Prophylactic HPV vaccine microarray patch: Target product profile - Draft June 2020
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Prophylactic HPV vaccine microarray patch: Target product profile Draft June 2020
Mailing Address PO Box 900922 Seattle, WA 98109 USA Street Address 2201 Westlake Avenue Suite 200 Seattle, WA 98121 USA www.path.org Copyright © 2020, PATH. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-sa/4.0/. All other rights reserved. Suggested citation: PATH. Prophylactic HPV Vaccine Microarray Patch: Target Product Profile. Seattle: PATH; 2020. Cover photo: PATH
Contents
ACKNOWLEDGMENTS ..............................................................................................................................IV
ABBREVIATIONS ........................................................................................................................................V
BACKGROUND ............................................................................................................................................ 6
TARGET PRODUCT PROFILE .................................................................................................................. 13
1. Indication.......................................................................................................................................... 13
2. Dosage and administration ............................................................................................................ 17
3. Safety and efficacy .......................................................................................................................... 20
4. MAP application and delivery ........................................................................................................ 23
5. Storage, handling, and distribution ............................................................................................... 27
6. Cost and cost-effectiveness........................................................................................................... 31
REFERENCES ............................................................................................................................................ 33
iiiDRAFT June 2020
Acknowledgments
The PATH Center of Excellence for Microarray Patch (MAP) Technology would like to thank the
many individuals involved in the development of this draft target product profile (TPP) for a
prophylactic HPV vaccine MAP. These individuals represent a broad range of backgrounds and
expertise including HPV immunology, vaccine development, clinical trials, microarray patch
technology, vaccine delivery, and vaccine manufacturing. The TPP was developed through
conducting background research on the landscape of HPV vaccination and MAP development.
Specific attributes were then refined through consultation with key stakeholders.
PATH staff that contributed to the drafting and review of this document include Niranjan Bhat,
Ben Creelman, Jennifer Foster, Collrane Frivold, Courtney Jarrahian, Scott LaMontagne,
Kristen Lewis, Mercy Mvundura, Manjari Quintanar Solares, and Darin Zehrung. We would also
like to thank the following individuals who provided comments on the document to date: Jon
Abramson (Wake Forest School of Medicine); Brian Atuhaire (World Health Organization),
Akhilesh Bhambhani (Merck), Paul Bloem (World Health Organization), Jeff Blue (Merck), Brian
Meyer (Merck), Angus Forster (Vaxxas), Jim Janimak (GSK), Ian Frazer (University of
Queensland), Birgitte Giersing (World Health Organization), Tracey Goodman (World Health
Organization), Mateusz Hasso-Agopsowicz (World Health Organization), Arunima Khanduri
(Gavi), Anissa Sidibe (Gavi), and Carole Tevi-Benissan (World Health Organization).
This version of the TPP serves as the first draft broadly distributed for public consultation.
Please send any feedback or comments on the document to maps@path.org. The TPP will
serve as a living document that will evolve over time as new data are generated.
ivDRAFT June 2020
Abbreviations
CTC controlled temperature chain
HIC high-income country
HPV human papillomavirus
IM intramuscular
LMIC low- and middle-income country
MAP microarray patch
TPP target product profile
VVM vaccine vial monitor
WHO World Health Organization
vDRAFT June 2020 Background Objective The objective of this target product profile (TPP) is to describe key attributes—minimal and optimal targets—for microarray patch (MAP) delivery of prophylactic human papillomavirus (HPV) vaccines. MAPs, also known as microneedle patches, consist of hundreds or thousands of microscopic projections that deliver dry vaccine or drug into the skin. They are applied to the body and projections penetrate the top layer of the skin. Some platforms require an applicator for delivery (integrated or separate). Administration may be perceived as less painful than an injection since microprojections are shorter than a needle and often do not reach dermal pain receptors. Wear times range from a few seconds to hours to release their payload, depending on their design. Development of prophylactic HPV MAPs is currently in early-stage preclinical development.a This TPP includes considerations for dissolving and solid-coated MAP subtypes. Although the goal of PATH’s MAP Center of Excellence is focused on advancing the MAP technology platform for high-priority needs in low- and middle-income countries (LMICs), a product with a dual market is more sustainable and could reduce costs in LMIC markets. Therefore, this TPP describes a global product driven by the needs of LMICs that would also benefit users in high- income countries (HICs). Ideally, an HPV MAP product could be suitable for both markets with minimal differences. Key targets that would differ between LMIC and HIC contexts are defined. Parameters that will be critical for the success of using a MAP to deliver a prophylactic HPV vaccine include the intended use case, schedule, breadth of protection, and use of adjuvants. The TPP will serve as a living document that will benefit from stakeholder input and evolve over time as new data are generated. HPV overview There are more than 100 identified HPV genotypes that infect human epithelium. Approximately 14 HPV types are classified as ‘high risk’ or oncogenic and cause low-grade cervical abnormalities, cancer precursors, and genital and anal cancers (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68). Four additional types (26, 53, 73, 82) are considered probable high-risk types based on epidemiologic classification. HPV infection causes cervical cancer, which is the fourth most common cancer in women. It is also linked to a proportion of cancers of the anus, vulva, vagina, penis, oropharynx, and head/neck. Other types of HPV can cause non-malignant conditions such as genital warts and respiratory papillomatosis. An estimated 570,000 women worldwide develop cervical cancer and 300,000 die annually of this disease, which can be prevented by vaccination or early detection and treatment of precancerous lesions.1 Cervical cancer prevention programs focus their efforts on vaccinating young girls, and screening is recommended for all women. Approximately 85% of the global burden falls on women in lower-income countries, and this proportion has been increasing. As of 2017, more than 270 million HPV vaccine doses have been distributed globally.2 Gavi, the a This TPP focuses on MAP delivery of a prophylactic HPV vaccine in order to expand access to prophylactic HPV vaccination through targeting healthy girls, which could have a larger impact on the cervical cancer burden compared to targeting women who are being treated clinically for cancer. However, delivery of a therapeutic HPV vaccine using a MAP could be technically feasible. Learnings from this TPP could be applied to a therapeutic HPV vaccine MAP.
