vaccine price, we ran alterna-
tive deterministic scenarios with different vaccine prices for each
product to evaluate the impact on results.
We applied a 5.33% discount rate to both costs and outcomes in
the base case analysis, based on formal guidance from the Philip-
pines HTAC for evaluating the cost-effectiveness of healthcare
interventions, and conducted scenario analyses using 3% and 10%
discount rates [27]. We converted all monetary data from Philip-
pine Pesos (PHP) to US Dollars (USD) using the average annual
exchange rate for 2020 (1 USD = 49.62 PHP) [29]. When applicable,
values were adjusted for inflation to 2020 prices.
2.4. Data inputs
2.4.1. Cervical cancer disease burden
Cervical cancer cases by stage (local, regional, and distant inva-
sive cancer), hospitalizations, and deaths were outcomes of disease
burden. Cervical cancer stages used in the model correspond to the
Federation of International Gynecology and Obstetrics (FIGO) stag-
ing system for cervical cancer [30].
Age-standardized mortality rates per age group were obtained
from the Global Cancer Observatory (GLOBOCAN) 2020, which rep-
resent an average of data from three cancer registries in the Philip-
pines between 2008 and 2012 [2]. We also estimated cervical
cancer incidence per five-year age groups and per stage. Since
there are no available nationwide data specific to cervical cancer
incidence per age group per stage, we applied the proportion of
new cases per stage seen at the Philippine General Hospital
(PGH) Department of Obstetrics and Gynecology in 2019 to age-
categorized GLOBOCAN cervical cancer incidence rates [31]. We
chose to apply case rates from PGH since it receives the highest
number of cervical cancer cases and tertiary referrals in the Philip-
pines. We assumed each woman who develops cervical cancer only
experiences one hospitalization or course of treatment.
In the absence of country-specific data on healthy time lost
while living with cervical cancer (disability weights), the following
disability weights from the 2017 Global Burden of Disease study
were used as proxies: diagnosis and primary therapy phase of cer-
vical cancer for local stage (0.288), metastatic phase of cervical
cancer for regional (0.451), and terminal phase of cervical cancer
for distant (0.54) [32]. As there are no local data on the average
duration of cervical cancer illness, local obstetricians and gynecol-
ogists provided 15, 7.5, and 2.5 years as estimates for local, regio-
nal, and distant cervical cancer, respectively. All disease burden-
related inputs to the UNIVAC model are shown in Table 1. Low-
and high-range values are included to account for heterogeneity
in data parameters, set at plus/minus 20% of the base case values.
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Vaccine 40 (2022) 3802–3811
2.4.2. Healthcare costs
We used 2018 insurance claims from the PhilHealth database to
estimate cervical cancer healthcare costs. For the government per-
spective, we assumed costs incurred by the government per cervi-
cal cancer case were equivalent to established PhilHealth case
rates, which are fixed rates or amounts PhilHealth reimburses for
specific clinical procedures. This includes health care professional
fees and all facility charges, such as room and board, diagnostics
and laboratories, drugs, medicines and supplies, and operating
room fees [33]. Expert opinion was obtained through the consulta-
tive meetings for the typical treatment procedure recommended
per cancer stage and estimated proportion of patients who receive
each procedure.
For the societal perspective, the healthcare cost is equal to the
total direct medical costs plus indirect costs. Direct medical costs
pertain to all medical goods and services used for diagnosis and
treatment; indirect costs reflect the loss of productivity or income
while seeking care [27]. The total direct medical cost includes the
PhilHealth case rates plus any marginal out-of-pocket expenses for
diagnosis and treatment charged to patients.
The full cost of treatment per stage from both the government
and societal perspectives was computed as a weighted average of
the costs of case rates for the different treatment procedures by
stage, adjusted to 2020 prices, then multiplied by the likelihood
of access to treatment. For the likelihood of access to treatment,
we obtained data on the percentage of cervical cancer cases that
are lost to follow-up without receiving treatment (31.5%) from
the 2019 PGH annual report and used the percentage that did
receive treatment (68.5%) as proxy [31]. Data on non-medical costs
were unavailable. Indirect costs were based on the average number
of days spent seeking care and the cost of a caregiver (assumed to
accompany the patient through the full course of treatment), mul-
tiplied by the median daily minimum wage of PHP 414 (US$8.34)
[34]. We obtained the estimated number of days for a procedure
or treatment via expert opinion.
We set low and high values for treatment costs at 50% and 200%
of the base case estimates, respectively, to account for the poten-
tially wide variation in treatment strategies, individual characteris-
tics, and care-seeking behavior among cervical cancer patients. A
summary of cervical cancer healthcare costs is in Table 2.
2.4.3. Vaccination program costs
HPV vaccination program costs are summarized in Table 2. Cer-
varixTM and GARDASILÒ prices were based on the DOH procurement
prices from 2015 (US$10.68) and 2019 (US$13.14), respectively.
Based on expert opinion, we anticipate the previously negotiated
prices per dose would remain constant for the DOH and, therefore,
were not inflated for this analysis. There is limited publicly-
available information on procurement prices for GARDASILÒ9
among middle-income countries like the Philippines. However, in
2019, the WHO Market Information Access to Vaccines (MI4A)
indicated the average procurement price in high-income countries
was US$157 [35]. Local expert opinion suggests similar pricing for
GARDASILÒ9 in the private sector in the Philippines; therefore, we
applied this value as the high-end price for GARDASILÒ9. To esti-
mate a defensible base-case price, we calculated a ratio of the his-
torical procurement price for GARDASILÒ (US$13.14) to the MI4A
mean procurement price among high-income countries (US
$46.38) and applied that ratio to the MI4A mean price for GARDA-
SILÒ9 among high-income countries (US$157). This reference-
based approach resulted in an assumed base-case procurement
price for GARDASILÒ9 in the Philippines of US$44.64 per dose.
In view of the recent licensure of CecolinÒ, price information is
very limited. To establish a plausible base case price, we found the
midpoint of the current Gavi-reported price indication for Ceco-
linÒ (US$3.00 per dose) and the average of the DOH procurement
C.L. Llave, Maria Esterlita V. Uy, H.Y. Lam et al. Vaccine 40 (2022) 3802–3811

