VIPS Phase I executive summary:
Microarray patches (MAPs)
June 2019
Microarray patches (MAPs)
About MAPs
? MAPs consists of an array of micro -projections on a patch .
? These micro -projections are coated with or are composed of vaccine in a dry formulation.
When a MAP is applied to the skin, the vaccine is delivered into the dermis and/or epidermis
layers.
? MAPs can be administered without an applicator , by applying pressure with fingers, or
using an integrated applicator a
Stage of development
? Various formats of MAPs are being developed for vaccine delivery by a number of different
developers.
? Three developers have tested influenza vaccine MAPs in phase I clinical trials , and
preclinical development is underway with other vaccines, including MR .
? MAPs for delivery of non -vaccine products, such as teriparatide (for osteoporosis) and
Zolmitriptan (migraine) have been evaluated in phase II and III trials respectively.
Vaxxas
, 15 May 2019
micronbiomedical.com
b
WHO
c
a Lead candidate MAPs for vaccine delivery either have no applicator or an integrated applicator. Therefore, MAPs with a separa te applicator are not considered in this assessmen t bhttp://micronbiomedical.com/technology/chttps://www.who.int/immunization/research/meetings_workshops/PDVAC_2017_Delivery_Tech_Update_Zehrung_PATH.pdf?ua=1

11.06.2019 Page 1 of 23
VIPS is a Vaccine Alliance project fro m Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Microarray patch es (MAP)
Comparator s? : Single dose vial ( liquid ) and autodisable (AD) needle and syringe (N&S) ;
SDV + diluent + reuse prevention (RUP) reconstitution N&S and AD N&S


Section 1: Summary of innovation
1.1 Example images :

Image source: a

Image source: b

Image source: c

1.2. D escription of innovation:
MAPs consist of an array of hundreds or thousands of micro -projections on a ?patch?. The projections are
coated with, or composed of, vaccine in a dry formulation. When applied to the skin, the vaccine is
delivered into the dermis and/or epidermis, which are rich in antigen presenting cell ( APCs ).
Several different formats of MAPs are being developed:
? With, or without, appl icators; when present, the applicator can be a separate component or
integrated with the MAP . The most advanced MAPs in development either have no applicator or an
integrated applicator. Therefore, MAPs with a separate applicator are not considered in this
assessment ;
? Solid micro -projections coated with vaccine;
? Micro -projections formed of vaccine plus biocompatible excipients that dissolve or biodegrade in the
skin;
? Hydrogel micro -projections that swell in the skin and act as a conduit fo r diffusion of the active
ingredient from a backing layer (primarily in development for drug delivery).
In theory, MAPs could be used for administration of any type of vaccine, although there might be some
vaccine -specific limitations: it might not be possible to formulate some vaccines so that they remain potent
during the manufacture or storage of MAPs; some vaccines ( in particular those formula ted with an
adjuvant) might have unacceptable levels of local reactogenicity when delivered into the skin; a nd in some
cases, MAPs might not have the payload capacity for the vaccine plus necessary excipients, or it might not
be possible to concentrate the antigen sufficiently so that it can be loaded onto the MAP.

? Single dose vials, rather than multi -dose vials (MDVs) were used for the comparator, because in most cases, the innovation being considered is a single -dose presentat ion. However, when multi -dose vials are commonly used by countries for specific vaccines, a comparison against the multi - dose vial will also be conducted under Phase II for those vaccines if this innovation is prioritised. a Image provided by David Hoey, V axxas, 15 May 2019 b http://micronbiomedical.com/technology/ c https://www.who.int/immunization/research/meetings_workshops/PDVAC_2017_Delivery_Tech_Update_Zehrung_PATH.pdf?ua=1

12.06.2019 Page 1 of 28
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Intradermal (ID) syringes
(not in cluding prefilled ID syringes or ID D isposable Syringe Jet Injector s)
Comparator: Bacille Calmette -Guerin ( BCG ) autodisable ( AD ) needle and syringe
(N&S) a, using Mantoux technique

Section 1: Summary of innovation
1.1 Examples of innovation types :

Syringe -adapter (without
needle): ID adapter


Needle -hub: MicronJet 600




Syringe adapter with needle:
Vax -ID (classified as a needle -
hub in this assessment)