DRAFT June 2020
Vaccine Alliance (Gavi) estimates that if they can vaccinate 14 million girls by 2020 then
300,000 cervical cancer deaths would be averted in this cohort.b,3
In 2018, the World Health Organization (WHO) issued a call to action toward global cervical
cancer elimination through introduction and high coverage of HPV vaccination in all countries.4
WHO’s draft global strategy toward elimination of cervical cancer was also presented to the
World Health Assembly in May 2020, which aims to reduce the incidence rate to less than 4
cases per 100,000 women by 2030. The strategy outlines three targets to achieve elimination,
known as the 90-70-90 targets: (1) 90% coverage of HPV vaccination of girls (by age 15);
(2) 70% coverage of screening (70% of women are screened with high-performance tests by the
ages of 35 and 45 years) and 90% treatment of precancerous lesions; and (3) management of
90% of invasive cancer cases. Modeling suggests that achieving the 90-70-90 targets by 2030
in LMICs could avert approximately 2 million deaths by 2040 and 62 million by 2120.5
Current presentation
Four prophylactic HPV vaccines are commercially available, which are subunit vaccines
consisting of virus-like particles formed from the L1 capsid protein (see Table 1). Three of these
vaccines, produced by Merck and GSK, are WHO prequalified. Another vaccine produced by
Xiamen Innovax Biotech Co. Limited (Innovax) is licensed in China. The vaccine is currently
only available for local markets but is expected to be WHO prequalified in 2021. Injectable
therapeutic HPV vaccines are also in development. However, they are not the focus of this TPP.
Table 1. HPV vaccine overview.
Cervarix6 Gardasil7 Gardasil 98 Cecolin9
Manufacturer GSK Merck Merck Innovax
Valency Bivalent Quadrivalent Nonavalent Bivalent
HPV types 16, 18 16, 18, 6, 11 16, 18, 6, 11, 31, 33, 16, 18
45, 52, 58
Adjuvant AS04 Aluminum Aluminum Aluminum hydroxide
hydroxyphosphate hydroxyphosphate
sulfate sulfate
Doses per 1, 2 1 1 1
container
Formulation Liquid Liquid Liquid Liquid
Route Intramuscular Intramuscular Intramuscular Intramuscular
Currently, only the bivalent and quadrivalent vaccine are available through UNICEF and in Gavi-
supported countries. The use of Merck’s nonavalent vaccine is currently limited to HIC markets,
and countries have not procured any nonavalent vaccine through UNICEF to date. After
Innovax’s vaccine is WHO prequalified, it is expected to be available through UNICEF and in
Gavi-supported countries.
Merck’s quadrivalent vaccine is also licensed for use in a controlled temperature chain (CTC) for
up to three days just prior to vaccine administration.8 To comply with WHO’s current definition of
b
Gavi’s original target was to vaccinate 40 million girls by 2020. However, due to surging global demand and vaccine supply shortages, the scope of
this goal was been reduced to reaching an estimated 14 million girls by 2020.
7DRAFT June 2020
CTC, a vaccine must be sufficiently heat stable at the end of its shelf life to allow exposure at
ambient temperatures up to at least 40°C for a minimum of three days just prior to
administration.
Efficacy and effectiveness
The currently available HPV vaccines are highly immunogenic (see Table 2). The bivalent and
quadrivalent HPV vaccines have been available for over a decade and have been shown to be
highly effective10 and safe.11 All commercially available HPV vaccines are highly effective at
preventing infection against virus types 16 and 18, which are responsible for approximately 70%
of cervical cancer cases globally. There is some evidence that the bivalent vaccines (Cervarix
and Cecolin) provide some level of cross-protection.
The quadrivalent vaccine protects against anogenital warts, a common genital disease
exclusively caused by infection with HPV types 6 and 11,12 and the newer nonavalent
formulation also provides protection against five additional oncogenic types (31, 33, 45, 52, 58).
These five types, combined with types 16 and 18, are cumulatively responsible for 90% of the
global cervical cancer burden (see Figure 1). Some regional differences in the HPV genotype
distribution have also been reported.13
Table 2. HPV vaccine efficacy and effectiveness.
Cervarix Gardasil Gardasil 9 Cecolin
Parameters Bivalent (16, 18) Quadrivalent (16, Nonavalent (16, 18, Bivalent (16, 18)
18, 6, 11) 6, 11, 31, 33, 45, 52,
58)
Indication HPV-related cancer HPV-related cancer; HPV-related cancer; HPV-related cancer
anogenital warts anogenital warts
Efficacy >95% efficacy >95% efficacy >95% efficacy >95% efficacy
against vaccine type against vaccine type against combined against vaccine type
endpoints among endpoints among 31, 33, 45, 52, 58 endpoints among
HPV-naïve HPV-naïve endpoints among HPV-naïve
populations14 populations15 HPV-naïve populations17
populations16
Cross- protection More consistent and higher cross-protective No cross-protection Some cross-
efficacy against types 31/33/45 has been reported16 protective efficacy
observed for Cervarix than Gardasil14,18 against types
31/33/45, but not
statistically
significant17
Years of duration 11 years19 10 years12 5.6 years12 5.5 years9
of protection
evaluated
Effectiveness 86% (CI 75%–92%) 57% (CI 47%–65%) No data from No data from
against CIN3+ for against CIN3/AIS for post-licensure post-licensure
women vaccinated women eligible to be effectiveness studies effectiveness studies
at age 12–13; 51% vaccinated at age 15
(CI 28%–66%) for or younger21
women vaccinated
at age 1720
Abbreviations: AIS, adenocarcinoma in situ; CI, confidence interval; CIN, cervical intraepithelial neoplasia; HPV,
human papillomavirus.
Adapted from Gavi-supported HPV vaccines profiles to support country decision-making.9
8DRAFT June 2020
Figure 1. Global contribution of HPV genotypes to cervical cancer.
Adapted from de Sanjose S, Quint WG, Alemany L, et al. Human papillomavirus genotype attribution in invasive
cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncology. 2010;11:1048–1056.
Vaccine schedule
All three WHO-prequalified HPV vaccines were originally licensed and marketed using a three-
dose vaccination schedule. However, a two-dose schedule for girls aged 9–14 years was
subsequently approved for all the vaccines, based on immune-bridging data. Approval of the
two-dose indication was based on demonstration of non-inferiority of the immune response
when compared to young adult women in whom efficacy had been proven.