Table 1
Data inputs for estimating cervical cancer burden, disability weights, and duration of illness.

Parameters (Base Case Estimates) Source

Cervical cancer age-specific rates per 100,000
Age group Local Regional Invasive Distant Invasive Deaths
(in years)
10–15 0.00 0.00 0.00 0.00 [2,31]
15–20 0.00 0.00 0.01 (0.1–0.01) 0.01 (0.01–0.01)
20–25 0.06 (0.05–0.07) 0.00 0.04 (0.03–0.05) 0.12 (0.10–0.04)
25–30 0.34 (0.27–0.41) 3.00 (2.26–3.38) 0.22 (0.18–0.26) 0.60 (0.48–0.72)
30–35 1.02 (0.82–1.22) 8.00 (6.79–10.19) 0.66 (0.53–0.79) 2.00 (1.60–2.40)
35–40 1.80 (1.44–2.16) 15.00 (11.96–17.94 1.16 (0.93–1.39) 4.70 (3.76–5.64)
40–45 2.80 (2.24–3.36) 23.00 (18.61–27.91) 1.80 (1.44–2.16) 8.40 (6.72–10.08)
45–50 3.77 (3.02–4.52) 31.00 (25.07–37.61) 2.43 (1.94–2.92) 13.40 (10.72–16.08)
50–55 4.48 (3.58–5.38) 37.00 (29.80–44.70 2.88 (2.30–3.46) 18.80 (15.04–22.56)
55–60 4.68 (3.74–5.62) 39.00 (31.07–46.61) 3.01 (2.41–3.61) 23.80 (19.04–28.56)
60–65 4.68 (3.74–5.62) 39.00 (31.09–46.63) 3.01 (2.41–3.61) 28.30 (22.64–33.96)
65–70 4.64 (3.71–5.57) 39.00 (30.86–46.28) 2.98 (2.38–3.58) 34.30 (27.44–41.16)
70–75 4.57 (3.66–5.48) 38.00 (30.36–45.54) 2.94 (2.35–3.53) 43.00 (34.40–51.60)
75–80 5.00 (4.00–6.00) 42.00 (33.21–49.81) 3.21 (2.57–3.85) 54.20 (43.36–65.04)
80–85 3.26 (2.61–3.91) 27.00 (21.67–32.51) 2.10 (1.68–2.52) 38.60 (30.88–46.32)
85–90 2.46 (1.97–2.95) 20.00 (16.36–24.54) 1.58 (1.26–1.90) 28.87 (23.10–34.64)
90–95 2.46 (1.97–2.95) 20.00 (16.36–24.54) 1.58 (1.26–1.90) 28.87 (23.10–34.64)
95–100 2.46 (1.97–2.95) 20.00 (16.36–24.54) 1.58 (1.26–1.90) 28.87 (23.10–34.64)
Estimate
Disability weights 0.288 (0.193–0.399 0.451 (0.307–0.600) 0.54 (0.377–0.687 [32]
Estimate (in years)
Average duration of illness 15.00 (12.00–18.00) 7.50 (6.00–9.00) 2.50 (2.00–3.00) Assumption, expert opinion

Table 2
Healthcare costs of cervical cancer and HPV vaccination program costs input.

