Proposal full title
Name of the coordinating person
List of participants
Participant
n°
1
2
3
Participant organisation
name
Short
name
Paticipant
name
Country
Table of Content
1
2
3
4
5
6
7
8
Project Overview ..................................................................................................................... 5
1.1 Project Goal ...................................................................................................................... 5
1.2 Project Rationale .............................................................................................................. 5
1.2.1 Biological Rationale/Validation ............................................................................. 5
1.2.2 Antigen/vaccine production processes ................................................................ 8
1.2.3 Antigen/vaccine characterisation .......................................................................... 9
1.3 Anticipated Clinical development start date ................................................................ 9
Project Assessment ...............................................................................................................10
Project History and Key Achievements to date ................................................................10
Project Executive Summary .................................................................................................10
4.1 Project Strategy Summary.............................................................................................10
4.2 Project Plan Summary ...................................................................................................10
4.2.1 Decision tree and main Go/No Go decision ....................................................10
4.2.2 Key activities on the critical path to next gate ...................................................10
4.2.3 Next gate review .....................................................................................................10
Functional Strategy ................................................................................................................10
5.1 Regulatory .......................................................................................................................10
5.2 Research ..........................................................................................................................11
5.2.1 Summary of Research strategy to support the project .....................................11
5.2.2 Summary of Operational plan for ongoing and next stages. Work-package ..11
5.3 Development ..................................................................................................................12
5.3.1 Summary of Development strategy to support the project .............................12
5.3.2 Summary of Operational plan for ongoing and next stages Work-package.....12
5.4 Toxicology ......................................................................................................................12
5.4.1 Summary of Toxicology strategy to support the project..................................12
5.4.2 Summary of Operational plan for ongoing and next stages Work-package.....12
5.5 Analytical Development................................................................................................12
5.5.1 Summary of Analytical Development strategy to support the project ...........12
5.5.2 Summary of Operational plan for ongoing and next stages Work-package 4 .13
5.6 Intellectual Property ......................................................................................................13
5.7 Ethical aspects (animal and human studies) ..............................................................14
5.7.1 Informed consent ...................................................................................................14
5.7.2 Data protection issues ...........................................................................................14
5.7.3 Use of animals ........................................................................................................14
5.7.4 Ethical issues table .................................................................................................14
5.8 External Collaboration ..................................................................................................14
5.8.1 Third party agreement ...........................................................................................14
5.8.2 Alliance management.............................................................................................15
Budget .....................................................................................................................................15
6.1 Resources to be committed (person-month) .............................................................15
6.2 Resources to be committed (euros) ............................................................................15
Bibliography ...........................................................................................................................15
Appendices .............................................................................................................................16
Appendix 1: Gantt chart (including milestones) .................................................................16
Appendix 2: Target Product Profile (if applicable).............................................................16
Appendix 3: Clinical Development Plan ..............................................................................17
Appendix 4: Lists of work-packages .....................................................................................17
Appendix 5: Lists of deliverables ..........................................................................................17
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Appendix 7: Glossary .................................................................................................................. 17
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Abbreviations
CDP
Clinical Development Plan
CTA:
Clinical Trial Application
SAC:
Scientific Advisory Committee
IMPD:
Investigational Medicinal Product Dossier
QC:
Quality Control
Please refer to EVI website regarding missing abbreviations part of the guidelines.
The list of abbreviations will have to be completed by the applicant.
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This template is intended to give guidelines for preparing and submitting the information about the project
for the selection process by EVI SAC. The listed information in this template is non exhaustive. The
applicant may provide additional information; which is not on the template and should in particular focus
on information; which is relevant to the candidate vaccine. The grey boxes are self-explanatory but are
not exhaustive.
1 Project Overview
 2-3 pages
1.1 Project Goal
Including the benefits of the innovation
1.2 Project Rationale
(1) Must explain why this project should be advanced in preference to other
alternatives the proponent is aware of
(2) Must identify advancement as (a) experimental. or (b) proof of concept
Scientific rationale:
Why, how should this approach work? Which paradigm?
Technical rational:
Why, how should the product be produced and what are the rational for the optimisation of the immune
response?
Strategic rational:
How does this project fit with EVI strategic objectives/ Malaria Vaccine Technology Roadmap (if
applicable)?
The following sections should be detailed:
1.2.1 Biological Rationale/Validation
A.
Antigen
 Life cycle stage of expression must be defined
Many proteins show stage specificity of expression, others do not. Specificity can be determined from
transcriptome/proteome or by detection with antibody
 In vivo protection
 In vivo protection after immunisation with the vaccine antigen in an animal model.
