Considerations for

Human
Papillomavirus (HPV)
Vaccine Product
Choice
second edition
Considerations for human papillomavirus (HPV) vaccine product choice, second edition

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Contents
Acknowledgements ........................................................................................................................................... iv
Background.........................................................................................................................................................1
Development ......................................................................................................................................................1
WHO position on HPV vaccines ..........................................................................................................................2
Vaccine characteristics .......................................................................................................................................2
Vaccine safety ....................................................................................................................................................4
Contraindications, precautions and use in pregnancy ...................................................................................5
Vaccine immunogenicity, efficacy and effectiveness.........................................................................................6
Immunogenicity..............................................................................................................................................6
Efficacy............................................................................................................................................................6
Effectiveness...................................................................................................................................................6
Cross-protection .............................................................................................................................................8
Duration of protection ...................................................................................................................................8
Programmatic considerations ............................................................................................................................8
Two-dose schedule .........................................................................................................................................9
Alternative single-dose schedule ...................................................................................................................9
Schedule for immunocompromised persons ...............................................................................................10
Interchangeability.........................................................................................................................................10
Co-administration with other vaccines ........................................................................................................10
Cost and financial considerations ....................................................................................................................10
Availability and supply......................................................................................................................................11
Prioritization of new vaccine introduction decisions .......................................................................................12
Inclusion of HPV vaccine into the National Immunization Strategy ................................................................12
References ........................................................................................................................................................13

iii
Acknowledgements
This document was prepared by the World Health Organization (WHO), Department of Immunization,
Vaccines and Biologicals (IVB) in collaboration with WHO regional colleagues and global partners working in
the technical area of HPV vaccine.

iv
Background
This is an updated, second edition of the document Considerations for Human Papillomavirus (HPV) Vaccine
Product Choice (1). It incorporates changes to reflect WHO prequalification of a new bivalent product
(Walrinvax®) in August 2024 and the review of evidence on the one-dose use of Cecolin® by WHO’s SAGE
Steering Group on Vaccination Policy Guidance on 23 August 2024.

This document summarizes current technical and programmatic information on WHO-prequalified human
papillomavirus (HPV) vaccine products in order to facilitate informed country choices for HPV vaccine
introduction (or product switch within immunization programmes). Since 2009, five HPV vaccine products
have been prequalified by WHO. They include three bivalent products (Cecolin®, manufactured by Xiamen
Innovax Co. Ltd., Cervarix™, manufactured by GlaxoSmithKline Biologicals, and Walrinvax®, manufactured by
Yuxi Zerum Biotechnology Co., Ltd.), one quadrivalent product (Gardasil®, manufactured by Merck Vaccines),
and one nonavalent product (Gardasil-9®, manufactured by Merck Vaccines). One quadrivalent product
(Cervavac®) is nationally licensed.

The primary objective of this document is to provide comprehensive information on HPV vaccine products,
including scientific evidence, vaccine pricing, presentations, cold chain and storage requirements and more.
This information enables countries to compare different HPV vaccine products and make informed decisions
regarding the inclusion of HPV vaccine in their national immunization programmes.

Development
A review was conducted with reference to the latest WHO position paper on HPV vaccines (2) which was
published in December 2022 and already contains a compilation of scientific evidence on HPV vaccine
efficacy, effectiveness and safety. The methods followed by SAGE and the processes for preparation of
vaccine position papers are described at: https://www.who.int/publications/m/item/who-position-paper-
process. A thorough manual search was also conducted to identify recently generated evidence, and the
original publications cited in the WHO position paper were revisited to verify the scientific evidence.
Additionally, product information was collected from publicly available sources.

The final draft was subjected to peer review which involved rigorous scrutiny of scientific evidence and
alignment with the requirements of countries. While it represents an expert summary, this paper is not a
formal WHO recommendation or guideline. Those contributing to the development of this document have
completed the WHO Declaration of Interests for WHO Experts and have been found to have no conflicts of
interest in the area of HPV vaccines.