Image source: (1) Image source: b Image source: c
1.2. D escription of innovation:
ID vaccination uses inexpensive and widely available BCG N&S. To achieve the correct depth of injection
the needle is inserted at an acute angle to the skin to deposit the vaccine just below the surface (Mantoux
technique) . The v olume administered is less than for subcutaneous ( SC ) or intramuscular ( IM ) injection,
typically 0.05 ml or 0.1 ml. This technique is widely used in lower and middle income countries ( LMICs ) as
BCG is given at birth to all infants in LMICs (2) .
Relatively few vaccines are given ID compared with the IM and SC routes . In recent years, there has been
interest in using the ID route with other vaccines because the epidermal and dermal layers of the skin are
rich in immune cells , so delivery of vaccines to these sites could increase vaccine immunogenicity, resulting
in the same immune response being induced with less antigen (?dose -sparing?) (3) . This can be important
for vaccines that are supply -constrained, or expensive, or that have sub -optimal immunogenicity in hard -to-
immunise subgroups. ID delivery does not result in dose -sparing for all vaccines however, and in some
cases (e.g. yellow fever), dose -sparing is possi ble without changing the route of the injection (4) .
Inactivated poliovirus vaccine (I PV) (5?7) and rabies virus vaccines (8) , are administered ID to large
numbers of people in some settings to take advantage of dose -sparing, and are given using the Mantoux
technique . Experience with these vaccines has shown that it is feasible to implement an immunization
campaign using BCG N&S to deliver ID IPV (9) , and to switch from IM to ID administration of rabies vaccine
for post -exposure prophylaxis (10) .
Some researchers however consider the Mantoux technique to have several drawbacks including :
a The N&S used for ID vaccination is referred to using several names including: 1 ml, 0.1 ml, BCG, insulin or allergy syringes. For clarity, these are all referred to as BCG syringes in this report. The technique used for ID injection is referred to as the Mantoux technique. b https://www.nanopass.com/technology/ c Vax -ID spec sheet https://novosanis.com/delivery -solutions/vax -id

VIPS Phase I executive summary:
Heat - stable/Controlled Temperature Chain
(CTC) qualified liquid formulations
June 2019
Heat -stable/controlled temperature chain (CTC)
qualified liquid formulations
About Heat -stable/CTC qualified liquid formulations
? This innovation refers to liquid vaccine formulations that are sufficiently heat stable to be kept in
a CTC.
? CTC use of vaccines allows for single excursion of the vaccine into ambient temperatures not
exceeding +40 ?C for a minimum of 3 days, just prior to administration.
? Heat -stable vaccines differ in the length of time they can be stored in a CTC and the maximum
temperature they can endure while remaining stable and potent.
? CTC qualification involves regulatory approval and prequalification by WHO.
Stage of development
? There are currently two liquid vaccines that are thermostable and qualified for CTC use .
? Merck?s Gardasil? 4 (quadrivalent human papillomavirus vaccine) that could be used at
temperatures up to 42 ?C for 3 days
? Shantha Biotechnics Shanchol ? (oral cholera vaccine) that could be used at temperatures up
to 40 ?C for 14 days.
? A number of vaccine manufacturers are in the process of qualifying their existing and pipeline liquid
vaccines for CTC use.
? Several developers have created approaches to stabilising formulations, some of which are proprietary,
that may be applicable to a variety of vaccines to improve their heat stability in liquid formulations.