Healthcare costs per treated case

Estimate (in USD)1 Sources
Government perspective
Local 2,770 (1,385–5,540) [30,33]
Regional 2,306 (1,153–4,612)
Distant 2,125 (1,063–4,250)
Societal perspective
Local 7,791 (3,896–15,582) [30,33,34], expert opinion
Regional 16,002 (8,001–32,004)
Distant 18,105 (9,052–36,210)

HPV vaccination program costs

Expected Vaccine Price Per Dose
Bivalent HPV vaccine (Cecolin) 7.47 (3.00–47.70) [35,38]
Bivalent HPV vaccine (Cervarix) 10.68 (5.18–14.14) Department of Health
Quadrivalent HPV vaccine (Gardasil-4) 13.14 (4.50–25.00) Department of Health
Nonavalent HPV vaccine (Gardasil-9) 44.64 (35.72–157.58) [35,38]
Fixed price assumptions for other vaccine supplies (USD)
Syringe price per dose 0.05 (0.04–0.06) Department of Health
Safety box/bag price per dose 0.15 (0.12–0.18)
Other charges (expressed as a % of vaccine price)
% Local handling, storage, and delivery 6% (5–7%) Department of Health
Wastage Rates (%)
Bivalent Vaccine (Cecolin, Cervarix) 5.00% (4.0–6.0%) Department of Health
Quadrivalent Vaccine (Gardasil-4) 5.00% (4.0–6.0%)
Nonavalent vaccine (Gardasil-9) 5.00% (4.0–6.0%)
Syringes 5.00% (4.0–6.0%)
Safety boxes/bags 5.00% (4.0–6.0%)
Incremental health system costs per dose
Expected health systems costs per dose for each type of vaccine delivery 2.85 (2.28–3.42) [37]
1
Cost in 2020 USD (1 USD = 49.62 PHP).

prices for CervarixTM and GARDASILÒ [35,38]. This resulted in a
base case price of US$7.47 for CecolinÒ. We applied a wide uncer-
tainty range to this parameter, with the upper bound fixed at US
$47.70, which is the private sector market price for CecolinÒ in
China.
DOH estimates for local handling, storage, and distribution
costs were 5–7% of the vaccine price, so an average of 6% was used
for the base case. DOH reported 5% wastage rates across vaccine
types, syringes, and safety boxes.
In the Philippines, up-to-date costs of delivery and logistics for
HPV vaccination—often paid by local government units—were
unavailable. For this reason, the cost of introduction and recurrent
cost of HPV vaccination in school-based settings in Vietnam were
utilized as proxy variables [37]. Costs included training the health