Demonstration with strong justification for further development
e.g. correlates of protection?
Immunisation and challenge studies in a primate model, rodent or primate parasite/virus/bacteria.
Passive immunisation with non-specific Ab may implicate antigen
 In vitro inhibition.
 Demonstration bolsters rationale for further development
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 Refers largely to antibody mediated inhibition of invasion or subsequent growth and development of
the parasite/virus/bacteria, often using monoclonal antibodies.
 e.g. growth inhibition assay; merozoite inhibition assay; sporozoite inhibition assay; ADCI; antigen
specific assays e.g. red cell binding assays, processing assays in case of Plasmodium
 Genetic analysis: Parasite/virus/bacteria dependence on antigen
(1) Must be characterised
(2) Rationale for development plan must be presented
Parasite/virus/bacteria dependence on antigen best determined by ability (or inability) to knock out gene
The product of an essential gene is probably a good target. However non-essential genes (e.g. members of
a family) may also be important.
Transfection e.g. inability to knock out corresponding gene due to lethality
 Antigenicity/Immunogenicity:
Must react with antibodies or cells of infected and/or immunised individuals
The response to an antigen that is ‘seen’ during an infection may be boosted by further natural infection.
e.g. reactivity with antibodies or cells of naturally exposed or artificially challenged donors
 Antigen size and solubility
Large and multidomain membrane spanning proteins are difficult to express well in a heterologous host.
e.g. small soluble proteins are easier to replicate as recombinant proteins
 Pre-existing clinical data: Must be considered in development plan
Data on immunogenicity and vaccine efficacy when possible are very useful in developing better products.
e.g. when some proteins have already been into human subjects
B.
Product Rationale/Validation
 Single antigen
e.g. a single subunit protein for a single stage of the parasite/virus/bacteria life cycle
 Multi-antigen approaches
e.g. a multiple subunit protein for one or different stage of the parasite/virus/bacteria life cycle
 Prime-boost strategies
e.g. does the proposed strategy include different delivery processes?
 Delivery systems / adjuvants. General considerations
(1) Rational and demonstration of advantage in preclinical model must be presented
(2) Rational and evidence that the regimen will be safe must be presented
(3) Evidence of scalability must be presented
(4) Must have credible intellectual proprietary and regulatory pathway to licensure
(5) Must induce specific humoral and/or cellular immune response
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Additional studies may be required (e.g. biodistribution, replication competence, toxicology) to assess
safety; Level of replication competence
 Delivery systems employing proteins produced through recombinant
technology or non-enzymatic polypeptide synthesis
(1) Multimeric presentation (i.e. VLPs) more desirable than monomeric
(2) Extemporaneous formulation for phase I, II preferred, but characterisation of formulated vaccine
essential
(3) Parenteral route preferred; other routes must be justified
 Delivery systems employing viral or bacterial vectors
(1) Must provide evidence of attenuation of replication competence
(2) Must provide review of previous clinical experience with this vector
(3) Must provide existing data on pre-existing anti-vector antibody in the target population and how the
issue will be dealt with
(4) Must address potential public health conflicts with other vaccines using this vector
e.g. DNA, virus, bacterium (e.g. biological rational, e.g. strong antigen-specific T- and B-cell responses
in majority of volunteers; data from rodent models; presence of pre-existing antibody vaccine is well
tolerated replication competence/attenuation antigen capacity; single/multiple genes antigen location in
host cells; vector yields and stability)
Since same vector cannot be used for two diseases, need to be aware of state of development of vectors for
other diseases to avoid developing same vector and to learn from results with other disease targets. Please
detail your knowledge about other vaccines using the same vectors (in development or already marketed).
 Synthetic antigen either as peptide/recombinant antigen or in vectored system
 Codon optimisation and exact sequence including any modifications (including non-natural amino
acids in peptide), exogenous sequences (e.g. tags) to be expressed
 Choice of expression vector and host (e.g. bacterium, yeast, other eukaryote)
 Antigen expression level
 Growth and genetic stability
 Fermentation and downstream purification (e.g. precipitation, chromatography)
 Antigen purity and stability
 Monomer/aggregation state.
 Fusion partners with VLPs facilitate purification because of large size - readily separated from
contaminating proteins
 Antigen characterisation
 Reducing/non-reducing conditions (e.g. purity by SDS-PAGE/HPLC (reverse phase, ion
exchange, size exclusion)
 Contaminants (DNA, protein, metal, endotoxin)
 Identity (N-terminal sequence analysis, amino acid analysis, Ellman’s test for cystines)
 Conformation: secondary/tertiary structure/posttranslational modifications (biophysical
characterisation: CD, MS, NMR etc.)