A two-dose schedule in girls aged 9–14 years is currently recommended by WHO, with the
second dose given at least 5 months from the first and ideally within 12–15 months.c Evidence
is also being generated to support further schedule reductions from a two-dose to a single-dose
schedule, which may be recommended by the time an HPV MAP could come to market.22 For
individuals 15 years of age and older and immunocompromised individuals, three doses are still
recommended. Although global recommendations and HPV vaccine programs in LMICs have
focused on vaccinating girls, vaccination of boys is included in the national immunization
schedule in some countries that can afford the extra costs associated with supply and delivery
to boys. Vaccination of boys is growing and may continue to do so once supply constraints have
eased and vaccine prices decrease.
During national HPV vaccine introduction, WHO currently recommends vaccinating multiple age
cohorts of girls aged 9–18 years to hasten early impacts on infections through catch-up
vaccinations. Focusing on girls 9–14 years of age is considered most cost-effective due to the
increased cost of the three-dose regimen required for individuals 15–18 years of age. This
c
However, in situations where countries are facing a supply constraint, they could consider an extended schedule of up to 3 years for dose 2. This
applies only to countries currently vaccinating and is an off-license recommendation, as there are no immunobridging or efficacy data for this schedule
in adolescents (or in adult populations).
9DRAFT June 2020
vaccine strategy results in faster and greater population impact than vaccination of single-age
cohorts through direct protection and herd immunity.12
Delivery strategies
Several common delivery strategies for HPV vaccination are outlined in WHO’s Guide to
Introducing HPV Vaccine into National Immunization Programmes.23 Different delivery
strategies may be used in different parts of a country (i.e., to reach a large proportion of out-of-
school girls) and the strategies may evolve over time as the HPV program transitions from initial
introduction to sustaining delivery.23 WHO reported that in 2018, the primary delivery strategies
were schools (66%), health facilities (24%), and mixed strategy (10%).24 The delivery strategies
under consideration for an HPV MAP are summarized below. For this TPP, self-administration is
also being considered as an alternative delivery scenario. However, the feasibility and logistics
of this scenario require further investigation. The acceptability of self-administration to regulators
and immunization programs also needs to be determined. This delivery scenario would likely be
most suitable for HICs, but may also be appropriate for LMIC contexts.
Table 3. HPV MAP delivery strategies.
Current delivery strategies
Facility-based Vaccination at a health facility where vaccinations are provided along with other health services.
immunization These facilities are available at different levels in the health care delivery system, in both the public
and private sectors, ranging from national-level hospitals to district-level health centers.
School-based School-based immunization is a common delivery strategy for HPV vaccine and facilitates reaching
immunization the target age population of 9–14 years since youth this age congregate in large numbers at
schools due to high enrollment and availability of universal primary school education. School-
based immunization is considered an outreach strategy since the health care worker must leave
their facility to deliver immunization services. In resource-constrained settings, if it is not integrated
with routine outreach visits or regular activities of health workers, school-based vaccination can
pose logistical and financial barriers related to transporting health workers, vaccines, and supplies
to schools; travel time; and per diem costs.
Community- Community-based outreach refers to vaccination outside of a health facility at a fixed or mobile site
based outreach (other than schools, described above). Outreach sessions can be organized at convenient
locations such as markets, community gathering places, schools, and churches. For HPV vaccine,
an outreach delivery strategy can be useful in settings where a large proportion of the population
lives in areas with limited access to health facilities and/or there is low school attendance for
target-aged girls.
Fixed-site HPV can be delivered through a large-scale campaign. Campaigns may be beneficial when
campaign introducing HPV, especially when targeting multiple age cohorts. However, the timing of campaign
opportunities that could include HPV vaccination is often insufficient to ensure delivery on a routine
basis, year after year, of HPV vaccine. Some countries have leveraged existing campaign days
(i.e., Child Health Days/Weeks, measles-rubella or tetanus toxoid supplemental immunization
activities, Vaccination Week) and successfully added HPV vaccination.
Alternative delivery strategy potentially enabled by a MAP
Self- Delivery of an HPV MAP through self-administration at the community level. The MAP could be
administration administered in a home setting with appropriate instructions/training.
Abbreviations: HPV, human papillomavirus; MAP, microarray patch.
HPV vaccines are currently delivered by trained vaccinators due to the delivery method
(intramuscular [IM] injection with needle and syringe) and the recommendation to monitor for
common non-serious adverse events, especially syncope, and rare serious adverse events and
to document immunization records. However, the 15-minute observation rule is often not
followed during IM delivery and may not be necessary for MAPs. The potential increased safety
and ease of use of the MAP presentation may also enable administration by other user groups
such as community health workers, trained volunteers, teachers, and/or self-administration.
10DRAFT June 2020
HPV demand and market considerations
As of December 2019, 122 countries and territories globally (51.8%) had introduced HPV
vaccine in their national immunization program. However, these countries only represent
approximately 30% of the global target population.25 Recent estimates indicated that 81% and
57% of high- and upper-middle-income countries, respectively, had national immunization
programs that included HPV vaccine. However, only 26% and 23% of low- and lower-middle-
income countries, which have the highest burden of cervical cancer, had introduced the vaccine.
Globally, the percentage of boys vaccinated increased to 10%, which is low due to the limited
number of HICs offering vaccination of boys.24
One barrier to vaccine uptake has been the supply situation. The global HPV supply is expected
to be constrained until at least 2024, assuming the base case supply scenario described in
WHO’s HPV Global Market Study.26 Sizeable increases in supply will be required to meet the
expected increase in demand. Key factors that will impact the supply situation include the
selected vaccination strategies, investment decisions of current manufacturers, and the
development timeline of the vaccine candidates currently in later-stage clinical studies. By the
time an HPV MAP could be available, the HPV supply is expected to be less constrained as
more manufacturers enter the market and scale up production.