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C.L. Llave, Maria Esterlita V. Uy, H.Y. Lam et al.
workers who would administer the vaccination, publication of vac-
cine records, time spent by healthcare workers during service
delivery, social mobilization, and overall program
planning/management.
2.4.4. Vaccine efficacy, cross-protection, and routine immunization
coverage
Vaccine efficacy (VE) is outlined in Table 3, including low and
high values used for uncertainty analysis. We accounted for poten-
tial cross-protection conferred in the base case analysis and con-
ducted scenario analyses without cross-protection. We calculated
a composite two-dose VE for cancer-associated genotypes present
in the Philippines by applying estimates of local HPV genotype dis-
tribution in the Philippines to the expected genotype-specific effi-
cacy afforded by each vaccine [11,12]. Cancer-associated HPV
genotypes are available in Supplementary Table 3. Given the cur-
rent lack of robust clinical data on CecolinÒ cross-protection, we
assumed that CecolinÒ would confer cross-protection similar to
GARDASILÒ, due to product similarities. There are no data suggest-
ing potential cross-protection to additional oncogenic types with
GARDASILÒ9 beyond those already targeted by the vaccine. In the
‘‘no cross-protection” scenarios, we calculated the two-dose VE
by applying the respective odds ratio from the PATRICIA and
FUTURE vaccine trials multiplied by vaccine-targeted high-risk
HPV genotype coverage (e.g., 16/18 for CervarixTM and GARDASILÒ
vaccines) [5,6]. We conservatively assumed that one-dose of the
HPV vaccine provides 90% of the VE of two doses based on early
indications of single-dose vaccine efficacy against persistent infec-
tion [36]. This study assessed CervarixTM and GARDASILÒ9 and
extended this assumption to the other vaccine products.
We applied the DOH’s average HPV vaccination coverage rates
from 2015 to 2017. The low and high coverage values were based
on the lowest and highest coverage rates during that three-year
period (Table 3).
3. Results
We report the lifetime costs and effects of routine HPV vaccina-
tion of 9-year-old girls vaccinated over the period 2022–2031 for
Table 3
Vaccine efficacy and immunization coverage data inputs.
Composite Vaccine Efficacy with cross-
protection (%)
Bivalent HPV vaccine 1-dose: 80.1 (57.0–81.6)2-dose: 89.0
(63.4–91.7)
(Cervarix)
Bivalent HPV vaccine 1-dose: 64.5 (39.5–64.6)2-dose: 71.7
(43.9–71.8)
(Cecolin)
Quadrivalent HPV vaccine 1-dose: 63.4 (56.7–64.3)2-dose: 70.4
(63.0–71.4)
(Gardasil-4)
Nonavalent HPV vaccine N/A
(Gardasil-9)
Estimate (%)
Dose 1: Expected coverage in Year 1 of 78.0 (77.0, 81.0)
vaccination
Dose 2: Expected coverage in Year 1 of 60.5 (53.0, 68.0)
vaccination
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Vaccine 40 (2022) 3802–3811
scenarios with cross-protection in Table 4 and Fig. 1. Additional
results for scenarios that only account for vaccine-targeted type
protection are reported in Supplementary Table 1 and Supplemen-
tary Fig. 2.
3.1. No vaccination scenario
The UNIVAC model estimated that with no vaccination, the
Philippines would see a total of 182,406 cervical cancer cases with
treatment, 176,887 DALYs, and 114,616 cervical cancer deaths dur-
ing the lifetime of females born from 2012 to 2021. Without the
vaccine, treatment of cervical cancer among this population would
result in total estimated government and societal healthcare costs
(discounted) of US$33,093,804 and US$216,468,126 respectively.
3.2. Cervarix HPV vaccine vs. No vaccination
When cross-protection was considered, a ten-year vaccination
program using CervarixTM was estimated to avert 123,795 cervical
cancer cases, 120,050 DALYs, and 77,788 cervical cancer deaths
(Table 4), as compared to no vaccination. In this scenario, total
vaccination program costs over ten years would amount to US
$178,500,596 and avert downstream government and societal
healthcare costs of US$22,460,078 and US$146,912,428, respec-
tively. The resulting ICER is estimated to be US$1,300 per DALY
averted from the government perspective and US$263 per DALY
averted from the societal perspective, as compared to no
vaccination. When only vaccine-type protection was included,
the ICERs were higher at US$1,693 and US$656 per DALY averted
from the government and societal perspectives, respectively.
3.3. CecolinÒ HPV vaccine vs. No vaccination
A ten-year vaccination program using CecolinÒ was estimated
to avert 99,703 cervical cancer cases, 96,687 DALYs, and 62,649
cervical cancer deaths in the Philippines as compared to no vacci-
nation when cross-protection was included. In this scenario, total
vaccination program costs over ten years would amount to US
$135,083,980 and avert downstream government and societal
Composite Source
Vaccine Efficacy without cross-
protection (%)
1-dose: 63.4 [5,6,11–13,36]
(49.9–64.0)
2-dose: 70.4
(55.5–71.2)
1-dose: 64.0
(39.3–64.0)
2-dose: 71.2
(43.7–71.7)
1-dose: 62.9
(56.5–63.7)
2-dose: 69.9
(62.8–70.7)
1-Dose 82.3
(72.2–83.8)
2-dose: 91.4
(80.2–93.2)
Department of
Health
C.L. Llave, Maria Esterlita V. Uy, H.Y. Lam et al. Vaccine 40 (2022) 3802–3811

Table 4
Lifetime costs and effects of routine HPV vaccination for 9-year-old girls over the period 2022–2031 in the Philippines (assuming vaccine cross-protection).