 Antigenicity (e.g. ELISA; reactivity with mAbs)
 Antigen-specific criteria, e.g. red cell binding)
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 Antigen immunogenicity e.g.
Immunogenicity of antigen using most rational immune assay should be included in antigen
characterisation to monitor changes in antigen immunogenicity during process development. e.g.:
 Immunogenicity in animal models (mice and rabbits) (e.g. Production of specific antibodies (western
blot, ELISA, immunoprecipitation, IFA…)
 Induction of T-cells that recognise specific antigens/ produce cytokines, ELISpot
 Functional activity
 Antigen-specific assays e.g. inhibition of processing, inhibition of binding
 Responses relative to standards?
 Prime-boost strategy: Must be shown to have an advantage in preclinical studies
Clinical data for other product using the same strategy should be reviewed with respect to the product in
question
 Evaluation of vaccine efficacy under conditions of natural exposure or
artificial challenge
Separate into two categories - there is a big difference between efficacy (preliminary, qualitative) in
challenge models vs natural exposure. e.g.
 Preclinical data for regulatory filing
 Ethical, scientific and regulatory approval for clinical trials
 Show tolerability and safety in first in-human clinical trial; immunogenicity and protection from
artificial challenge (where relevant ie pre-erythrocytic)
 Show safety and efficacy in target population
1.2.2 Antigen/vaccine production processes
 Recombinant protein production processes
Must describe:
(1) Expression system
(2) Rationale for codon usage employed
(3) Purification scheme
(4) Largest scale used
 Non-enzymatic polypeptide synthetic processes
Must describe:
(1) Type of chemistry
(2) Purification scheme
(3) Largest scale used
 Viral and bacterial vectored vaccine production processes
Must describe:
(1) Host cell system
(2) Transfection process
(3) Purification scheme
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(4) Largest scale used
1.2.3 Antigen/vaccine characterisation
 General characterisation requirements: Actual data, not just conclusions, must be
provided
Must provide:
(1) Target primary sequence(s), identifying non disease-related residues
(2) Evidence of purity (for example by SDS-PAGE, identifying any contaminants and minor
components derived from the recombinant product
(3) Evidence for identity (e.g. using N-terminal analysis, amino acid analysis, Ellman’s test for cysteins,
mass spectro-scopy, etc
(4) Evidence for native-like conformation (if required for immunogenicity) using MAB panel, CD, MS,
NMR, etc.
(5) Evidence for antigenicity (e.g., reactivity with MAb, etc.)
(6) Evidence for immunogenicity in at least two species (mice and one other) using functional assays if
possible
(7) Endotoxin content
(8) Methodology for data acquisition
 Non-enzymatic synthetic peptide/protein characterization
Must describe:
(1) Type of chemistry
(2) Purification scheme
(3) Largest scale used
 Viral and bacterial vectored vaccine characterization
Must describe
(1) Host cell system
(2) Transfection process
(3) Purification scheme
(4) Ratio of particles to plaque-forming centers
(5) Largest scale used
 Virus like particle or other particulate delivery vaccine characterisation
Must describe
(1) General structure of particles
(2) Size and size distribution of particles
(3) Conjugation process
(4) Epitopes accessible on surface
(4) Number of antigen molecules per particle
1.3 Anticipated Clinical development start date
List the dates for the CTA and Ethical Approval. The planning should include the process of EVI
submission, EVI SAC evaluation, and EVI Board decision.
1.
Most probable
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2.
3.
Optimistic
Worst Case scenario
 1 page
2 Project Assessment
Include here all the previous project assessment (by other funding agencies or by SAC or by Institutional
review committee (scientific and/or ethics). Can be attached as separate docs or as Appendix
3 Project History and Key Achievements to date
 1 page
Summary of key scientific, technical and pre-clinical achievements (clinical if any) and key decisions
Indicate changes of strategy when ever
4 Project Executive Summary
 1 page
4.1 Project Strategy Summary
4.2 Project Plan Summary
Please include the Gantt chart including deliverables and milestones
Please provide with Microsoft project file (Appendix 1)
4.2.1 Decision tree and main Go/No Go decision
4.2.2 Key activities on the critical path to next gate
4.2.3 Next gate review
5 Functional Strategy
5.1 Regulatory
 1 page
Executive part of the Regulatory strategy
Specific Guidelines and highlights
Strategy:
Under IND (US)
In Europe, IMPD submission to which regulatory agency? Describe the different expected steps.