1
WHO position on HPV vaccines
The 2022 WHO position paper presents the current policy recommendations for HPV vaccines in prevention
of HPV-related disease in children aged 9 years or older, with the priority purpose of preventing cervical
cancer. Cervical cancer accounts for 82% of all HPV-related cancers in 2018 (3). The 2020 WHO global strategy
to accelerate the elimination of cervical cancer as a public health problem recommends that HPV vaccines
should be included in all national immunization programmes and should reach 90% of girls of 15 years of age
by 2030 (4). The HPV position paper does not express a preference between prequalified HPV products and
states the following:

• All currently licensed bivalent, quadrivalent and nonavalent HPV vaccines have excellent safety profiles
and offer comparable immunogenicity, efficacy and effectiveness for the prevention of cervical
precancer and cancer, which are mainly caused by HPV types 16 and 18.
• Most HPV vaccines are licensed for use in females and males. Currently, Cecolin® and Walrinvax® are
only licensed for use in females.
• The choice of HPV vaccine should be based on an assessment of locally-relevant data and on a number
of considerations, including the scale of the HPV-associated public-health problem (cervical cancer,
other HPV-associated cancers, anogenital warts), the population for which the vaccine has been
approved, product characteristics (including single-dose efficacy if the single-dose schedule option is
being considered), price and programme considerations.

Vaccine characteristics
• All HPV vaccines are produced by using recombinant DNA and cell-culture technology. They do not
contain live biological products or viral DNA and are therefore non-infectious. HPV vaccines are prepared
from the L1 structural protein of HPV in the form of virus-like particles (VLPs) 1, using different expression
systems (producer cells). HPV vaccine products contain different adjuvants and do not contain
preservatives or antibiotics. They are administered by intramuscular injection.
• When considering the composition of the four prequalified HPV vaccine products, there is a key
difference in the number and selection of VLPs/HPV types included in the products. The qualitative
differences in composition of the currently prequalified HPV vaccines are included in Table 1, and those
of HPV vaccines currently under review for WHO prequalification are shown in Table 2.

1HPV type-specific empty shells named virus-like particles (VLPs) self-assemble spontaneously from pentamers of the L1 major
capsid protein.
2
Table 1. Characteristics and qualitative composition of prequalified HPV vaccines (5)

Vaccine Bivalent Quadrivalent Nonavalent

Trade name Cecolin® Cervarix™ Walrinvax® Gardasil® Gardasil-9®

Walvax
Xiamen Innovax GlaxoSmithKline
Manufacturer Biotechnology Merck Vaccines Merck Vaccines
Biotech Co. Ltd. Biologicals SA
Co. Ltd.

Date of WHO 14 October 08 July 02 August 20 May 09 February

prequalification 2021 2009 2024 2009 2018

HPV 16, HPV 18,

HPV 16
HPV 31, HPV 33,
Antigens HPV 16 HPV 16 HPV 16 HPV 18
HPV 45, HPV 52,
(VLP types) HPV 18 HPV 18 HPV 18 HPV 6*
HPV 58,
HPV 11*
HPV 6*, HPV 11*

AS04
(Aluminium Aluminium Aluminium
Aluminium hydroxide and 3- Aluminium hydroxy- hydroxy-
Adjuvant
hydroxide deacylated phosphate phosphate phosphate
monophosphoryl Sulfate Sulfate
lipid A)

Expression Baculovirus Saccharomyces Saccharomyces

system/ Escherichia coli derived from cerevisiae cerevisiae
producer cells
Pichia pastoris
Trichoplusia ni (baker’s yeast) (baker’s yeast)

*HPV types considered non-oncogenic cause approximately 90% of genital warts (6).