No vaccine CECOLIN CERVARIX GARDASIL-4 GARDASIL-9

Lifetime costs (US$) and effects
Cervical cancer cases (local) 18,334 8,313 5,891 8,492 5,552
Cervical cancer cases (regional) 152,280 69,043 48,931 70,531 46,117
Cervical cancer cases (distant) 11,792 5,347 3,789 5,462 3,571
Cervical cancer cases with treatment 182,406 82,703 58,611 84,484 55,240
Cervical cancer deaths 114,616 51,967 36,829 53,086 34,711
DALYs (discounted*) 176,887 80,200 56,838 81,928 53,569
Vaccine program costs (discounted*) $0 $135,083,980 $178,500,596 $211,773,143 $637,881,788
Government healthcare costs (discounted*) $33,093,804 $15,004,693 $10,633,725 $15,327,916 $10,022,155
Societal healthcare costs (discounted*) $216,468,126 $98,146,405 $69,555,698 $100,260,618 $65,555,386
Differences (comparator = no vaccine)
Cervical cancer cases (local) – 10,021 12,443 9,842 12,782
Cervical cancer cases (regional) – 83,236 103,349 81,749 106,163
Cervical cancer cases (distant) – 6,446 8,003 6,330 8,221
Cervical cancer cases with treatment – 99,703 123,795 97,922 127,166
Cervical cancer deaths – 62,649 77,788 61,530 79,906
DALYs (discounted*) – 96,687 120,050 94,959 123,318
Vaccine program costs (discounted*) – $135,083,980 $178,500,596 $211,773,143 $637,881,788
Government healthcare costs (discounted*) – -$18,089,110 -$22,460,078 -$17,765,888 -$23,071,649
Societal healthcare costs (discounted*) – -$118,321,721 -$146,912,428 -$116,207,508 -$150,912,740
Cost (US$) per DALY averted (comparator = no vaccine)
Government cost perspective
Cost (discounted*) – $116,994,870 $156,040,518 $194,007,255 $614,810,139
DALYs averted (discounted*) – 96,687 120,050 94,959 123,318
Cost per DALY averted (discounted*) – $1,210 $1,300 $2,043 $4,986
Societal cost perspective
Cost (discounted*) – $16,762,259 $31,588,168 $95,565,634 $486,969,048
DALYs averted (discounted*) – 96,687 120,050 94,959 123,318
Cost per DALY averted (discounted*) – $173 $263 $1,006 $3,949
Cost (US$) per DALY averted
(comparator = next least costly non-dominated** option)
Government cost perspective
Cost (discounted*) – $116,994,870 $39,045,648 Dominated** $458,769,622
DALYs averted (discounted*) – 96,687 $23,363 Dominated** 3,269
Cost per DALY averted (discounted*) – $1,210 $1,671 Dominated** $140,345
Societal cost perspective
Cost (discounted*) – $16,762,259 $14,825,909 Dominated** $455,380,880
DALYs averted (discounted*) – 96,687 23,363 Dominated** 3,269
Cost per DALY averted (discounted*) – $173 $635 Dominated** $139,309
*
Future costs/effects were discounted at a rate of 5.33% per year;
**
a product is dominated if at least one other product provides greater benefits at less cost.

healthcare costs of US$18,089,110 and US$118,321,721, respec-
tively, with ICERs of US$1,210 and US$173 per DALY averted. When
no cross-protection was considered, the cost per DALY averted was
US$1,220 from the government perspective and US$184 per DALY
averted from the societal perspective.
3.4. GARDASILÒ HPV vaccine vs. No vaccination
When cross-protection was considered, use of GARDASILÒ was
estimated to avert 97,922 cervical cancer cases, 94,959 DALYs,
and 61,530 cervical cancer deaths in the Philippines (Table 4), as
compared to no vaccination among the ten birth cohorts. The
ten-year vaccination program was projected to cost US
$211,773,143 and avert total government healthcare costs of US
$17,765,888 and total societal healthcare costs of US
$116,207,508 (Table 4). This yielded a cost of US$2,043 per DALY
averted from the government perspective and US$1,006 per DALY
averted from the societal perspective. When no cross-protection
was considered, the cost per DALY averted was slightly higher at
US$2,060 from the government perspective and US$1,023 per
DALY averted from the societal perspective.
3.5. GARDASILÒ9 HPV vaccine vs. No vaccination
A ten-year vaccination program using GARDASILÒ9 was esti-
mated to avert 127,166 cervical cancer cases, 123,318 DALYs, and
3807
79,906 cervical cancer deaths in the Philippines (Table 4) com-
pared to no vaccination. Total estimated ten-year vaccination pro-
gram costs would amount to US$637,881,788 and avert US
$23,071,649 government healthcare costs and US$150,912,740
societal healthcare costs. This represents US$4,986 per DALY
averted from the government perspective and US$3,949 per DALY
averted from the societal perspective. Results were the same with
and without cross-protection, given the lack of evidence for protec-
tion against additional oncogenic types beyond those already tar-
geted by the vaccine.
3.6. Cost-effectiveness of vaccines
While there is no explicit threshold of cost-effectiveness in the
Philippines, local HTAC guidance indicates that cost-effectiveness
thresholds based on GDP per capita (US$3,485 in 2019) may be
used for determining whether an intervention is considered good
value for money (i.e., cost-effective if less than 1xGDP per capita
per DALY averted) [27,39]. Compared to no vaccination, the UNI-
VAC model estimated that CecolinÒ had the lowest ICER for a
ten-year vaccination program among 9-year-old girls, regardless
of whether potential cross-protection was included, followed by
CervarixTM, GARDASILÒ, and GARDASILÒ9. When evaluated against
GDP per capita, vaccination programs with CecolinÒ, CervarixTM,
and GARDASILÒ would be cost-effective in the Philippines com-
pared to no vaccination. GARDASILÒ9 would not be cost-effective
C.L. Llave, Maria Esterlita V. Uy, H.Y. Lam et al. Vaccine 40 (2022) 3802–3811