VIPS Phase I executive summary:
Freeze damage resistant liquid formulations
June 2019
Freeze damage resistant liquid formulations
About Freeze damage resistant liquid formulations
? Many vaccines are freeze -sensitive , including those containing aluminium adjuvants. When
vaccines containing aluminium adjuvant are frozen, the antigen -adjuvant particles
agglomerate (form a cluster) and sediment resulting in the irreversible loss of potency.
? Developing novel freeze -stable formulations using different excipients (stabilising agents)
could prevent agglomeration and stabilise the potency of vaccines .
? The addition of excipients such as glycerin, polyethylene glycol 300, or propylene glycol (PG)
has been demonstrated to reduce the freeze -sensitivity of hepatitis B vaccine and other
vaccines containing aluminum -salt adjuvants including diphtheria, tetanus and pertussis
(DTP); and pentavalent (hepatitis B, DTP, Haemophilus influenza type b) vaccines.
Stage of development
? Excipients that could be used to improve freeze resistance of vaccines are known and
available but are not used in any approved vaccines ? though they are used in other
parenteral drugs, including for pediatric use.
? There has been some testing and pre -clinical studies with hepatitis B, pentavalent,
diphtheria, tetanus toxoid and pertussis vaccines , but overall, the approach is at an early
phase of development.
www.myelomacrowd.org
a
Freeze damage resistant liquid vaccines
www.publichealthontario.ca
b
Freeze damage resistant liquid vaccines
ahttps://www.myelomacrowd.org/wp -content/uploads/2015/05/vials.jpg bhttps://www.publichealthontario.ca/en/BrowseByTopic/InfectiousDiseases/PIDAC/Pages/Infection -Prevention -and -Control -for-Clinica l-Office -Practice -Multidose -Vials.aspx

12.06.2019 Page 1 of 15
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Freeze damage resistant liquid formulations
Comparator : Use without innovation (i.e. current liquid formulations)

Section 1: Summary of innovation
1.1 Example images :

Image s ource : a


Image s ource : b


1.2. D escription of innovation:
? Vaccines need to be stored at their proper temperature to maintain their potency, which is
commonly at 2 -8oC.
? Vaccines can be exposed to multiple freeze -thaw cycles and long durations of sub -zero
temperatures along the different segments of the cold chain . For freeze -sensitive vaccines, this can
result in physical, chemical and immunological changes to the formulation, reduced potency of the
vaccine, administration of sub -optimal vaccine , local reactions to the vaccine such as st erile
abscesses, and increased wastage (if the freeze exposure is identified and the vaccine is
discarded) (1) .
? Many vaccines are freeze -sensitive, including those containing aluminium adjuvants. When
vaccines containing aluminium adjuvant are frozen, the anti gen -adjuvant particles agglomerate and
sediment which results in the irreversible loss of potency.
? Freeze damaged vaccines can be detected using the ?shake test?, but it is not always performed
given lack of training and the need for a control vaccine to c onduct the test.
? Developing novel freeze stable formulations using different excipients could prevent agglomeration
and stabilize the potency of vaccines.
? The addition of excipients such as glycerin, polyethylene glycol 300, or propylene glycol (PG) have
been demonstrated to reduce the freeze sensitivity of Hepatitis B vaccine (2) and other vaccines
contai ning aluminum adjuvant including diphtheria, tetanus and pertussis (DTP); and pentavalent
(hepatitis B, DTP, Haemophilus influenza type b) vaccines (3) .

a https://www.myelomacrowd.org/wp -content/uploads/2015/05/vials.jpg b https://www.publichealthontario.ca/en/BrowseByTopic/Infectio usDiseases/PIDAC/Pages/Infection -Prevention -and -Control -for-Clinical -Office - Practice -Multidose -Vials.aspx

VIPS Phase I executive summary:
Freeze indicator on primary vaccine
containers
June 2019
Freeze indicator on primary vaccine containers
About Freeze indicator on primary vaccine containers
? Freeze indicators are labels that respond by changing color or activating alarm
devices in case of exposure to freezing temperatures and that can be attached
to a vaccine primary container.
? There are two types of freeze indicators:
? Electronic , which are digital devices
? Chemical -based
? The indicators are single -use only and are irreversible, so even if the
surrounding temperature in which the vaccine is stored increases after a freezing
event, the alarm or colour change on the freeze indicator will remain unchanged.
Stage of development
? Many freeze indicators are commercially available , however, some have not yet
been miniaturized to make them suitable for placement on a vaccine primary
container.
Tempmate
a
Electronic device ( Tempmate .?-i1)
C TI Links
b
Freeze alert technology ( BlindSpotzTM )
Temptime
c
A self -adhesive label
(Temptime FREEZEmarker ?)
ahttps://www.tempmate.com/wp -content/uploads/sites/2/tempmate -i1-Datasheet -EN.pdf bhttps://www.ctiinks.com/blindspotz -freeze -alert chttp://temptimecorp.com/temperature -indicators -sensors/freeze -indicator/