HPV pipeline
Several other manufacturers are also developing HPV vaccines. UNICEF is aware of 27 new-
generation HPV vaccine candidates in the pipeline; of these candidates, 60% are in the
discovery or preclinical stage and 40% are in clinical development. 27 Xiamen Innovax’s vaccine
attained licensure by China’s National Medical Products Administration in 2019 and is expected
to be WHO prequalified in 2021. Walvax (China) has completed a phase 3 study.28
CNBG/CDIBP (China) and Serum Institute of India (India) are currently in phase 3 trials.28
These additional manufacturers are anticipated to help increase supply and diversify the market,
and this may reduce vaccine costs. New, lower cost HPV vaccines in the pipeline are likely to
cost US$3.00 or less per dose. UNICEF expects one new manufacturer to supply Gavi from
2021 and one other to enter the market by 2023.27
Cost considerations
Cost is a key reported barrier to HPV vaccine introduction and sustaining HPV programs in low-
resource settings. In 2020, Gavi, through UNICEF, procured the HPV vaccine at US$4.50 or
US$4.60 per dose from the manufacturers.29 Gavi-supported countries then co-finance a portion
of the vaccine’s cost, with the co-financing obligation depending on the country’s annual Gross
National Income per capita (GNI pc).30 For instance, countries in the initial self-financing phase
(i.e., countries with an annual GNI pc less than US$1,005) pay US$0.20 per dose, and countries
in the transition phases pay an increasing share of the vaccine price.31
Fully self-financing countries pay the full vaccine price. The prices offered by manufacturers to
middle-income countries that self-finance their HPV vaccine purchased through UNICEF have
been significantly higher, ranging from US$10.25 to US$31.50 per dose.27 Sustaining the
recurrent costs of HPV vaccination programs is another obstacle for low-resource settings.
Maintaining high coverage beyond initial introduction is a barrier in both LMIC and HIC contexts.
The draft Global Strategy for elimination of cervical cancer has set a target of 90% coverage of
HPV vaccination of girls by 15 years of age by 2030.5 However, very few HICs have maintained
11DRAFT June 2020
70% coverage in the target population. Most countries in Europe in particular, are well below
this threshold.
HPV microarray patch value proposition
For LMIC contexts, delivery of HPV vaccination to adolescents relies heavily on outreach
programs, including school-based vaccination; this differs from early childhood immunizations,
which are typically administered in a health facility. Financial and programmatic barriers to HPV
vaccine uptake have been identified related to outreach, including the increased cost of delivery
(e.g., transportation and per diem costs),32 logistics of outreach activities needed to reach the
target age group,32 and storage and transport of the vaccine to administration sites,33 as well as
the disruption of health services when a trained vaccinator is required to conduct outreach.34
Due to increased ease of use, a MAP presentation could enable delivery by a community health
worker, trained volunteer, or teacher, or through self-administration. If a trained vaccinator is not
required, HPV vaccination could be integrated with the delivery of other health interventions in
schools by non-trained staff such as de-worming programs. A MAP could also improve
thermostability and enable storage in a CTC for an extended time period, which could simplify
the storage and distribution of vaccines delivered in outreach settings and improve access in
remote areas.
For HIC contexts, the key barriers to HPV vaccination are related to acceptability and
community trust, including safety concerns.32,35 An HPV MAP may improve acceptability,
especially among vaccinees, as it is needle-free and could reduce pain after delivery,
needlephobia, and anxiety associated with fainting after injection, which has been reported in
this age group.36 Development of innovations that mitigate pain was also identified as a
research priority in the WHO position paper on reducing pain at the time of vaccination including
interventions suitable for adolescents and that are effective in mass campaigns and school-
based immunization settings.37
The potential HIC market could also increase the value proposition for a commercialization
partner to bring this novel technology to market and help subsidize products targeted at LMIC
markets, assuming HIC and LMIC product attribute needs are sufficiently similar. The global
demand for HPV could increase substantially over the next decade to possibly reach 120 million
doses per year by 2030 when an HPV MAP could potentially come to market. Key drivers that
could increase demand include the global cervical cancer elimination strategy and efforts to
prevent cervical cancer through vaccination, introduction of the vaccines in China and India, and
gender-neutral immunization strategies.27
12DRAFT June 2020
Target product profile
The following section describes minimally acceptable and optimal targets for a prophylactic HPV MAP (dissolving and solid-coated). The
baseline presentation for comparison (as defined in many of the minimally acceptable targets) is the current liquid HPV vaccine delivered
by needle and syringe. The TPP describes an HPV MAP product that would be clinically and programmatically suitable for use informed by
the current development status and understanding of this early-stage technology. Unless otherwise specified, the targets apply to both
LMIC and HIC contexts.
1. Indication
Attribute Minimally acceptable Optimal target Rationale/notes
target
1.1 Indication Prophylactic vaccination Same as minimally • An HPV MAP is intended to be a prophylactic vaccine to prevent HPV
against some types of acceptable target. infection like the current injectable vaccine.
HPV infection, • The use of a MAP presentation is not likely to increase or decrease the
depending on the HPV effectiveness of the vaccine.
types included in the
vaccine formulation (see
below).
1.2 Breadth of LMIC context: The HPV MAP should • A bivalent HPV MAP is considered the minimally acceptable target for
protection The HPV MAP should protect against at least LMIC contexts since types 6 and 11 are not cancer-causing and additional
protect against at least five additional bivalent vaccines are currently in the pipeline.
HPV types 16 and 18 to oncogenic types (31, 33, • Increasing the number of oncogenic types included in the HPV MAP
have comparable 45, 52, 58) to have increases the proportion of the global cervical cancer burden that the
protection to the bivalent comparable protection MAP can prevent. However, incorporating multiple virus-like particle (VLP)
vaccine. to nonavalent vaccine if antigens into a MAP will increase the technical and regulatory complexity
not more. of developing an HPV MAP, raise the cost of clinical development, and
HIC context: impact the price per dose.
The HPV MAP should • Increasing the number of VLPs included in an HPV MAP would also
protect against at least increase the antigen payload that must be incorporated into the MAP,
HPV types 16, 18, 6, which could be a challenge for some MAP designs.
and 11 to have • Broadly protective HPV vaccines based on the L2 protein are also in
comparable protection development and there is some evidence that the bivalent vaccines
to the quadrivalent (Cervarix and Cecolin) offers some cross-protection against HPV types
vaccine. not included in the vaccine.
13DRAFT June 2020
Attribute Minimally acceptable Optimal target Rationale/notes
target
1.3 Target LMIC context: LMIC context: • Currently available HPV vaccines are indicated for the following age
population Girls aged 9–14 years. Individuals aged 9 and groups:
above. o Gardasil (Merck): Individuals aged 9–15 years; females aged 16–26.7
HIC context: o Gardasil 9 (Merck): Individuals aged 9–45.8
Individuals aged 9–26 HIC context: o Cervarix (GSK): Individuals aged 9 and above.6
years. Individuals aged 9 and • Although currently available Gardasil and Gardasil 9 vaccines are
above. licensed for both males and females, some countries focus their
immunization programs on vaccinating girls only. The age of vaccinees
may also vary by national immunization program guidelines.