Fig. 1. Incremental cost (US$) and benefit (DALYs averted) of introducing different HPV vaccines in the Philippines from a societal cost perspective (assuming vaccine
cross-protection) Caption: Incremental costs and benefits are shown for CECOLIN (blue squares), CERVARIX (pink circles), GARDASIL-4 (gold diamonds), and GARDASIL-9
(orange triangles). For each vaccine, the cloud of small shapes represents 1,000 individual probabilistic runs, and the large shape is the deterministic result based on central
input parameters. Probabilistic runs capture uncertainty in all model input parameters, apart from the discount rate (5.33%), number of doses (two), level of cross-protection
(included) and vaccine price (CECOLIN = $7.47, CERVARIX = $10.68, GARDASIL-4 = $13.14, GARDASIL-9 = $44.64). The influence of these parameters is explored separately in
deterministic scenario analysis (supplementary appendix, Table 2). The dashed line indicates a willingness-to-pay (WTP) threshold set at 0.5 times the national GDP per
capita. In this scenario, CECOLIN has the most favorable cost-effectiveness ratio. CECOLIN dominates GARDASIL-4 because it provides more benefit at lower cost. CERVARIX
would provide more benefit than CECOLIN. If a WTP threshold set at 0.5 times the GDP per capita is acceptable, then it would be cost-effective to choose CERVARIX, because
the gradient of the line between CECOLIN and CERVARIX is not steeper than the gradient of the WTP threshold line. GARDASIL-9 would provide slightly more benefit than
CERVARIX, but it would not be cost-effective to pay for these additional benefits because the gradient of the line between CERVARIX and GARDASIL-9 is far steeper than the
gradient of the WTP threshold line. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

compared to no vaccination when evaluated against GDP per
capita. When vaccines were compared to each other, CecolinÒ
was the most cost-effective option. GARDASILÒ was dominated in
both cross-protection and no cross-protection scenarios, meaning
that at least one other product provides greater benefits at less
cost; CervarixTM was also dominated when cross-protection was
not considered.
4. Sensitivity analysis
Supplementary Appendix Table 2 reports the results of the
univariate sensitivity analysis. Across vaccines, results were sensi-
tive to the discount rate. Results ranged from potentially cost-
effective (government perspective) or cost-saving (societal per-
spective) with a 3% discount rate to ICERs greater than GDP per
capita with a 10% discount rate. Vaccine price was also highly
influential on results for all vaccines. When high-end price
assumptions were used, we found that CecolinÒ and GARDASILÒ
were no longer projected to be cost-effective at a threshold of
GDP per capita. Conversely, lower prices (25% and 50% less than
the base case) for GARDASILÒ9 yielded ICERs less than GDP per
capita— indicating price points at which this vaccine could be
3808
cost-effective. Additionally, when high disease burden or high
health care costs were assumed, CecolinÒ, CervarixTM, and GARDA-
SILÒ were projected to be cost-saving from the societal
perspective.
Results from the PSA are presented as cost-effectiveness accept-
ability curves in Fig. 2 and Supplementary Figure 4, showing the
probability that each vaccine is cost-effective at different cost-
effectiveness thresholds. When cross-protection is considered,
CecolinÒ and CervarixTM have a > 80% probability of being cost-
effective at a threshold of approximately US$500 per DALY averted.
If CecolinÒ and CervarixTM were not available, then GARDASILÒ would
have a > 80% probability of being cost-effective at a threshold of
approximately US$1250. GARDASILÒ9 would not be cost-effective.
5. Discussion
The analysis suggests that continued administration and
nationwide scale-up of HPV vaccination through the NIP with
either the CervarixTM, CecolinÒ, or GARDASILÒ HPV vaccines will
be cost-effective at a threshold of 2019 GDP per capita compared
to no vaccination. Under modeled assumptions, CecolinÒ was
expected to provide better value for money compared to no vacci-
C.L. Llave, Maria Esterlita V. Uy, H.Y. Lam et al. Vaccine 40 (2022) 3802–3811