Which status has the vaccine (orphan vaccine?)
In Africa, CTA where? Describe the different expected sites
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5.2 Research
5.2.1 Summary of Research strategy to support the project
5.2.2 Summary of Operational plan for ongoing and next stages.
Work-package
Workpackage
number
Workpackage title
Participant number
Person-months
participant
1
Start date or starting event:
Month
per
Objectives
Description of work
Task 1:
Task 2:
Task 3:
Task x:
Deliverables
D1:
D2:
D3:
Dx:
Milestones
M1:
M2:
M3:
Mx:
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5.3 Development
 1-2 pages
5.3.1 Summary of Development strategy to support the project
Define the key drivers and assumptions:
Product substance (active ingredient) specification and Final product specifications
Yield/cost
Chosen scale of development
Chosen scale of purity
Ability to scale up
Robustness
Number of clinical batches
Number of doses (total and per batch)
Describe the process development strategy, scale up strategy and transfer plan
5.3.2 Summary of Operational plan for ongoing and next stages
Work-package
Key points of the plans including specific functional activities and objectives supporting the strategy
 1-2 pages
5.4 Toxicology
5.4.1 Summary of Toxicology strategy to support the project



Vaccine reactogenicity or toxicity (e.g. rabbit CPK assay for local reactogenicity; GLP tox study
using rabbits at full human dose at n+1 doses for formal tox)
Adjuvant also tested alone for novel adjuvant
Rhesus study where adjuvant has not been used in humans previously. Define the key drivers and
assumption and when appropriate the guidelines
5.4.2 Summary of Operational plan for ongoing and next stages
Work-package
Key points of the plans including specific functional activities and objectives supporting the strategy
 1-2 pages
5.5 Analytical Development
5.5.1 Summary of Analytical Development strategy to support the
project
Define the key drivers and assumption or rate-limiting factors: assays, equipment costs, anticipated
complexity of methods (potency test, QC tests, functional tests…)
Describe test development strategy and stability testing plan
Describe validation strategy
Key steps for the optimisation of the process
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Plan for transferring assay technology through project life cycle
5.5.2 Summary of Operational plan for ongoing and next stages
Work-package
Define the key drivers and assumption and when appropriate the guidelines
5.6 Intellectual Property
 1 page
Must be described in detail for antigen, expression system, adjuvant, delivery system, etc.
Note when any patents will expire.
Please describe and precise when the last assessment has been done?
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5.7 Ethical aspects (animal and human studies)
5.7.1
Informed consent
5.7.2
Data protection issues
5.7.3
Use of animals
5.7.4
Ethical issues table
Informed Consent
Yes
Does the proposal involve adult healthy volunteers?
Does the proposal involve Human Genetic Material?
Does the proposal involve Human biological samples?
Does the proposal involve Human data collection?
Privacy
Does the proposal involve processing of genetic information or
personal data (eg. health, sexual lifestyle, ethnicity, political opinion,
religious or philosophical conviction)
Does the proposal involve tracking the location or observation of
people?
Research on Animals
Does the proposal involve research on animals?
Are those animals transgenic small laboratory animals?
Are those animals non-human primates?
Research Involving Developing Countries
Use of local resources (genetic, animal, plant etc)
Benefit to local community (capacity building i.e. access to healthcare,
education etc)
Dual Use
Research having potential military / terrorist application
I CONFIRM THAT NONE OF THE ABOVE ISSUES APPLY
TO MY PROPOSAL
Page
 1 page
5.8 External Collaboration
5.8.1 Third party agreement
#
Institution/company
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license option, contract testing …)
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5.8.2 Alliance management
For each of the agreement describe
Contacts in the partner institution
Who is managing and following the progress
Who are the members of the management committee/team, decision making process
Location of legal and business development documentation
6 Budget
6.1 Resources to be committed (person-month)
Partners
WP1
WP2
WP3
WP4
WP5
WP6
Personmonth
WP6
Euro
Total
6.2 Resources to be committed (euros)
Partners
WP1
WP2
WP3
WP4
WP5
Total
7 Bibliography
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8 Appendices
Appendix 1: Gantt chart (including milestones)
Appendix 2: Target Product Profile (if applicable)
Target Product Profile
DESCRIPTION
 General
Expected action on parasite/virus/bacteria cycle
Strategy : Monovalent/multivalent (intra species) – stage focus, multi stage
Combination (interspecies – vivax/falciparum)
 Composition
Active pharmaceutical ingredient (antigens description including sequence…)
Excipient
Adjuvant
 Pharmaceutical Form
Liquid/ lyophilised
 Product Presentation
Unidose, multidose
Vial, syringe
INDICATIONS
 Target Populations
Transmission level, epidemiology burden, mortality vs morbidity
 Target Countries
 Indication
Infant, toddler, children adults, pregnant women….