• In 2018, the FDA approved expanded use of Gardasil to include
individuals 27–45 years of age.38 In 2019, the CDC Advisory Committee
on Immunization Practices (ACIP) recommended “catch-up of HPV
vaccination for all adults through age 26. ACIP did not recommend catch-
up vaccination of adults age 27–45 years, but recognized that some
adults who are not previously vaccinated may be at risk for new HPV
infection and might benefit from vaccination in this age range; therefore,
ACIP recommended shared clinical decision making regarding potential
HPV vaccination for these individuals.”39
• For the prevention of cervical cancer, WHO recommends focusing on
immunizing girls aged 9–14 years, prior to becoming sexually active, as
the primary target population. Achieving high coverage in girls (>80%)
also reduces the risk of HPV infection for boys.12
• WHO recommends vaccination of females aged ≥15 years or males as a
secondary target population; this is recommended only if it is feasible,
affordable, cost-effective, and does not divert resources from vaccination
of the primary target population or from effective cervical cancer
screening programs.12
1.4 Intended For use through current Same delivery • Use of an HPV MAP should integrate into the immunization delivery
use case delivery strategies such strategies as minimally platform established for HPV vaccination, which may vary by country. The
as health facility, school- acceptable target. majority of countries currently deliver HPV vaccines through school-based
based, community programs.
outreach, or campaign With the increased ease • An HPV MAP could increase ease of use and enable delivery by other
by a trained health care of use, the MAP could user groups including community health workers, trained volunteers,
provider. also be delivered by a teachers, and/or self-administration.
community health • The MAP presentation may have the most value for intended use cases
worker, trained outside of a health facility at schools or other outreach locations.
volunteer, teacher, or • Campaign settings would also benefit from the ease of use and speed of
through self- delivery of a MAP presentation including large-scale campaign days,
administration. catch-up campaigns, and campaigns to reach multiple age cohorts.
14DRAFT June 2020
Attribute Minimally acceptable Optimal target Rationale/notes
target
• Currently, WHO recommends that countries with very small and difficult-
to-access populations (i.e., island states) may benefit from campaign
delivery for the injectable HPV vaccine.23 A MAP presentation could also
be beneficial in these settings.
• If delivery of an HPV MAP requires an observation period after
administration, similar to the current injectable formulation, delivery of an
HPV MAP in a home setting may not be suitable. However, it is unknown
whether the same recommendation would apply to an HPV MAP, and the
15-minute observation period is often not followed in practice with needle
and syringe delivery.
• In some countries, particularly HICs, vaccines may also be administered
at pharmacies.
1.5 Target All countries currently Availability and use of • WHO recommends that all countries introduce HPV vaccination.
countries providing HPV vaccines an HPV MAP in all • As of December 2019, 122 countries globally (51.8%) had introduced
with initial launch of countries. HPV vaccine in their national immunization program. However, these
MAP technology in countries only represent approximately 30% of the global target
HICs. population.25
• Recent estimates indicated that 81% and 57% of high- and upper-middle-
income countries had national immunization programs that included HPV
vaccine. However, only 26% and 23% of low- and lower-middle-income
countries, which have the highest burden of cervical cancer, had
introduced the vaccine. Globally, the percentage of boys vaccinated
increased to 10% of countries.24
• Although the programmatic benefits (i.e., increased ease of use, improved
thermostability) of an HPV MAP would have the greatest impact in low-
resource settings where the disease burden of cervical cancer is the
greatest, the cost of an HPV MAP is likely going to restrict uptake since
these markets are more price sensitive. Gavi support will likely impact the
ability of LMICs to switch from an injectable to MAP presentation.
• With a sustainable market, particularly a dual market in HICs, the price of
an HPV MAP could decrease and enable use in LMIC markets.
• HICs and upper-middle income countries, which are less price sensitive,
may be more likely to introduce an HPV MAP if the MAP presentation is
more expensive than the lowest available price from Gavi or UNICEF.
15DRAFT June 2020
Attribute Minimally acceptable Optimal target Rationale/notes
target
1.6 Product LMIC context: Same as minimally • Cervarix, Gardasil, and Gardasil 9 were all approved by the FDA. Cecolin
registration Approval by any acceptable target and was approved by China’s National Medical Products Administration.
path functional NRA as HPV MAP launched with • The EMA is the responsible NRA for the currently WHO-prequalified
defined by WHO, product registration in vaccines.6,7,8
followed by WHO LMICs. • An HPV MAP would be regulated and approved as a novel combination
prequalification. (device/biologic) product and the vaccine manufacturer would likely be the
sponsor for the IND/BLA. In this role, the vaccine manufacturer instead of
HIC context: the MAP developer would lead the discussions with the NRA and take on
Approval by NRA. the regulatory and investment risk.
• It is recommended to engage regulatory authorities early to discuss the
potential regulatory pathway as this could streamline the approval process
of a novel combination product.
• WHO prequalification would be needed for UNICEF procurement of HPV
MAPs. The MAP product should also be programmatically suitable for
low-resource settings, which is part of the WHO prequalification process
to ensure the “suitability of the vaccine for the immunization services
where it is intended to be used.”40
• Experience with similar technologies such as transdermal patches,
intradermal injection devices, or MAPs for other vaccine and drug
applications may be useful for drafting initial regulatory strategies. For
instance, Zosano Pharma submitted a New Drug Application to the FDA
in December 2019 for a migraine treatment MAP (QtryptaTM).41
Nevertheless, regulatory pathways for vaccine MAPs are still untested
and are a new concept for both manufacturers and regulators.
• If the adjuvant is removed from the MAP formulation (see ‘Use of
adjuvants’ attribute below) then additional evidence may be required from
a regulatory perspective to demonstrate non-inferiority.
Abbreviations: ACIP, CDC Advisory Committee on Immunization Practices; BLA, Biologics License Application; CDC, US Centers for Disease Control and Prevention;
EMA, European Medicines Agency; FDA, US Food and Drug Administration; GSK, GlaxoSmithKline; HIC, high-income country; HPV, human papillomavirus; IND,
Investigational New Drug; LMIC, low- and middle-income country; MAP, microarray patch; NRA, national regulatory authority; UNICEF, United Nations Children’s
Fund; WHO, World Health Organization.