Fig. 2. Cost-effectiveness acceptability curves (CEAC) showing the probability that each HPV vaccine is cost-effective at different willingness-to-pay thresholds,
compared to no vaccination (assuming vaccine cross-protection) Caption: Cost-effectiveness acceptability curves (CEACs) are shown for CECOLIN (blue), CERVARIX (pink),
GARDASIL-4 (gold), and GARDASIL-9 (orange). The dashed line indicates a willingness-to-pay (WTP) threshold set at 0.5 times the national GDP per capita. Probabilistic runs
capture uncertainty in all model input parameters, apart from the discount rate (5.33%), number of doses (two), level of cross-protection (included) and vaccine price
(CECOLIN = $7.47, CERVARIX = $10.68, GARDASIL-4 = $13.14, GARDASIL-9 = $44.64). Both CECOLIN and CERVARIX have a > 80% probability of being cost-effective at a WTP
threshold set at around $500 per DALY averted. If CECOLIN and CERVARIX were not available, then GARDASIL-4 would have a > 80% probability of being cost-effective at a
WTP threshold set at around $1,250. GARDASIL-9 would not be cost-effective. (For interpretation of the references to colour in this figure legend, the reader is referred to the
web version of this article.)

nation than CervarixTM, GARDASILÒ, or GARDASILÒ9 under all sce-
narios. GARDASILÒ9 was not projected to be cost-effective. We rec-
ognize that economic considerations are important but only one
component of vaccine decision making. These findings imply that
policy makers consider the use and scale-up of CervarixTM, CecolinÒ,
or GARDASILÒ. CecolinÒ is the preferred choice from an economic
perspective. Modelled differences between products depend on
uncertain assumptions around the price and the level of cross-
protection associated with each product.
5.1. Vaccine price
Vaccine price assumptions are highly influential on model
results. Vaccine pricing has been discussed in several studies as a
significant parameter affecting cost-effectiveness in low- and
middle-income countries [28,40,41]. However, tender prices for
vaccines vary widely among countries not eligible for Gavi support
[35]. We relied on historical procurement pricing for CervarixTM and
GARDASILÒ, extrapolated prices for CecolinÒ based on indicative
pricing for Gavi-eligible countries, and extrapolated prices for GAR-
DASILÒ9 based on reported procurement prices among high-
income countries. These prices may not reflect present or future
actual tender prices. To address this limitation, we conducted a
wide range of deterministic sensitivity analyses to assess the
impact of different pricing assumptions on outcomes.
In the Philippines, only two HPV vaccines—CervarixTM and GAR-
DASILÒ—are included in the Philippine National Drug Formulary,
which is a requirement for national procurement [42]. GARDA-
SILÒ9 is available on the private market at a high price that limits
its use. Currently in the Philippines, only one manufacturer of GAR-
DASILÒ (Merck Sharp & Dohme) has entered public bidding to sup-
ply the needs of the NIP. The entry of new (and possibly less-costly)
HPV vaccines, like CecolinÒ, into the global market may ease sup-
ply constraints and bring down prices further. This would make
3809
the vaccines more cost-effective and support financial sustainabil-
ity of ongoing HPV vaccination programs over time.
5.2. Epidemiologic data
The disease event rates used in the model were from GLOBOCAN
estimates, which were derived from hospital-based cancer registries
in only three areas in the country [2]. These only capture cases seen
in hospitals and may not be reflective of the real burden of cervical
cancer in the entire country, including cases that remain undiag-
nosed or untreated. The underestimation of local cervical cancer
burden may result in more conservative cost-effectiveness
estimates.
5.3. Health system costs
We used vaccine program delivery cost estimates from Vietnam
that may not be reflective of the actual cost in the Philippines. In
the absence of local data, we varied this parameter in the univari-
ate analysis (US$2.28-$3.42 per dose) with minimal effect on our
results. However, a systematic review of cost-effectiveness of
HPV vaccination in LMICs noted that these costs can constitute
as much as 40% of the total cost per vaccinated girl and therefore
are an important parameter in determining cost-effectiveness
and affordability [40]. In the Philippines, the HPV vaccination pro-
gram has been implemented through a school-based strategy.
Because the country has a devolved health system, the government
establishes policies and guidelines for immunization and procures
vaccines and supplies for the NIP. Local government units subse-
quently provide logistics for the delivery and implementation of
services in community health facilities and, in the case of HPV vac-
cination, in schools [43]. Therefore, the cost of delivery may vary
among the different municipalities across the country and be lar-
gely dependent on the local financial resources; however, this
information is not currently known.
C.L. Llave, Maria Esterlita V. Uy, H.Y. Lam et al.
5.4. Model structure
The UNIVAC model is a static cohort model based on propor-
tional outcomes. As such, it does not include effects of herd immu-
nity, which would likely result in greater impact on health
outcomes. While a proportional outcomes model does not account
for dynamic changes between health states, it provides a flexible
and transparent approach for examining the impact of HPV vaccine
product and programmatic choices on costs and health outcomes
