Workpackage 8

 

Work package number

8

Start date or starting event:

M1

Work package title

Project management

Activity Type[1]

MGT

Participant number

1

4

 

 

 

 

 

Participant short name

IQUR

UCL

 

 

 

 

 

Person-months per participant:

4.2

17.0

 

 

 

 

 

                   

 

Objectives

The objectives of this work package are to ensure an efficient organisation and management structure for a successful completion of the Project and to monitor progress of the tasks and objectives identified in the proposal as well as to provide an effective dissemination and exploitation plan for the project results.

 

Description of work (possibly broken down into tasks), and role of participants

The overall day-to day management of the project will be the responsibility of the Project Coordinator, Dr Whelan (IQUR), assisted by a specialist European Project Manager based within University College London’s European Research and Development Office (ERDO).

Work Package Leaders (WPLs) will assist the Coordinator in the technical and scientific coordination of the Project and a Governing Board (GB) consisting of one representative of each partner will be the ultimate decision making body of the Consortium.

 

Management tasks will be:

 

Task 8.1 Project financial, contractual and administrative management (iQur, UCL, M1-M43)

The project financial, contractual and administrative management tasks will be performed by a designated European Project Manager of ERDO. The Project Manager will report to the Coordinator and will be in charge of:

8.1.1. Providing the interface between the  Consortium and the European Commission and acting as a focal point for project communications and day-to-day queries from inside and outside the consortium;

8.1.2. Establishing the infrastructure required for the project’s efficient administration, including:

  • Developing and maintaining individualised templates for tracking and reporting partners’ progress, finances and dissemination activities;
  • Establishing and maintaining of the project’s communication and documentation storage systems, including the development of a Project website to be used for both internal and external communication;
  • Maintaining the project contact lists and other project databases for reporting and controlling.

8.1.3. Maintaining the project’s Consortium Agreement and monitoring and addressing all related matters, including Intellectual Property issues, legal issues and issues relating to publication and dissemination;

8.1.4. Carrying out financial management activities, including financial planning, financial monitoring and the distribution of pre-financing to partner organisations;

8.1.5. Organising Steering Committee meetings, project Advisory Board meetings and EC project reviews;

8.1.6. Collating information and inputs for the contractual project periodic reports

8.1.7. Drafting and negotiating additional agreements and other documents as necessary, such as Grant Agreement amendment requests, Memoranda of Understanding or competitive calls for new project partners.

 

Task 8.2 Dissemination and exploitation of Project’s results (all partners, M1-M43)

8.2.1. The knowledge generated by the Project will be disseminated in both written publications in targeted scientific journals and participation to high profile conferences.

8.2.2. IPR ownership and exploitation of project results issues will be negotiated within the Partners and addressed in the Project Consortium Agreement, to be signed by all Beneficiaries before the signature of the EC Grant Agreement. Adequate and effective legal protection measures will be investigated and implemented every time the Project results can be protected. 

8.2.3. An audit of existing patent portfolio will be carried out at the beginning of the Project and updated on an annual basis to provide the Consortium with the most detailed information on market analysis and competitor profiling.

8.2.4. A detailed exploitation plan will finally be prepared by WP leaders and the Coordinator and maintained throughout the Project, to ensure that the technology developed by FLUTCORE will generate novel and competitive marketable products. Possible exploitation barriers (including ethical and regulatory aspects) will be identified and their impact assessed to optimize the vaccine’s market entry strategy. The emergence of other competing technologies will also be analysed.

 

 

Deliverables** (brief description and month of delivery)

D 8.1 Project website (P4-UCL, M4)

D 8.2 Dissemination plan (IQUR, M12)

D 8.3 Exploitation plan (IQUR, M25)

 



[1]   Please indicate one activity per work package: RTD = Research and technological development; DEM = Demonstration; MGT = Management of the consortium; OTHER = Other specific activities, if applicable (including any activities to prepare for the dissemination and/or exploitation of project results, and coordination activities).

Workpackage 7

 

Work package number

7

Start date or starting event:

M32

Work package title

Phase I clinical trial

Activity Type[1]

 

Participant number

1

4

5

6

7

 

 

Participant short name

IQUR

UCL

CRP-Santé

3P

ICS

 

 

Person-months per participant:

2.0

0.6

32.6

1.0

0.9

 

 

                   

 

Objectives

A Phase I clinical trial will be conducted in 20 individuals to ensure safety and immunogenicity in humans. Immunogenicity will be tested ex vivo using the assays described in WP3.  

 

Description of work (possibly broken down into tasks), and role of participants

Introduction

This WP includes study design, execution, reporting and evaluation of a phase I clinical trial to demonstrate safety and immunogenicity, based on pre-clinical immunogenicity and toxicology reports developed in previous WPs 1-6.