Vaccination schedule: Number of doses and interval between doses
DOSAGE
AND
ADMINISTRATION
Target dosages for phase I CT
Target dosage for phase IIb if any data already available
Administration : sub-cutaneous/intra-muscular …
INTERACTIONS
If any available data
ADVERSE EVENTS
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For vaccine/adjuvant already tested in humans
PHARMACODYNAMICS1
STORAGE CONDITIONS AND SHELF LIFE
What is the goal for the vaccine
OTHER CONSIDERATIONS
Appendix 3: Clinical Development Plan
See attached doc
Appendix 4: Lists of work-packages
Workpackage
No
WP1
WP2
WP3
Workpackage title
Lead
participant
No
Personmonths
Start
month
End
month
Appendix 5: Lists of deliverables
Deliverable Deliverable title
No
Delivery Nature2 Dissemination
date
level3
WP1
WP2
WP3
Appendix 7: Glossary
Combined vaccine: as defined by EMEA; “Combined vaccines are product intended
for protection against a single infectious disease complex caused by different strains or
serotypes or organisms”
Monovalent vaccine: vaccine containing one antigen from the same strain
Multivalent vaccine: vaccine containing more than one antigen from the same strain
1
See Guidelines EMEA/CPMP/BWP/4548/03
2
R : report, P: product ; O: other
3
PU: public ; PP : Public for partners
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Active Pharmaceutical Ingredient or Drug Substance: Any substance or
mixture of substances intended to be used in the manufacture of a drug (medicinal)
product and that, when used in the production of a drug, becomes an active ingredient of
the drug product. Such substances are intended to furnish pharmacological activity or
other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease
or to affect the structure and function of the body.
Excipient: An excipient is is an inactive substance used as a carrier for the active
ingredients of a vaccine.
Adjuvant: as defined by EMEA; a vaccine adjuvant is a component that potentiates the
immune responses to an antigen and/or modulates it towards the desired immune
responses. These adjuvants include for instance:
 Mineral salts, e.g., aluminium hydroxide and aluminium or calcium phosphate gels.
 Oil emulsions and surfactant based formulations, e.g., MF59 (microfluidised
detergent stabilised oil-in-water emulsion), QS21 (purified saponin), AS02 [SBAS2]
(oil-in-water emulsion + MPL + QS-21), Montanide ISA-51 and ISA-720 (stabilised
water-in-oil emulsion).
 Particulate adjuvants, e.g., virosomes (unilamellar liposomal vehicles incorporating
influenza haemagglutinin), AS04 ([SBAS4] Al salt with MPL), ISCOMS (structured
complex of saponins and lipids), polylactide co-glycolide (PLG).
 Microbial derivatives (natural and synthetic), e.g., monophosphoryl lipid A (MPL),
Detox (MPL + M. Phlei cell wall skeleton), AGP [RC-529] (synthetic acylated
monosaccharide), DC_Chol (lipoidal immunostimulators able to self organise into
liposomes), OM-174 (lipid A derivative), CpG motifs (synthetic oligonucleotides
containing immunostimulatory CpG motifs), modified LT and CT (genetically
modified bacterial toxins to provide non-toxic adjuvant effects).
 Endogenous human immunomodulators, e.g., hGM-CSF or hIL-12 (cytokines that
can be administered either as protein or plasmid encoded), Immudaptin (C3d
tandem array)
 Inert vehicles, such as gold particles
Other novel types of adjuvants not listed above may be under development and this
guideline applies to these also.
Product Specification File: A reference file containing, or referring to files containing,
all the information necessary to draft the detailed written instructions on processing,
packaging, quality control testing, batch release and shipping of an investigational
medicinal product.
The Product Specification File should be continually updated as development of the
product proceeds, ensuring appropriate traceability to the previous versions. It should
include, or refer to, the following documents:
 Specifications and analytical methods for starting materials, packaging materials,
intermediate, bulk and finished product.
 Manufacturing methods.
 In-process testing and methods.
 Approved label copy.
 Relevant clinical trial protocols and randomisation codes, as appropriate.
 Relevant technical agreements with contract givers, as appropriate.
 Stability data.
 Storage and shipment conditions.
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
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The above listing is not intended to be exclusive or exhaustive.
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