INYVAX

PHARVAT

1 Confidential

ADJUVANT ACTIVITIES

Adjuvants – immunologists dirty

little secret

• Added to vaccines to:

• Enhance immune response

• Bias immune response

• Induce cell mediated immunity

• Induce immunity in poorly responsive population

• Reduce antigen dose

• Reduce number of doses needed

Addressing the challenges to

adjuvants • Access

–TRANSVAC : adjuvant supply and formulation

service, know-how, training

• Harmonization

–PHARVAT : standardised comparison kits

• Know-how

– INYVAX : Strategy on adjuvant use and

training

WHO Global Adjuvant Development Initiative

Jan 2010: Creation of a centre for adjuvant technology transfer /

training

Hosted by University of Lausanne

WHO Collaborating Centre

Experience in vaccine formulation, ex-industry staff

TRANSVAC – providing access to Adjuvants, formulation service and know-how

Objectives

• Provide open-access to generic-type adjuvants to

public sector vaccine research (preclinical)

• Undertake vaccine formulations (GLP)

• QC (GLP)

• Know-how

• Training

• Technology transfer

– Future GMP availability

Adjuvant laboratory at UNIL

January 2010 – Creation of the Vaccine Formulation Laboratory

Manufacturing (lab-scale, pilot-scale) and QC of adjuvants

47 custom formulations to provide under Transvac “Transnational Access “

2 Transvac training courses scheduled in 2012 and 2013

Adjuvant inclusion criteria:

Mature technologies; demonstrated safety in human trials

Favourable intellectual property status (freedom-to-operate/research)

October 2011

- Aluminium salts - Oil-in-water emulsions - Water-in-oil emulsions

- Liposomes - Saponin - TLR4 agonists

UNIL Adjuvant Portfolio

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ONH

O

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NH OH

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(HO)2P

O

OO

O

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O

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Et3N

1 Formulation: testing and characterization of 1 Antigen + 1 Adjuvant

Antigen is provided by user (with adequate information) Adjuvant is usually provided by VFL

Compatible formulations are sent back to user; non-compatible formulations are discarded In vivo evaluation is not included 1 formulation allows up to 50 single IM injections in mice

All SOPs and formulation protocols shared with user

On-site TRAINING is offered

Transvac WP8: Formulation Services

28/47 access units already attributed. Formulation work to be started. Examples:

MUCOSTIM - Dr Stéphane Paul, Centre Hospitalier Saint-Etienne

Evaluation of 9 original formulations with HIV P24 PLA-coated antigen

TARGET PART-QS21 - Dr Karen Misstear, Trinity College of Dublin Evaluation of 5 original formulations with H1N1 influenza antigen and QS21

Formulation services requested beyond TRANSVAC scope: biotechs, academics…

Transvac WP11: Formulation Services

Transvac WP8: Modular course on vaccine development

Antigen systems

Fermentation and media

Downstream processing

Formulation

Animal models

Stability studies & QC

Toxicology – GLP

Clinical dossier

Business development

Discussion

1 course in August 2012

1 course in August 2013

Training centre – dedicated trainers

100m2 space with dedicated training suite

Several trainings organized for tech transfer

Ex: training course on oil-in-water adjuvants March 2011, Vaccine Formulation Laboratory

Technology transfer

• Oil-in-water emulsion adjuvant for

pandemic influenza vaccines

• Indonesia, BioFarma

–GMP consistency lots completed

• Vietnam IVAC

–Training 2012

• Requests from India, Argentina, China,…

Deutsche Gesellschaft für Internationale Zusammenarbeit

World Health Organization

US HHS BARDA

Developing Countries Vaccine Manufacturers’ Network

Wellcome Trust

European Commission

VFL partners

Contact: nicolas.collin@unil.ch

PHARVAT: harmonization of

adjuvant screening

• No two publications on adjuvant use the

same antigen, schedule, assay etc

–Comparison impossible

• EVI / BPRC / WHO / UNIL

– Identification of 'best practices' in adjuvant

comparison

–Provision of reference reagents

Pharvat Adjuvant Screening Kit

• 3 standard antigens (GMP grade, single

batch)

–HBsAg, AMA1, Ag85A.

• Mouse, Rabbit serum

• Immunization protocol

– (strain, route, volume, dose, schedule)

• ELISA protocol

INYVAX

• How to optimise immune response to

antigens

–Which adjuvants to use, how to select

adjuvants ?

• Risk management

• Adjuvant Selection Procedure:

– 7 steps. Increasing risk with each step.

Rule 1 : Don’t use an adjuvant !

• Work on the antigen to make it as immunogenic as possible !

–VLPs, lipo-proteins, fusion partners, conjugates,..

–Time spent on doing this will be saved later trying to get adjuvant accepted.

• But once optimised, if you really NEED an adjuvant…

Rule 2. Use an adjuvant that is

already in an APPROVED vaccine

• Alum - use know-how to optimise use

• MF59, AS04, AS03, AS01, RC-529,

virosome..

–Extensive safety database, know-how,..

• If access not possible or effect

inadequate…

Rule 3. Use a 'generic' form

• Same chemical composition (biosimmilar)

• o/w emulsion, QS21, virosome,..

• Same mode of action (not biosimmilar)

• Higher risk : eg TLR4 agonists

– E6020, GLA, MPLA from Neisseria, Pertussis,..

–Overcomes access issue – enables preclinical /

early clinical trials.

• If access not available or effect inadequate…

Rule 4. Use and adjuvant that is in

late-phase clinical studies

• >n clinical studies with NO SAEs.

– prioritise based on

• number of clinical trials & reject all with adverse events.

• Then prioritise on immune bias reported in clinic, safety in

age group & GMP-supply & cost

• Induces type of immunity you think you need

• If access not available or effect inadequate…

Rule 5. Use an adjuvant that is

already in early clinical development

• GMP material available, tox study completed,

clinical trial underway…

• Where activity on mouse cells and human

cells are parallel…

• Induces type of immunity you think you need

• If access not available or effect inadequate…

Rule 6. Use an adjuvant that has only

been used in preclinical trials…

• prioritise based on:

–Preclinical toxicological studies;

–Approved veterinary use?;

–Primate>Rabbit>Mouse;

–Access or access to generic form;

–GMP timeline

• If access not available or effect inadequate…

Rule 7. When all else fails…

• Find a different antigen

– If that doesn’t work:

• Find a different disease to work on

– If that doesn’t work:

• Try another profession...