 

Task 7.1: Design of the study and approvals (IQUR & ICS, M32-M34)

Includes the review of the available evidence from previous stages, the drafting of study protocol and obtaining the approvals to conduct the study from the Clinical Research Ethics Committee (CREC) of Vall d’Hebron Hospital, the Spanish Agency of Medicines and Medical Devices, and any other regulatory requirements at the moment of the study.

 

Task 7.2: Conduction of the study (IQUR & ICS, M34-M42)

Task 7.2.1 Recruitment (ICS);

Recruitment of potential trial participant subjects among healthy adult (≥18 years old) female (without bearing potential) and male volunteers.

Task 7.2.2 Screening (ICS);

Inclusion and exclusion criteria will be considered for all potential trial participants. Screening activities comprise: medical history, clinical examination, and urine pregnancy test if applicable.

Task 7.2.3 Obtaining informed consent (ICS);

Trial candidate subjects will receive fully oral and written information, and should provide their consent to participate in the writing form approved by the CREC.

Task 7.2.4 Randomization (ICS);

Trial subjects allocation will correspond with the code used for packaging the trial vaccine to guarantee concealment and will be assigned randomly.

Task 7.2.5 Vaccine administration (ICS & 3P);

Vaccine will be delivered to ICS from 3P. After confirmation of normal axilar body temperature, verification of inclusion and exclusion criteria, and signed informed consent, assigned vaccine will be administered intramuscular in the deltoid muscle of the non-dominant arm. Further in this document, this will be considered day 0 and timing will be mentioned as number of days since vaccination.

Task 7.2.6 Close monitoring (ICS);

Following the administration of the vaccine, all trial subjects will stay in the observational area for 30 minutes, with appropriate emergency treatment available if needed.

Task7.2.7 Safety follow-up (ICS);

Trial subjects will receive a diary card to record any adverse event until day 21. Concomitant medication, other vaccination, or any new medical condition will be recorded. Safety follow-up visits will be scheduled on days 7 and 21. Routine safety blood test will be done on day 0 and 21. Patients will be contacted by phone 180 days after vaccination to register any serious adverse event between days 21 and 180. Subject will be instructed to contact the investigator immediately in case of perception of any serious sign or symptom. A standard procedure will be in place to report and evaluate any serious adverse event.

 

Task 7.3 Data analysis (ICS & IQUR, M38-M42) The statistical analyses will be performed in two steps. The main analysis will be performed when all data on immunogenicity and safety upon day 21 post vaccination is available. A second analysis will include safety data until day 180 after vaccination.  Descriptive statistics for the vaccination group and for each individual on day 0, 21 and 180 will be provided. Geometric mean titres, seroconversion rates, conversion factors, protection rates, frequency of influenza specific-antibody forming cells and other immunogenicity related parameters will be analysed according to the protocol of the study. Missing or non-evaluable measurements will not be replaced.

 

Task 7.4 Reporting and evaluation. (ICS & IQUR, M38-M42).  A preliminary report will be presented with data upon day 21, followed by an annex study report including data of days 21-180.  Analysis and discussion will be performed on final and cleaned data and published properly.

 

Task 7.5: Seroconversion (ICS & UCL, M36-M43)

A minimal of 30ml of whole blood sample to measure humoral and cell mediated immune response will be taken on days 0 and 21. These samples will be adequately processed, and delivered to CRP-Sante for detailed analysis of the nature and quantity of the immune response.

Sera will be transferred to UCL (Prof Rosenberg) and tested for antibody responses by ELISA to both core protein vector and inserted antigens.

 

Task 7.6: T&B receptor usage (ICS & CRP-SANTÉ, M36-M43)

PBL will be shipped to Luxembourg for full immunological screening. This will be similar to that outlined for murine responses in WP 3.6 and 3.7.

 

 

Deliverables** (brief description and month of delivery)

D 7.1: Report of clinical data proving immunogenicity and safety in volunteers (M42)

Immunological data showing seroconversion and T-cell activity will be processed from the blood samples of trial participants extracted on days 0 and 21 after immunization. Safety data about any local or systemic reactions produced within 180 days after immunization will be analysed and presented.

D 7.2: Seroconversion (M43)

Proof of VLP induced seroconversion. Antibodies specific for IAV generated.

D 7.3: T&B cell receptor usage (M43)

Evidence of systemic anti-IAV immunity



[1]   Please indicate one activity per work package: RTD = Research and technological development; DEM = Demonstration; MGT = Management of the consortium; OTHER = Other specific activities, if applicable (including any activities to prepare for the dissemination and/or exploitation of project results, and coordination activities).