that have been shown to produce results consistent with more
complex modeling approaches for comparing vaccination to no
vaccination scenarios in LMICs [44].
5.5. Healthcare costs
We obtained government perspective healthcare costs from
PhilHealth, which only insures 84.9% of the population. There
may be cervical cancer cases that are treated in public hospitals
which are financed by the national or local governments and not
reimbursed by PhilHealth [45]. As such, the estimated government
costs per cervical cancer case may be an underestimation and
therefore lead to a more conservative cost-effectiveness result.
The healthcare costs for cervical cancer are considerable and the
large gap between the government and societal perspectives
(Table 2) shows that a substantial financial burden is passed onto
the patient’s household. According to the Philippine Statistics
Authority, in 2019, household out-of-pocket payment for all health-
care services comprised 47.9% of current health expenditure in the
country [46]. In a study of the economic impact of cancer on Filipi-
nos, it was found that at 12 months after a cancer diagnosis, 40.6%
of patients had experienced financial catastrophe and 26.4% had
died. The same study showed that having insurance did not protect
against financial catastrophe in the Filipino household [47]. Hence,
preventing cancer whenever effective modalities like vaccination
are present should be a priority in national health programs.
5.6. Vaccine program costs
The cost to implement a nationwide school-based HPV vaccina-
tion is substantial. With GARDASILÒ or CervarixTM, cost projections
to vaccinate a cohort of 9-year-old girls in year one of nationwide
implementation are on the order of 10% of the NIP budget [48].
While program costs would be lower if CecolinÒ was used, costs
are still substantial. Furthermore, there are several other priority
vaccines which have yet to be introduced or scaled-up in the NIP,
including a Japanese encephalitis vaccine and a rotavirus vaccine.
The government may be required to make tradeoffs to accommo-
date these competing priorities within budget constraints. Infor-
mation on the value of different vaccine program investments
can support this decision-making, yet other factors such as afford-
ability are critical and must be considered to ensure sustainability
of health investments.
6. Conclusion
In the Philippines, continued administration and nationwide
scale-up and incorporation of CecolinÒ, CervarixTM, or GARDASILÒ
into the NIP are projected to be cost-effective at a threshold of less
than the GDP per capita, when compared to no vaccination. New
products with lower prices are promising from an economic per-
spective and may even be cost saving, depending on vaccine price,
discount rates, disease burden, and healthcare costs. This study
demonstrates the substantial health and economic benefits of a
nationwide scale-up of HPV vaccination in the Philippines and will
help inform policymaker decisions.
3810
Vaccine 40 (2022) 3802–3811
Declaration of Competing Interest
The authors declare the following financial interests/personal
relationships which may be considered as potential competing
interests: Cecelia Llave reports financial support was provided by
GSK. Cecelia Llave reports financial support was provided by MSD
Vaccins.
Acknowledgements
We recognize the contributions and expert opinions given by the
representatives of following organizations during the consultative
meetings: World Health Organization-Country Office (Dr. Achyut
Shrestha); National Integrated Cancer Control Program- Depart-
ment of Health (Dr. Clarito Cairo); Health Technology Assessment
Unit (Drs. Anna Melissa Guerrero and Anne Julienne Marfori); Dis-
ease Prevention and Control Bureau- DOH (Ms. Luzviminda Gar-
cia); Dr. Jean Anne Toral (Coalition of Gynecological Cancer
Societies); Dr. Rachel Marie Rosario (Philippine Cancer Society);
Society of Gynecologic Oncologists of the Philippines (Drs. Maria
Lilibeth Sia-Su, Filomena San Juan and Ana Victoria Dy Echo); Soci-
ety of Adolescent Medicine of the Philippines, Inc. (Dr. Vanessa Tic-
zon); Philippine Obstetrical and Gynecological Society (Dr.
Benjamin Cuenca); Philippine Society of Cervical Pathology and
Colposcopy (Dr. Maria Julieta Germar); Philippine Infectious Dis-
ease Society for Obstetrics and Gynecology (Dr. Erwin De Mesa);
Asia-Oceania Research Organization in Genital Infection and Neo-
plasia (Dr. Doris Benavides); Philippine Foundation for Vaccination
(Drs. Lulu Bravo and May Montellano); Philippine Oncology Nurses
Association (Ms. Cecilia Paje, Joshua Nario, Mariano Torres III, R.N);
and Cancer Coalition Philippines (Ms. Carmen Auste). We thank the
UNIVAC model developer, Andy Clark, for reviewing the model and
providing comments on the manuscript prior to submission. Thank
you to Drs. Clint Pecenka and D. Scott LaMontagne of PATH for
their scholarly advice. We would also like to express our gratitude
to Dr. Eva Maria Cutiongco- De La Paz, executive director of the
National Institutes of Health of the University of the Philippines
Manila for her encouragement. We thank KFW for funding to sup-
port this work.
Funding statement: This work was funded through PATH by a
grant from BMBF (German Federal Ministry of Education and
Research) administered through KfW development bank.
Appendix A. Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.vaccine.2022.05.025.
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