3
Table 2. Characteristics and qualitative composition of HPV vaccines currently nationally licensed
(not WHO-prequalified)

Vaccine Quadrivalent

Trade name Cervavac®

Manufacturer Serum Institute of India Pvt. Ltd. (SII)

WHO prequalification status Not submitted

HPV 16 HPV 6*
Antigens (VLP types)
HPV 18 HPV 11*
Adjuvant Aluminium hydroxide
Expression system/ producer cells Hansenula

Vaccine safety
• The safety of HPV vaccines has been reviewed as part of the WHO prequalification process and by the
Global Advisory Committee on Vaccine Safety (GACVS). No safety concerns have been identified (7).
• Post-marketing surveillance has detected no serious safety issues to date except rare hypersensitivity
reports including anaphylaxis. Data from all sources continue to be reassuring regarding the safety
profile of HPV vaccines currently in global use. A summary of local and systemic reactions following
vaccination is included in Table 3.
• A systematic review of studies on the safety of HPV vaccines found little-to-no difference among
recipients of bivalent, quadrivalent and nonavalent HPV vaccines with regard to serious adverse events
or new-onset chronic disease, including new-onset autoimmune disease (8).
• A well-conducted population-based study on post-marketing safety surveillance showed no association
between HPV vaccine and new-onset chronic conditions, including autoimmune disease, after
vaccination (9). Data are reassuring that HPV vaccine does not increase risk of Guillain-Barré syndrome,
Bell’s palsy, complex regional pain syndrome (CRPS), or postural orthostatic tachycardia syndrome
(POTS). No association was found between HPV vaccination and infertility.

4
Table 3. Local and systemic adverse events following HPV vaccination

Vaccine Bivalent Quadrivalent Nonavalent

Trade name Cecolin® Cervarix™ Gardasil® Gardasil-9®
Overall reported: Injection site pain (35–88%), redness (5–40%),
swelling (4–35%), severe pain* (6%)
Local
Slightly more likely to report
reactions (8) May result in more local reactions than
pain and swelling than
quadrivalent
quadrivalent
Overall reported events generally mild and self-limiting: headache, dizziness, myalgia,
Systemic arthralgia, gastrointestinal symptoms (nausea, vomiting, abdominal pain)
reactions (9) 49% 69% 55%
Rare: hypersensitivity reactions including anaphylaxis
Post-vaccination syncope and immunization stress-related responses have been observed
Special but can be minimized with appropriate preparation (10). To avoid injury from fainting,
considerations vaccine recipients should be seated and observed for at least 15 minutes after administration
of HPV vaccine.
*Spontaneous pain or pain preventing normal activities.

Contraindications, precautions and use in pregnancy

• Contraindications: known history of severe allergic reaction to any component of HPV vaccine, or severe
allergic reaction after the first dose of HPV vaccine.
• Precautions: to prevent syncope and/or injury from fainting, vaccine recipients should be seated and
observed for at least 15 minutes following administration of HPV vaccine.
• In the absence of well-controlled studies in pregnant women, vaccination of pregnant women is not
recommended. Pregnancy testing is not necessary before vaccination.
• Inadvertent vaccination during pregnancy is not an indication for pregnancy termination.
• If pregnancy occurs following the first dose of vaccination, the subsequent doses, if applicable, should
be delayed until after pregnancy.

5
Vaccine immunogenicity, efficacy and effectiveness
Immunogenicity
• HPV vaccines are highly immunogenic; seropositivity after vaccination is close to 100%. Antibody titres
are higher with younger age at vaccination2. The serological response to vaccine is much stronger than
the response after natural infection.
• The high HPV vaccine efficacy seen in clinical trials to date has precluded identification of a minimum
protective antibody titre.
• Systematic reviews and one randomized controlled trial have shown seropositivity among subjects who
received one dose of HPV vaccine to be non-inferior to that after two or more doses (2, 11).

Efficacy
• For the initial licensure and three-dose schedule, all HPV vaccines have been found to have high efficacy
in an HPV-naïve population in studies that used HPV disease endpoints – i.e. cervical intraepithelial
neoplasia grade 2 or worse (CIN2+), adenocarcinoma in situ (AIS), and high-grade, vulvar and vaginal
lesions – approaching or equalling 100% (12, 13, 14).
• Subsequent studies evaluating two doses in young people aged 9–14 years versus three doses in 15–26-
year-olds (prompted by post-hoc analyses of trials in which not all subjects completed a three-dose
schedule) showed non-inferiority in seroconversion and geometric mean titres in a two-dose schedule
group (15).
• Several studies have shown high efficacy against HPV persistent infection of a single-dose vaccination
schedule comparable to a multi-dose schedule (2, 16).

