INNOVATIVE VECTOR SYSTEMS, ADJUVANTS AND

OTHER DELIVERY SYSTEMS

THE SCIENTIFIC CHALLENGES

Else Marie Agger

Infectious Disease Immunology

Statens Serum Institut

Denmark

New horizons for vaccine research and innovation, Bruxelles, 2014

ADJUVANTS OFFER A RANGE OF BENEFITS

Reed, Nature Medicine, 2013

MOVING FROM EMPIRICAL APPROACHES

1925: Ramon recognize that a variety of substances increase antigen

specific antibody production to diptheria and tetanus toxoids

1926: Glenny introduce aluminium salts as adjuvants

TIMELINE

1925 Adjuvant effect of: -Agar -Tapioca -Lecitin -Starch oil -Saponin -Bread crumps

1961 Thymus function

1968 T & B cells

1975 MHC

1986 TH1 & TH2

1996 Immuneact. by TLR

1973 DC’s

1994 TLR

1998 TLR-4 act. by LPS

ADJUVANTS IS A GROWING RESEARCH FIELD

PubMed search on vaccine adjuvants

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ADJUVANTS APPROVED FOR HUMAN USE

1920 1940 1930 1950 1960 1970 1980 1990 2000 2010

Aluminum-adjuvants

Virosomes

MF59

AS04

AS03

TIMELINE

EXAMPLES OF ADJUVANTS IN CLINICAL TESTING

Name Mechanism Profile

GLA-SE TLR4, emulsion Ab, Th1

AS01 TLR4, QS21 liposomes Ab, Th1

AS02 TLR4, QS21, emulsion Ab, Th1

AS15 TLR4 and 9, QS21, liposomes Ab, Th1, CD8

ISCOMS Unknown Ab, Th1/Th2, CD8

CD1d ligands CD1d Ab, Th1/Th2, CD8 NKT

CAF01 Mincle, liposomes Th1/Th17

IC31 TLR9, cationic peptides Th1/Th2

Flagellin TLR5 Ab, Th1/Th2

Imidazoquinolines TLR7/8 Ab, Th1

IMMUNOMODULATORS SIGNALLING THROUGH PRR´S

MPL/GLA

Flagellin

CpG polyIC

Resi- quimod

TDB

SYNTHETIC PAMPS IN VACCINE ADJUVANTS

Olive, Exp. Rev. Vaccine 2012

How can we use cross-talk between PRRs

to achieve:

- Balanced responses (CD4/CD8,

Th1/Th17/Tfh)

- Optimal magnitude, avidity, memory

Synergy/antagony: Is is better to combine

different classes of PAMPS signalling

through different signal pathways

(MYD88/TRIF/SYK)

The distribution of PPR´s: on various APC´s,

in neonates and in different species

(rodent/non-rodents and humans)

FUTURE CHALLENGES AND POSSIBILITIES

How to obtain tissue-specific responses:

- Chemokine receptors

- Vitamins

- Targeted immunisations

FUTURE CHALLENGES AND POSSIBILITIES

How to obtain tissue-specific responses:

Accelerate clinical evaluation of novel adjuvants

IC31, CAF01 and AS01 have been used in phase I trials in Leiden and

Lausanne with H1 and 72f (now M72) respectively, supported by TBVAC

LTK63 have been used in phase I trials, supported by MUVAPRED

FUTURE CHALLENGES AND POSSIBILITIES

How to obtain tissue-specific responses:

- Chemokine receptors

Accelerate clinical evaluation of novel adjuvants

H2H comparison of adjuvants

FUTURE CHALLENGES AND POSSIBILITIES

How to obtain tissue-specific responses:

- Chemokine receptors

Accelerate clinical evaluation of novel adjuvants

H2H comparison of adjuvants

Heterologous prime/boost strategies

FUTURE CHALLENGES AND POSSIBILITIES

How to obtain tissue-specific responses:

- Chemokine receptors

Longevity of responses?

Accelerate clinical evaluation of novel adjuvants

H2H comparison of adjuvants

Heterologous prime/boost strategies

H1:IC PHASE I CLINICAL TRIALS

THYB-01

Ag85B ESAT-6

Phase I - Safety (high endemic, ET)

M.tb. naive / BCG vacc / LTBI

Adults, N=48

Phase I – Safety (low endemic, NL)

Adjuvant dose escelation study

Healthy adults, N=36

THYB-02

Phase I – Safety (low endemic, NL)

BCG vacc / LTBI

Adults, N=36 THYB-03

Vaccine generates long term memory in all phase I trials

FUTURE CHALLENGES AND POSSIBILITIES

How to obtain tissue-specific responses:

- Chemokine receptors

Can potency and inflammation be dissociated

Accelerate clinical evaluation of novel adjuvants

H2H comparison of adjuvants

Heterologous prime/boost strategies

Longevity of responses?

ACKNOWLEDGEMENTS

TB vaccine research

Claus Aagaard

Rolf Billeskov

Truc Thanh Hoang

Joshua Woodworth

Thomas Lindenstrøm

Jacob Munk Hansen

Jonathan Filskov

Niels Peter Knudsen

Iben Sohn

Ahmad Ahmad

Adjuvant research

Dennis Christensen

Karen Korsholm

Jes Dietrich

Signe Tandrup Schmidt

Rasmus Julsgaard Mortensen

Collaborators:

University of Göteborg:

Ali Harandi

IDRI:

Rhea Cöler

Steven Reed

Valneva:

Andreas Meinke

Andreas Fritzer

Novartis:

Cecilia Buonsanti

Ugo D´Oro

LUMC:

Tom Ottenhoff

Simone Joosten

Vaccine development

Ingrid Kromann

Charlotte Green Jensen

Kirsten Bisgaard-Frandtzen

Peter Bang

Birgit Thierry-Carstensen

Lars Vibe Andreasen

Vice president, R & D

Peter L. Andersen