16DRAFT June 2020
2. Dosage and administration
Attribute Minimally acceptable Optimal target Rationale/notes
target
2.1 Formulation Formulation containing Same as minimally • The current liquid vaccine formulations are prepared from the purified L1
HPV VLP antigen as the acceptable target. capsid protein that self-assembles to form HPV type-specific empty shells,
active ingredient with or termed virus-like particles (VLPs).12 None of the vaccines contain live
without non-alum biological products or viral DNA, and are therefore non-infectious; they do
adjuvant that is safe for not contain antibiotics or preservative agents.12
skin delivery (see ‘Use • Some other HPV antigens are in the pipeline such as 2A Pharma’s
of adjuvants’ attribute). vaccine, which targets the L2 capsid protein and has portions that are well
conserved across HPV types. In preclinical studies, 2A Pharma’s
Necessary excipients unadjuvanted HPV vaccine candidate provided protection against more
and/or additives (e.g., than 20 HPV types.42
stabilizers, polymer, • An HPV MAP formulation should contain VLPs as the vaccine antigen.
other inactive The number of VLP types included in the formulation will depend on the
ingredients) may be valency of the vaccine (see ‘Breadth of protection’ attribute). The VLPs
added that are currently could be prepared from the L1 capsid protein, similar to currently available
used clinically and vaccines, or from L2 capsid protein.
generally regarded as • The formulation should facilitate dose-sparing (see ‘Dosage’ attribute) and
safe (GRAS) by the improve thermostability (see ‘Heat stability’ attribute) and light sensitivity
FDA. compared to the current presentation.
o HPV vaccine package inserts recommend that the vaccine should be
protected from light.
• The necessary excipients/additives will depend on MAP format (solid-
coated or dissolving), particularly to improve stability and release.
• Concentration of the antigen will be important for both dissolving and
solid-coated microprojections. MAP delivery will require a higher antigen
concentration than the current liquid formulation.
2.2 Use of The HPV MAP includes The HPV MAP is • Merck’s vaccines (quadrivalent and nonavalent) are formulated with an
adjuvants an adjuvant that is able shown not to require an aluminum hydroxyphosphate sulfate adjuvant. 12
to be formulated into the adjuvant. • GSK’s bivalent vaccine is formulated with an AS04 adjuvant.12
MAP and is safe for skin •
Innovax’s bivalent vaccine is formulated with an aluminum hydroxide
delivery. adjuvant.9
• Inclusion of adjuvants currently included in the injectable formulation is
likely to be unacceptable in an HPV MAP because of concerns around
delivering alum to the skin and potential for increased reactogenicity.
• There is a potential opportunity to reduce the adjuvant dose or completely
remove adjuvants from MAP formulations since MAP delivery into the
dermal layer of the skin could improve immunogenicity compared to IM
injection.
17DRAFT June 2020
Attribute Minimally acceptable Optimal target Rationale/notes
target
• Preclinical studies of several MAP systems for other antigens have found
adjuvant-sparing effects. For example, in pregnant mice, an unadjuvanted
tetanus toxoid MAP elicited a stronger immune response compared to
intramuscular injection and protected their offspring from lethal challenge
of tetanus toxin.43 It is unknown whether adjuvant-sparing effects of MAPs
as a technology platform will translate to humans.
• Unadjuvanted HPV MAPs have been successfully formulated and
previously evaluated in non-human primates.44
• Alum is included in the current liquid formulations to improve the stability
of the VLPs. In theory, the VLPs should be stable in a dry MAP
formulation and alum should not be required. However, the impact on
immunogenicity of removing the adjuvant requires further evaluation in
preclinical studies.
• Removal of an adjuvant could impact the duration of protection and
require additional studies to demonstrate non-inferiority and duration of
protection compared to the current presentation.
• Novel adjuvants may be more suitable for MAP delivery, but they will
increase regulatory hurdles.
2.3 Dose A single-dose, single- Same as minimally • The MAP is a combination product that integrates a vaccine delivery
presentation use presentation, acceptable target. device, and the antigen is incorporated into solid-coated or dissolving
composed of an microarray projections.
integrated HPV vaccine
delivery device in which
HPV vaccine is
presented as a solid-
coated or dissolving
microarray format.
2.4 Vaccine The HPV MAP should The HPV MAP should • The recommended MAP vaccine schedule will depend on the schedule
schedule follow a two-dose follow a one-dose that generates a comparable immune response to an IM injection.
(duration, clinic vaccine schedule in vaccine schedule in • In individuals 9–14 years, although the second dose is recommended 5–
visits) individuals 9–14 years of individuals 9–14 years 15 months after the first dose, some off-license recommendations extend
age (0, 5–15 months). of age. this recommendation to up to 3 years. However, there are no empirical
data for this recommendation.
The HPV MAP should The HPV MAP should • A vaccine schedule with fewer doses has cost-saving and programmatic
follow a three-dose follow a two-dose advantages—particularly beneficial in low-resource settings.
vaccine schedule (0, 1– vaccine schedule (0, 5– • Although a single-dose schedule is not currently licensed, evidence is
2, 6 months) in 15 months) in being generated to support further schedule reductions from a two-dose
individuals ≥15 years of individuals ≥15 years of to a single-dose schedule, which may be recommended by the time an
age as well as those age as well as those HPV MAP could come to market.22 HPV MAP development should
younger than 15 years younger than 15 years evaluate the feasibility of a single-dose HPV MAP schedule.
18DRAFT June 2020
Attribute Minimally acceptable Optimal target Rationale/notes
target
who are who are • If the MAP could generate the same potency in older adolescents, young
immunocompromised immunocompromised women, and those younger than 15 years who are immunocompromised
and/or HIV-infected. and/or HIV-infected. and/or HIV-infected then the schedule could shift from three to two doses
in this target population.
The HPV MAP may be The HPV MAP may be • Controlled release technology could potentially be used to increase the
used interchangeably used interchangeably immunogenicity of a single-dose HPV MAP. In this approach, after the
with currently with currently MAP is applied and removed, the formulation is designed to slowly
available HPV vaccines available HPV vaccines release vaccine for prolonged antigen presentation, which can simulate
administered IM. administered IM. prime and boost vaccine doses in a single administration. However, this
approach would increase the technical and regulatory challenges of MAP
development.