Effectiveness
• Effectiveness data from post-licensure studies involving more than 60 million individuals show that the
prevalence of HPV 16 and HPV 18 decreased significantly – by 83% among girls aged 13–19 years and by
66% among women aged 20–24 years – after 5–8 years of vaccination programme (17). There is evidence
of indirect protection of unvaccinated females through herd protection effects (18).
• Data for bivalent Cervarix™ vaccine from one population study showed 86% effectiveness against CIN3+
for females vaccinated at 12–13 years of age, and 51% for those vaccinated at the age of 17 years (19).
Quadrivalent Gardasil® data using demographic and health register to follow over 1 million females aged
10–30 years show 88% lower risk against invasive cervical cancer for those vaccinated before 17 years
of age compared with those who had never been vaccinated (20). An observational study using
population-based cancer registry data for women up to 30 years of age shows that the introduction of
bivalent Cervarix™ in the national immunization programme resulted in near-elimination of cervical
cancer among women who were vaccinated at 12–13 years of age (21).
• In several countries, substantial decreases in cases of genital warts have occurred following the
introduction of quadrivalent HPV vaccine in the national immunization programme, with reductions
observed in unvaccinated young men in settings with female-only programmes, indicating herd
protection.
• Vaccine-induced HPV type replacement is deemed unlikely although it is still too early to preclude it.

2The age extension of original licensure of HPV vaccines to pre-adolescent and adolescent girls and boys – in whom efficacy trials
were not deemed feasible because of ethical considerations – was granted on the basis of immunobridging studies demonstrating
non-inferiority.
6
Table 4 summarizes information on immunogenicity and efficacy for multi and single-dose schedules.

Table 4. Immunogenicity and efficacy of prequalified HPV vaccines

Vaccine Bivalent Quadrivalent Nonavalent

Trade name Cecolin® Cervarix™ Walrinvax® Gardasil® Gardasil-9®

Immunogenicity
All highly immunogenic (minimum antibody titre for protection not established)
97.7% (95%CI Little or no
Efficacy 86.2–99.9); 98% (95%CI difference
81% (95%CI
persistent 93–100, for compared to
53–94, for
(studies using infection >6 79% (95%CI 23- CIN2+) (24) quadrivalent
CIN2+) (22)
disease endpoints months) 96) for CIN2+ Gardasil® for
in naïve population, 95.3% (95%CI (21) >90% types targeted by
93% (95%CI
except for 70.7–99.9; (for vulvar both vaccines,
79–99, for
Cecolin®) persistent and vaginal 96.7% for 5
CIN3+) (23)
infection >12 lesions) (23) additional types
months) (5) (5)
Availability of 1- Efficacy inferred
Immunobridging Efficacy data
dose efficacy or through Efficacy data Efficacy data
study planned available
immunobridging 3 immunobridging available (26) available3
(27)
data (25)

3 Definition: GMT levels at 6- and 24-months non-inferior to a product with 1-dose efficacy data
7
Cross-protection
• Data suggest that bivalent and quadrivalent HPV vaccines provide partial cross-protection against HPV
types not included in the vaccine. More consistent and higher cross-protection against prevalent
infection with HPV types 31, 33 and 45 has been observed in countries that introduced bivalent
Cervarix™ vaccine than in countries using quadrivalent Gardasil®. A review concluded that, compared to
direct protection against HPV types included in the vaccines, cross-protection is inconsistent and wanes
over time (28). The extent of cross-protection for Cecolin®, Walrinvax® and Gardasil-9® is not yet known.