11.06.2019 Page 1 of 18
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Freeze Indicator on primary vaccine container s
Comparator s: No freeze indicator on the primary vaccine container and use of
standalone freeze indicators and temperature monitoring devices


Section 1: Summary of innovation
1.1 Examples of innovation types:

Electronic Freeze indicators Chemical indicators
Tempmate.? -i1(electronic
device)

BlindSpotz TM freeze alert
technology

Temptime FREEZEmarker ?? A
self -adhesive label


Image source: a Image source: b Image source: (1)

1.2. D escription of innovation:
? The innovation is a freeze indicator that can be attached to a vaccine primary container. These devices
are single -use only and irreversible , so even if the ambient temperature goes back to normal or
increases, the alarm or colour change on the freeze indicator will remain unchanged.
? There are two types: electronic indicators and chemical indicators (refer to Section 1.1).
? For detailed explanation about the different indicators refer to Table 1.



a Photo source: https://www.tempmate.com/wp -content/uploads/sites/2/tempmate -i1-Datasheet -EN.pdf b Photo source: https://www.tempmate.com/wp -content/uploads/sites/2/tempmate -i1-Datasheet -EN.pdf

VIPS Phase I executive summary:
Intradermal (ID) Devices
June 2019
Intradermal (ID) Devices
About ID Devices
? ID devices and delivery devices used to inject vaccines into epidermal and dermal layers of the
skin . They have been developed to improve the ease and accuracy of ID injections which are
given at an acute angle to the skin to deposit the vaccine just below the surface (Mantoux technique).
? ID devices are grouped into three sub -types for this assessment:
1. Needle hubs and syringe adapters (with needles) that fit onto the end of luer syringes. They
have an integrated short needle or needles (typically less than 1.5 mm) that only penetrate the
skin to the depth of the dermis.
2. Syringe adapters (without needles) that attach to standard Bacille Calmette -Guerin (BCG) or
insulin syringes with needles are designed to control the angle & depth of needle penetration.
3. Field -filled ID syringes that resemble a standard syringe but incorporate some form of needle
(e.g. plastic needle) for filling and a short (less than 1.5 mm) needle for injection.
Stage of development
? Some ID devices have received regulatory approval as medical devices e.g. 510(k) in the USA or
CE mark in Europe. One ID adapter and one needle -hub are available commercially.
? ID devices are not combination products and might not require approval with a specific vaccine
from a named manufacturer.
? Several other devices are in very early stage of development and most/all of the devices in
development do not include auto -disable (AD) features .
www.nanopass.com
Needle -hub
Tsals I, Jarrahian C
b
Syringe -adapter
(without needle)
www.cugh.org
a
Field -filled ID syringe.
Star intradermal safety
device
ahttps://www.cugh.org/sites/default/files/TS01.2_Zehrung.D.pdfbTsals I, Jarrahian C, Snyder FE, Saganic L, Saxon E, Zehrung D, et al. Clinical performance and safety of adapters for intradermal delivery with conventional and auto disable syringes. Vaccine. 2015 Sep 8;33(37):4705 ?11.

11.06.2019 Page 1 of 22
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF

Heat -stable/ controlled temperature chain ( CTC )
qualified dry formulations
Comparator s? : Use without innovation (i.e. c urrent liquid or lyophilized formulation )


Section 1: Summary of innovation
1.1 Examples of innovation types :
Lyophilised formulation

Foam -dried , freeze -dried , and spray -dried formulations

Image source: a Image source: a
1.2. D escription of innovation:
The controlled temperature chain (CTC) is an innovative approach to vaccine management allowing
vaccines to be kept at temperatures outside of the traditional cold chain of +2?C to +8?C for a limited period
of time under monitored and controlled conditions , as appropriate to the stability of the antigen. A CTC
typically involves a single excursion of the vaccine into ambient temperatures not exceeding +40?C and for
a defined duration , just prior to administration. b An example of a CTC qualified vaccine is the
meningococcal A conjugate vaccine, MenAfriVac, which was granted a label variation by the appropriate
National Regulatory Authority and WHO for its use in a CTC at temperatures of up to 40 oC for four days. c
The innovation being assessed refers to dry formulations that are heat -stable and CTC -qualified . Vaccines
with these attributes are able to be exposed to ambient temperatures below a defined threshold
temperature without losing their potency and have received regulatory and WHO prequalification approvals
to allow CTC storage. Dry formulations vary in their sensitivity to heat and suitability for use in a CTC.
Therefore, this innovation only considers a subset of dry formulations that meet these criteria.
Curr ently all dry vaccine formulations that are commercially available require reconstitution with a diluent
and are delivered in a liquid presentation (injectable and oral routes) . New delivery technologies, such as