• Data are limited on the safety, immunogenicity, or efficacy of using the
currently available liquid HPV vaccines interchangeably. However, studies
are underway to support interchangeability and generate such data. WHO
currently recommends that every effort should be made to administer the
same vaccine for all doses given the different characteristics,
components, and indications of the vaccines.12
2.5 Antigen The antigen content of The antigen content of • Target dosage for the HPV MAP should be the minimum required to give
content an HPV MAP should be an HPV MAP should be a non-inferior immune response to the currently available liquid vaccine
the minimum required to reduced compared to delivered by IM injection, as the antigen content will have a significant
give a non-inferior quantity of antigen impact on MAP cost and production capacity.
immune response to the contained in an IM
currently available liquid injection. Vaccine HPV L1 protein Adjuvant12,17
vaccine delivered by IM components12,17
injection. Cervarix 16 (20 μg); 18 (20 μg) AS04
Gardasil 16 (40 μg); 18 (20 μg); Aluminum
6 (20 μg); 11 (40 μg) hydroxyphosphate
sulfate
Gardasil 9 16 (60 μg); 18 (40 μg); Aluminum
6 (30 μg); 11 (40 μg); hydroxyphosphate
31 (20 μg); 33 (20 μg); sulfate
45 (20 μg); 52 (20 μg); 58
(20 μg)
Cecolin 16 (40 μg); 18 (20 μg) Aluminum
hydroxide
• There is the potential that the MAP may require a reduced dose of antigen
to induce an equivalent immune response due to the immune-enhancing
benefits of MAP delivery. Eliminating the adjuvant could reduce the
feasibility of achieving dose-sparing with a MAP presentation.
19DRAFT June 2020
Attribute Minimally acceptable Optimal target Rationale/notes
target
• Dose-sparing of an unadjuvanted nonavalent HPV MAP was previously
evaluated in non-human primates. In this study, approximately 1/5 of the
IM dose (14 mg) was delivered by a MAP, which resulted in a significantly
lower immune response compared to adjuvanted full-dose HPV vaccine
delivered IM. Although this study did not demonstrate dose-sparing
compared to IM delivery with an alum adjuvant, further optimization of the
formulation, delivered dose, and MAP design could improve the immune
response of an HPV MAP.44
2.6 Route of Product should be Same as minimally • Some patches might deliver primarily intradermally, but others might
administration suitable for delivery to acceptable target. deliver to both the epidermis and dermis. There are insufficient data to
dermis and/or epidermis specify the optimal depth or target tissue within the skin.
at an anatomic site that
is acceptable to users
and immunization
programs.
2.7 Application Site of application Same as minimally • It is recommended that liquid HPV vaccines be delivered IM in the deltoid
site should be accessible acceptable target. region.
and acceptable to the • MAPs in development are being tested on various anatomical sites such
majority of intended as the deltoid, wrist, and forearm.
recipients. • Multiple application sites may be evaluated in clinical studies to ensure
that different anatomical sites do not have an impact on vaccine efficacy.
• In a previous in-country usability study for vaccine MAP delivery in
Ghana, easily accessible sites (lower arm) were preferred for delivery in
adult women over sites that required removal of clothing (upper arm or
back), if administered by a health care provider in a clinic setting. 45
Abbreviations: FDA, US Food and Drug Administration; HPV, human papillomavirus; IM, intramuscular; MAP, microarray patch; VLP, virus-like particle; WHO, World
Health Organization.
3. Safety and efficacy
Attribute Minimally acceptable Optimal target Rationale/notes
target
3.1 Systemic Systemic adverse Minor and severe • Liquid HPV vaccines are considered to be safe. Post-licensure
reactions events should be no systemic adverse surveillance data concerning the safety profiles for each of the currently
more serious and events should be less available HPV vaccines have detected no serious safety issues to date
frequent than those of frequent and less except rare reports of anaphylaxis.2
the current injectable serious compared to the • In pre-licensure clinical trials of the quadrivalent vaccine, pyrexia was the
vaccines.2 only reported adverse event, occurring in >10% of vaccinees and more
20DRAFT June 2020
Attribute Minimally acceptable Optimal target Rationale/notes
target
current injectable frequently than in placebo groups (10.1% and 8.4%, respectively). Other
vaccines. mild system adverse events possibly related to vaccination included
headache, dizziness, myalgia, arthralgia, and gastrointestinal symptoms
(nausea, vomiting, abdominal pain).2 Post-marketing surveillance of HPV
vaccination has documented several cases of syncope in adolescent girls.
The rate of syncope may be higher when HPV vaccine is delivered as
part of a school-based program.2 Cluster vaccination anxiety reactions
associated with HPV vaccination have been observed.12 These reactions
are likely due to the age group and have been suggested to be
psychogenic. As a needle-free presentation, a MAP could potentially
reduce anxiety and fear during HPV vaccination in adolescents.
• The safety of HPV MAPs would need to be established in pre-licensure
safety studies in the target population for whom this product is indicated.
3.2 Local The severity and/or Local reactogenicity is • An HPV MAP has the potential to reduce pain of vaccine administration,
reactions frequency of local similar to or less than IM which is one of the most commonly reported local reactions for this
reactogenicity at the injection. vaccine. Therefore, an HPV MAP has the potential to improve
application site may acceptability and reduce vaccine hesitancy related to fear of pain and
increase with MAP Pain at the application injections.
delivery due to the route site should be less in • In a pre-licensure trial of the quadrivalent vaccine, injection site reactions
of administration severity and/or duration consisted of pain (84%), erythema (DRAFT June 2020
Attribute Minimally acceptable Optimal target Rationale/notes
target
between 2 and 3 days. Of MAP recipients, 20% reported pain after
vaccination compared to 44% of IM injection recipients.46
o In a recent phase 1 study of a solid-coated seasonal influenza MAP,
the skin response following vaccination peaked at 3 days and faded
between days 7 and 28. All application site reactions were mild or
moderate, with the exception of a single subject with ‘severe’
coloration at 10 minutes after application. Erythema and edema were
reported.47
o Similar local reactions (i.e., visible erythema) are expected to occur
post vaccination with an HPV MAP and may take weeks to fully
resolve. However, since reactogenicity is likely to be antigen-
dependent, local reactions observed for an HPV MAP may differ from
those observed following vaccination with a seasonal influenza MAP.
• The frequency and severity of such reactions should be assessed in pre-
licensure clinical safety trials and prior to introduction to assess vaccine
acceptability, taking into consideration other benefits of the HPV MAP
vaccine compared to the injectable presentation.
• A visible local reaction, if highly reliable, may be a desirable feature as an
indicator of the success of vaccination.