Duration of protection
• With a multi-dose schedule, antibody titres remain high for at least 12 years for the bivalent Cervarix™
and quadrivalent Gardasil® vaccines, and at least 6 years for the more recently licensed Gardasil-9®
vaccine. For a single-dose schedule, antibody titres have shown to be stable for at least 10 years (15).
• In a post-hoc analysis comparing one-, two- and three-dose schedules, vaccine efficacy was high (>90%)
against HPV 16/18 for at least 10 years post-vaccination for all schedules.
• There is no evidence to suggest that a booster dose is needed after primary HPV vaccination.

Programmatic considerations
• Several programmatic characteristics are similar or identical across the HPV vaccine products (e.g.
administration, formulation, storage temperature, vaccine vial monitor, wastage rate).
• Other important factors – such as presentation, CTC indications, cold chain and storage requirements,
doses per container, and price – differ by product and may require additional planning for countries
choosing to switch or to incorporate multiple products (Table 5).
• The primary target population for HPV vaccination is girls aged 9–14 years. Secondary target populations
such as females ≥15 years of age, boys, older males or men who have sex with men, are recommended
to be vaccinated only if this is feasible and affordable. Not all currently available products are licensed
for boys.
• Supply availability and cold chain implications should be considered when planning catch-up vaccination
of multi-age cohorts up to 18 years of age at the time of introduction.
• Training of immunization staff is required for use of all HPV vaccine products prior to introduction,
including in situations where the correct application of the multi-dose vial policy should be undertaken
before switching to a product with 2-dose vial presentation.

Presentation, storage requirements and packaging details for prequalified HPV vaccines are included in Table
5.

8
Table 5. Storage and packaging characteristics of prequalified HPV vaccines

Vaccine Bivalent Quadrivalent Nonavalent

Trade name Cecolin® Cervarix™ Walrinvax® Gardasil® Gardasil-9®

Liquid, ready to
Liquid, ready Liquid, ready to
use
Presentation to use use Liquid, ready to use
1- and 2-**dose
* and dosage 1-dose vial 1-dose vial 1-dose vial (0.5 ml/dose)
vial
(0.5ml/dose) (0.5ml/dose)
(0.5 ml/dose)
Vaccine vial
Type 14 Type 30 Type 14 Type 30 Not included
monitor

Storage
At +2 to +8 °C: At +2 to +8 °C: At +2 to +8 °C: At +2 to +8 °C:
temperature
36 months 60 months 24 months 36 months
and shelf-life
From +8 to +25
Stability and °C: From +8 to +40 °C: 4 days (CTC)
-
CTC*** 3 days; from +25 - From +8 to +42 °C: 3 days (CTC)
to +37 °C: 1 day

Cold chain Carton Carton containing: Carton Carton Carton containing:

volume/dose containing: 1 vial – 28.8 cm3 containing: containing: 10 vials, supplied by
(secondary 10 vials – 14.29 10 vials – 5.7 cm3 20 vials – 11.8 1 vial – 75 cm3 a) UNICEF – 18.4 cm3
packaging) cm3 100 vials – 4.8 cm3 cm3 10 vials – 15 cm3 b) PAHO – 15.11 cm3

*Pre-filled single-dose syringes are also commercially available for Cervarix and Gardasil HPV vaccines.
**Any unused vaccine in opened 2-dose vials should be discarded six hours after opening or at the end of the
immunization session, whichever comes first (29).
*** Controlled temperature chain (30)

Two-dose schedule
• Can be used from 9 years of age until the maximum age for which the products are licensed with a
suggested interval of 12 months for programmatic and efficiency reasons.
• Minimum interval between doses: 6 months.
• There is no maximum interval between doses; if programmatically opportune, longer intervals up to 3
or 5 years can be considered.

Alternative, single-dose schedule

• Can be used in females and males aged 9–20 years.
• Given the current evidence of comparable efficacy and duration of protection to a two-dose schedule, a
one-dose schedule may offer programme advantages, be more efficient and affordable, and contribute
to improved coverage.

9
• From a public health perspective, the single-dose schedule can offer substantial benefits that outweigh
the potential risk of lower levels of protection if efficacy wanes 4 over time.