? Single dose vials, rather than multi -dose vials (MDVs) were used for the comparator, because in most cases the innovation being considered is a single -dose presentation. However, when mu lti-dose vials are commonly used by countries for specific vaccines, a comparison against the multi - dose vial will also be conducted under Phase II for those vaccines if this innovation is prioritised. a Lovalenti, P.M., Anderl, J., Yee, L. et al. Pharm Re s (2016) 33: 1144. https://doiorg.ezp.welch.jhmi.edu/10.1007/s11095 -016 -1860 -1. b https://www.who.int/immunization/programmes_systems/supply_chain/ctc/en/ c https://www. who.int/immunization/documents/WHO_IVB_13.04_5_6/en/

VIPS Phase I executive summary:
Dual - chamber delivery devices
June 2019
Dual -chamber delivery devices
About Dual -chamber delivery devices
? Dual chamber delivery devices are fully integrated
reconstitution technologies that are prefilled with liquid and dry
vaccine components, which are mixed within the device and
administered.
Stage of development
? A wide variety of technologies are at various stages of
development, from early design stage through commercial
availability.
? No vaccines are licensed in dual chamber delivery devices.
www.pharmaceutical
-
networking.com
a
Dual chamber syringe
(Vetter Lyoject)
PharmaPan
b
Dual chamber blister with
frangible seal
Neopac
c
Dual chamber blister with
frangible seal
ahttps://www.pharmaceutical -networking.com/vetter -dual -chamber -delivery -systems/ bhttps://www.pharmapan.com/sites/default/files/downloads/2017 -10/PHARMAPAN_Dual_Chamber_Blister_1.1.pdf chttps://www.webpackaging.com/en/portals/webpac/assets/11138717/neopacs -fleximed -now -in-large -format/

11.06.2019 Page 1 of 20
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Dual -chamber delivery d evice s
Comparator ? : Single dose vial , diluent , reuse prevention recon N&S and autodisable
(AD ) needle and syringe (N&S )


Section 1: Summary of innovation
1.1 Examples images:
Dual -Chamber delivery device:
Vetter Lyo -Ject? Syringe


Fleximed? Easymix


Image source : b Image source: Neopac c

1.2. Description of innovation:
? Integrated reconstitution technologies such as d ual -chamber delivery devices and dual -chamber
vials pair dry vaccine with diluent in one technology to simpl ify the process of reconstitution.
Vaccine components are stored in different compartments of the same device and then more easily
mixed and administered at the time of use. Dual -chamber delivery devices are fully integrated
reconstitution technologies that include the delivery device.
? The reconstitution of vaccines for immunization represents a public health challenge due to the
potential for error during the transfer of diluent to the vial cont aining lyophilized (freeze -dried)
vaccine using a reconstitution syringe . Errors in using t raditional reconstitution systems include use
of the incorrect volume of diluent ; reuse of reconstitution syringes, causing contamination; use of
improperly stored diluent that can render a vaccine ineffective ; use of an incorrect diluent ; or worse,
using a potentially deadly liquid drug as a diluent by mistake. Adverse events as a result of
reconstitution errors can include local abscesses, toxic shock syndrome, or even death (1).
? Single dose vials, rather than multi -dose vials (MDVs) were used for the comparator, because in most cases the innovation being considered is a single -dose presentation. However, when multi -dose vials are commonly used by countries for specific vaccines, a comparison against the multi - dose vial will also be conducted under Phase II for those vaccines if this innovation is prioritised. b https://www.pharmaceutical -networking. com/vetter -dual -chamber -delivery -systems/ c https://www.webpackaging.com/en/portals/webpac/assets/11138717/neopacs -fleximed -now -in-large -format/