• In a preclinical study of unadjuvanted HPV MAPs in non-human primates,
erythema and petechiae were observed on the surface of the skin
immediately following MAP administration. No signs of pain or distress
were observed.44
3.3 Immunological Immunological • HPV vaccines were licensed based on clinical efficacy in young adult
Immunogenicity endpoints should be endpoints should be women and, for the quadrivalent and nonavalent vaccines, also in young
non-inferior to a non-inferior to a adult men.12
currently licensed HPV currently licensed HPV • The age extension for pre-adolescent and adolescent girls for all three
vaccine, indicated by vaccine, indicated by vaccines and boys for Gardasil and Gardasil 9, in whom efficacy trials
type-specific GMC ratio type-specific GMC ratio would not be feasible (due to ethical considerations and follow-up time
multiplicity-adjusted multiplicity-adjusted from infection to development of detectable lesions), was granted
confidence intervals confidence intervals because studies demonstrated that antibody responses in adolescent
greater than 0.5 one greater than 0.67 one girls were not inferior to those elicited in women (immunological
month after the last month after the last bridging).12
dose measured by dose measured by • No immune correlate of protection currently exists for HPV vaccine. Very
ELISA. ELISA. few breakthrough type-specific cases in HPV-naive subjects have
occurred due to the high vaccine efficacy, making determinants of
protection difficult. Given the extremely low prevalence of breakthrough
cases, determining serologic correlates of protection will only be possible
in well-followed vaccinated populations.48
22DRAFT June 2020
Attribute Minimally acceptable Optimal target Rationale/notes
target
• GMTs have been used in previous studies to compare the
immunogenicity of two- versus three-dose schedules.48,49 Non-inferiority
of each alternative vaccination dosing schedule was achieved if the lower
bound of the multiplicity-adjusted confidence interval of the type-specific
GMT ratio was greater than 0.5 (primary outcome).50 This non-inferiority
margin was based on benchmarks set by Merck for other bridging studies
leading to licensure, according to regulatory guidance.50
o Initial licensure studies used neutralizing antibody titer (GMT); current
studies now use IgG concentration measured by ELISA (GMC).
• It is assumed that similar endpoints could be used in non-inferiority
studies to license HPV MAPs.
• An optimal target of 0.67 has been proposed since this is the
immunological endpoint that was used for initial comparisons during
licensure (except in the post-licensure, the less stringent margin of 0.5
was used).
Abbreviations: ELISA, enzyme-linked immunosorbent assay; GMC, geometric mean concentration; GMT, geometric mean titer; HPV, human papillomavirus; IgG,
immunoglobulin G; IM, intramuscular; MAP, microarray patch.
4. MAP application and delivery
Attribute Minimally acceptable Optimal target Rationale/notes
target
4.1 Human A summative usability Same as minimally • For intended users and the scenarios of use for an HPV MAP (see
factors and evaluation must acceptable target. Section 1. Indication), usability/human factors of the device must be
usability demonstrate that assessed in the relevant target population (i.e., adolescents) and
safety-related user geography.
errors related to the • The usability engineering process in IEC 62366-1:2015 Medical devices –
device, applicator (if Part 1: Application of usability engineering to medical devices should be
needed), labeling, and followed to verify and validate the final HPV MAP design and applicator (if
training have been required for use). This includes establishing a usability engineering file.
identified and mitigated. • Human factors principles outlined in ANSI/AAMI HE75 Human factors
engineering – Design of medical devices should be followed.
• Key components of usability for an HPV MAP are described in other
sections of this TPP, including labeling, packaging, user training
requirements, application site, delivery time, wear time, applicator,
indication of successful vaccination, and disposal.
• To guide user-centered product development efforts, formative usability
testing should be conducted iteratively throughout the development
23DRAFT June 2020
Attribute Minimally acceptable Optimal target Rationale/notes
target
process to ensure the “suitability of the vaccine for the immunization
services where it is intended to be used,” which is part of the WHO
prequalification process.40
4.2 Applicator If an applicator is Use of an applicator is • Some MAP platforms may require an applicator, either a separate
required, MAP is not required. Similar to component or integrated with the MAP, for successful delivery.
delivered using a standard transdermal • Ideally, the MAP could be successfully applied to the skin by manual
simple, single-use, patches, the MAP is a pressure without the use of an applicator, since an integrated applicator
disposable applicator stand-alone patch that could increase the packaging volume in the cold chain, and a separate
(integrated or separate) can be successfully applicator would increase logistical complexity. However, a simple, single-
while maintaining administered manually. use disposable applicator may be required to ensure the MAP is applied
compliance with consistently and correctly (dependent on MAP design).
packaging • Regardless of the need for an applicator, usability studies will be required
requirements. to ensure that the MAP can be successfully applied by intended users.
If self-administration is an intended use case for the MAP, the applicator
If an applicator is not should be suitable for self-administration and evaluated through usability
required, MAP is studies with the intended user group.
applied similar to • The geometry and design of the MAP and its projections will inform the
standard transdermal need for an applicator.
patches. • If an applicator is required, an integrated applicator would be preferable
from a usability and logistics perspective, provided this has no
unacceptable negative impact on cost or cold chain storage volume.
4.3 Delivery Total time for delivery Total time for delivery of • Preparation and application of a MAP should be comparable to the
time of an HPV MAP should an HPV MAP should be estimated time required for delivery of the current HPV vaccine by IM
be comparable to less than delivery by IM injection. This excludes wear time, which is described below.
delivery by IM injection. injection. • Decreasing the time required to deliver each dose could be beneficial to
Delivery time should be overall program logistics and capacity. These benefits would likely be
acceptable to the health most suitable in school-based and high-throughput campaign settings.
care system in question
(informed by usability
testing).
4.4 Wear time Up to 5 minutes, under Less than 1 minute, • Required wear times for vaccines are expected to range from seconds to
observation, before under observation, minutes depending on the MAP design.
removal of MAP by before removal of MAP • Wear time will depend on technical feasibility and must be evaluated in
health worker, trained by health worker, trained preclinical and clinical studies to ensure successful delivery of the
lay health worker, lay health worker, required antigen dose.
teacher, or patient. teacher, or patient. • A wear time of 5 minutes is deemed acceptable and to fit within current
workflows since it is currently recommended to observe vaccinees after
vaccination including those administrated by needle and syringe.
o For HPV vaccination, health care providers are currently encouraged
to observe vaccinees for approximately 15 minutes after HPV
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