Workpackage 5

 

Work package number

5

Start date or starting event:

M12

Work package title

GMP Manufacture

Activity Type[1]

DEM

Participant number

1

3

4

6

 

 

 

Participant short name

IQUR

LBMC

UCL

3P

 

 

 

Person-months per participant:

2.0

2.0

1.8

94.9

 

 

 

                   

 

Objectives

The selected clone will be expanded under non-GMP conditions and tested for scalability. Once achieved, this will be transferred to our contract manufacturer and a master cell bank (MCB) will be prepared followed by a working cell bank (WCB). Finally, a GMP compliant batch of material will be prepared.

 

Description of work (possibly broken down into tasks), and role of participants

Lead candidate VLP will be transferred to 3P for scale-up and GMP manufacture. This is a prerequisite for future clinical studies. This work will occur in two phases; one non-GMP and one GMP.

 

Task 5.1: Technical transfer (3P, UCL, LBMC, M12_M24)

The starting material for this phase will be the Research Cell Bank (RCB) generated and characterised. IQUR, LBMC and UCL will transfer to 3P all existing documentation for the manufacture and analytics of tandem core. These will include procedures and records to facilitate the understanding of the process and its variables. Transfer of intellectual property and reagents will be under a Material Transfer Agreement (MTA) that will form part of the consortium agreement.

3P will prepare a technical transfer (TT) document split and will perform a Biosafety Evaluation as well as an RCB testing to ensure cell banks optimal conditions.

A Tech transfer run (10L) at the sending facility will be performed by 3P to gain a solid knowledge of the process. Furthermore, 3P will carry out one Tech Transfer run and one engineering run in its facilities with the goal of adjusting parameters to the process in its facilities.

Finally, extended head to head comparability studies between the material generated at 3P and the material generated at the sending facilities will be performed.

It is assumed that no optimisation will be required to the process or analytical methods that will be transferred to 3P since these will be developed in WPs 1 and 2.

 

Task 5.2: Generation and Characterisation of Master and Working Cell Bank (MCB-WCB) (3P, M24-M29)

3P will generate 200 vials of MCB and WCB under GMP conditions. GMP characterisation of MCB/WCB will be outsourced and performed according to phase I requirements.

 

Task 5.3: Non-GMP run (3P, M24-M27)

3P will perform scale-up and non-GMP production at 100L. Moreover, a Reference standard will be generated for one of these batches.

 

Task 5.4: Seroconversion and analytics (IQUR/UoL, M27-M28)

Samples from the non-GMP batch will be sent to IQUR for preclinical testing (seroconversion as described in WP 3.1). Concurrently, samples will be sent to UoL for analysis as described in WP2. Successful completion of both studies will act as the go-no-go point for vaccine manufacture.

 

Task 5.5: GMP run (3P, M24-M30)

3P will perform the validation of the analytical methods developed and transferred adequate for Phase I clinical trials.

Next, 3P will manufacture one GMP batch in 100L to obtain material for Phase I trials.

 

Task 5.6: Fill/finish (3P [s/c], M30-M32)

Final vials prepared. Material will be returned to 3P for product release by a Qualified Person (QP).

 

 

Deliverables** (brief description and month of delivery)

 

D 5.1: Technical transfer documentation (M24)

D 5.2: MCB and WCB generated and fully characterised (M29)

D 5.3: material made available for (a) preclinical toxicology (b) seroconversion and (c) structural analysis (M28)

D 5.4: GMP compliant batch release report (M32)



[1]   Please indicate one activity per work package: RTD = Research and technological development; DEM = Demonstration; MGT = Management of the consortium; OTHER = Other specific activities, if applicable (including any activities to prepare for the dissemination and/or exploitation of project results, and coordination activities).

Workpackage 6

 

Work package number

6

Start date or starting event:

M25

Work package title

Preclinical and regulatory affairs

Activity Type[1]

RTD

Participant number

1

 

 

 

 

 

 

Participant short name

IQUR

 

 

 

 

 

 

Person-months per participant:

2.0

 

 

 

 

 

 

                   

 

Objectives

Preclinical toxicology will be carried out prior to the final submission of a clinical trial application (CTA).

 

Description of work (possibly broken down into tasks), and role of participants

Preclinical toxicology testing is required for all material which will be used in human studies. The regulatory framework is described in the following documents;

ICH Document S6 (CPMP/ICH/302/95): Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals.

CPMP/SWP/2145/00 Note for guidance on non-clinical local tolerance testing of medicinal products.

CPMP/SWP/465/95 Note for Guidance on Preclinical Pharmacological and Toxicological Testing of Vaccines

 

Task 6.1: Preclinical testing (IQUR[s/c], M25-M30)

Although the vaccine guidance document CPMP/SWP/465/95 suggests that a single dose study in at least one species would be sufficient for many new vaccine products, including combined vaccines, the guidance also states that recombinant DNA protein vaccines should be addressed by ICH S6 ( CPMP/ICH/302/95). This guidance for biotechnology derived pharmaceuticals states that safety evaluation programmes should normally include two relevant species. As a result of this apparent inconsistency, we propose to carry out studies in two species approach in the first instance.