Schedule for immunocompromised persons

• Multi-dose schedule is recommended for immunocompromised or HIV-infected persons (regardless of
age or antiretroviral therapy status):
o at least two doses with a minimum interval of 6 months between the first and the second dose
(0, 6);
o where possible, three doses with a 0, 1–2, 6 months dosing schedule.

Interchangeability
• The same HPV vaccine product should be used in multi-dose vaccination schedules.
• If the product used for the prior dose(s) is unknown or unavailable, any HPV vaccine can be
administered to complete the recommended schedule.
• Data are available on safety and immunogenicity of a mixed schedule combining Gardasil-9® and
Cervarix™(2).

Co-administration with other vaccines

• HPV vaccines can be co-administered with other vaccines (including live vaccines) at the same visit,
using a separate syringe at a different anatomical site (2).

Cost and financial considerations

• HPV vaccine pricing varies by product, presentation, procurement mechanism and country income
group. The median prices for self-procuring middle-income countries (MIC) and high-income countries
(HIC) are significantly higher than the prices of Gavi and the PAHO Revolving Fund.
• In 2021, the MIC median price for quadrivalent HPV vaccine was US$ 39 per dose, while the HIC median
price for bivalent HPV vaccine was US$ 27 and for nonavalent vaccine was US$ 101 (31). Figure 1 below
includes reported price per dose of HPV vaccine by procurement method and income group according
to MI4A purchase data (32).
• Indicative current Gavi prices (33) for HPV vaccines that can be used for budgeting purposes are:
US$ 2.90 per dose for Cecolin®, US$ 5.18 per dose for Cervarix™, and US$ 4.50 per dose for quadrivalent
Gardasil®.
• The WHO Cervical Cancer Prevention and Control Costing tool (C4P) on HPV vaccine has been developed
to support countries to plan for introducing HPV vaccine into an existing immunization programme (34).
There is a dedicated costing tool for calculating the cost of switching products (35).

4 There is no current evidence of waning efficacy over time.

10
• Several studies indicate that, at current vaccine prices and recommended schedules, girls-only
vaccination compared with no vaccination is cost-effective, even when no cross-protection or herd
protection is assumed (36). To assess cost-effectiveness in the national context, the PRIME tool can be
used (37).

Figure 1. Price per dose HPV vaccines by procurement methods and income group (Source: WHO HPV
Global Market Study, April, 2022)

Median values in bold.

Source: 2021 MI4A Purchase Data (country-reported).
Note: Reduction in Gavi/UNICEF price is the result of new products being available. Gavi/UNICEF will pay this price when
countries elect to introduce the relevant product into their national immunization systems.
PAHO RF= Pan American Health Organization Revolving Fund

Availability and supply

• WHO monitors the global HPV vaccine market and publishes regular updates. According to the latest
report (2022) (38) the global supply is expected to improve and reach a healthy situation in the mid-term
(2024-2026). Currently, given a limited buffer, careful phasing of multi-age cohort campaigns and
countries’ willingness to use any of the available HPV vaccines, are the most critical elements for
ensuring that all countries can access supply.

11
• Widespread adoption of (off-label) single-dose schedule can lead to improvement of the supply–demand
balance in the short term but may have an impact on the sustainability of the HPV market in the medium
and long term.
• All manufacturers require a six-month lead time from purchase order to in-country delivery.

Prioritization of new vaccine introduction decisions

The WHO CAPACITI tool (39) is available to support standardized country decision-making and comparison
of multiple product choice options for introduction, product switch, or changes of schedule. The tool allows
for evidence and different stakeholder views to be combined in order to come to a recommendation and
document both processes and outcomes.

Inclusion of HPV vaccine into the National Immunization Strategy

Countries may consider the introduction or switch of HPV vaccine products as part of the prioritization
process and in the broader context of immunization planning within the National Immunization Strategy
(NIS) (40). The NIS is designed for better integration of immunization with other health interventions,
universal health coverage targets and national planning cycles and focuses on long-term goals with
intermediate objectives and prioritized strategies.

12
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