We will carry out repeated dose study designs in two species, to cover the potential repeated dosing in the clinic. Immunogenicity assessment will been included to look for immunological toxicity. Local tolerance to the vaccine can be assessed as part of the repeated dose toxicity study.

These studies will be carried out in GLP approved subcontractor’s facility and will be designed in accordance with regulatory advice.

 

Task 6.2: Regulatory application (IQUR/ICS [s/c], M24-M28)

Prior to the submission of any CTA, clinical advice will be sought from the Spanish regulator. A regulatory professional will be subcontracted to act for the consortium in preparation for this meeting and also to assist in the preparation of the final CTA.

Once a complete set of preclinical data has been collected a final CTA application will be submitted which will enable clinical trials to begin.

 

 


 

Deliverables** (brief description and month of delivery)

 

D 6.1: Preclinical safety report. (M30)

Safety testing will be carried out in two species and a suitable GCP compliant report prepared by the CRO. This will be used as part of the CTA process.

 

D 6.2: Regulatory application. (M30)

When sufficient laboratory and preclinical data has been generated, a formal filing to being clinical studies will be made with the Spanish Agency of Medicines and Medical Devices.

 



[1]   Please indicate one activity per work package: RTD = Research and technological development; DEM = Demonstration; MGT = Management of the consortium; OTHER = Other specific activities, if applicable (including any activities to prepare for the dissemination and/or exploitation of project results, and coordination activities).

Workpackage 4

 

Work package number

4

Start date or starting event:

M19

Work package title

Immunogenicity studies in ferrets

Activity Type[1]

RTD

Participant number

1

4

5

 

 

 

 

Participant short name

iQur

UCL

CRP-Santé

 

 

 

 

Person-months per participant:

2.0

3.0

1.1

 

 

 

 

                   

 

Objectives

Short-listed vaccine candidates will be further tested in the ferret IAV model.

 

Description of work (possibly broken down into tasks), and role of participants

 

The ferret is generally considered as the best animal model for investigating human influenza infections, due to the similarity in the clinical course and pathological lesions of the infection in both species. Work will be coordinated by iQur and subcontracted on a best-buy for money basis to a GLP accredited contract research organisation in order to ensure compliance with clinical trial legislation. In principle, despite the differences between influenza subtypes these experiments will be limited to the most distant IAV subtypes successfully tested in mice.

 

Task 4.1: Expression of lead candidate (UCL, IQUR, M19-M20)

The optimal VLP construct will be chosen on the basis of the immunogenicity and efficacy studies in mice (WP 3). The VLP will be produced by UCL at small (5 litre) scale (approximately 2g). Purification will be carried out using the methodology developed in WP 1.5. The purified candidate VLP will be characterized (i) by ELISA (antigenicity, conformation) (ii) Western blot (purity) (iii) for stability (see WP2) and (iv) to confirm its immunogenicity in mice. 

 

Task 4.2: Protection from lethal challenge (IQUR (s/c), M19-M21)

Ferrets will be immunised sub-cutaneously using the optimal dosing strategy developed in WP 3.1. Serum will be taken from immunised ferrets to confirm seroconversion.  At this point, the animals will be challenged with a lethal (5xLD50) dose of a homologous seasonal IAV. Virus replication (nasal swabs), and survival will be monitored. At the end of the experiment, surviving animals will be sacrificed to test for immunohistochemistry and virus titres in the lung. Protection against lethal IAV infection should be reproducibly 100% after vaccination with the optimal VLP. If protection is incomplete another short-listed candidate will be tested or another round of optimization will be initiated.

 

Task 4.3. Efficacy testing against heterologous subtypes (IQUR (s/c), M22-M24)

If efficacy of the candidate vaccine against the homologous challenge can be confirmed, animals will be challenged with heterologous seasonal subtypes including pandemic H1N1 (2009).  If animals are protected against sequential heterologous challenges, a group of animals will be vaccinated and challenged with the most “distant” heterologous subtype.

 

 

Deliverables** (brief description and month of delivery)

 

D.4.1 Demonstration of efficacious prophylactic regimen of best candidate VLP in ferrets. (M21)

Prophylaxis from lethal IAV infection should be 100% after vaccination with the optimal VLP. If this is not the case, as further round of optimisation will be recommended (WP 1.6).

 

D.4.2 Clinical lead candidate selected. (M24)

Reproducible complete protection from lethal challenge will be used as the final go-no-go point for initiating GMP production and, ultimately, clinical trial

 



[1]   Please indicate one activity per work package: RTD = Research and technological development; DEM = Demonstration; MGT = Management of the consortium; OTHER = Other specific activities, if applicable (including any activities to prepare for the dissemination and/or exploitation of project results, and coordination activities).