Place de l’inflammation dans la réponse aux vaccins adjuvantés

Dr. Arnaud Didierlaurent R&D GSK Belgium

I-Reivac

Paris, 01/04/2016

Stratégies pour adresser les challenges dans le

développement des vaccins

Populations

nourrissons, personnes

agées, immuno-

compromis, femmes

enceintes etc.

Pathogenes

ou maladies

Malaria, HIV, TBC, HZV

CMV etc.

New

Adjuvants

New delivery

strategies

(live vectors)

New antigen

presentation

(DNA)

New Antigens

Garçon N et al. Understanding Modern Vaccines: Perspectives in Vaccinology, Vol 1. Amsterdam: Elsevier; 2011 (chapter 6: p151–99) CMV = Cytomegalovirus

The Role of Adjuvants and Adjuvant Systems in Vaccine Design and Development

Challenges

Strategies

Observed benefits of adjuvants in candidate or

licensed adjuvanted vaccines

Persistent CD4 and antibody response 1

Dose sparing effect 2

Increase breadth of the antibody response (MF59/AS03-adjuvanted flu)3

Possibility to use lower dose of adjuvant in paediatric formulation 4

Evidence of cross-reactive T cell response 5

AS are being used in vaccines in special populations, such as in immunocompromised6 or

HIV+7, and no safety concerns have being raised

3

References:

1 Leroux-Roels et al. Vaccine, 2015 (HBs/AS01); Leroux-Roels et al., Clin. Vaccine Immunol. 2014 (F4/AS01); Roteli-Martins et al.,

Hum Vaccin Immunother 2012 (HPV/AS04) 2 Baras et al. PLoS One 2008; Leroux-Roels et al. Lancet 2007 ; Nolan et al, J Infect Dis 2015 3 Khurana et al. Sci Transl Med. 2011 (MF59); unpublished (AS03) 4 Nolan et al, J Infect Dis 2014 5 Moris et al. J. Clin. Immunol. 2011 (H5N1/AS03); Wheeler et al, Lancet Oncol 2012 (HPV/AS04-Cervarix);

Einstein et al, Hum Vaccines 2011 6 Stadtmauer et al. Blood 2014 (Zoster gE/AS01); Tong et al. Kidney Int 2005 (HBs/AS04-Fendrix); Siegrist et al, Plos One 2012

(H1N1/AS03) 7 Denny L, et al. Vaccine 2013 (HPV/AS04Cervarix); Ho J et al. AIDS 2011 (H1N1/AS03); Harrer et al. Vaccine 2014 (F4/AS01)

Pré-clinique

5-15 ans

Clinique

5-15 ans

Après mise sur le marché

Pour le cycle de vie

complet

Évaluation de l'innocuité et son suivi1

Les vaccins sont évalués avec soin avant leur homologation. Ils sont fabriqués et distribués selon des

processus de contrôle stricts surveillés par les autorités réglementaires.

Mise en place d’un suivi étroit après mise sur le marché, notamment l’identification potentielle d’effets

secondaires rares liés aux vaccins

Ces informations sont rendues publiques et, le cas échéant, des mesures sont prises rapidement, comme

la mise en place d’études spécifiques pour étudier la causalité avec le vaccin

1. Leroux-Roles et al., chapitre 5 de Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011, pp. 115–50; 2

L‘évaluation de l’innocuité est d'une importance primordiale,

depuis la création et tout au long de la vie d'un vaccin

Biodistribution study: supportive but not a regulatory

requirement (according to guidelines)

Business Use only 5

Radioactive AS03 components

mice

J. Appl. Toxicol. 2015; 35: 1564–1576

Fit-for-purpose formulation can reduce reactogenicity

(ex: development of AS01)

6

• Appropriate formulation eliminates undesired activity of molecules, allowing their use as adjuvants. Ex: QS-21

Free QS-21 QS-21 in a liposome + cholesterol

AS01 Physiological solution

Local reaction in the muscle in injected OFA rats

QS-21 is quenched by

cholesterol and is no

longer haemolytic in

the final formulation

unpublished Confidential

Immunostimulants can also be “attenuated”

7

Ex: development of MPL

Special Considerations & Challenges of the Safety

Evaluation of Adjuvanted Vaccines

8

Challenges:

• Adjuvants have the potential to invoke complex immune responses

• Mode of action of adjuvants not always known

• Predictive animal models not always available

• Adjuvants are not administered alone

Often cited potential risks

• Severe local and/or systemic reactogenicity ?

• Systemic inflammation ?

• Combined effects :antigen- adjuvant ?

• Theoretical risk of adverse immunological responses that may lead to immune-mediated disorders, linked to: homology of the antigen to a human constituent or non-specific immune enhancement properties of the adjuvant used

9

Post-licensure experience

with AS03 & AS04

Additional evidence on the safety of (AS03) A/H1N1

vaccines in real-life settings

• No difference in reporting rates between adjuvanted and non-adjuvanted

H1N1 vaccines in EU study of spontaneous safety reports of auto-

immune diseases to Eudravigilance1

– Adjuvanted vaccines: 6.87 (95% CI: 6.06–7.68) per million

– Non-adjuvanted vaccines: 9.98 (95% CI: 6.81–13.16) per million

• No evidence of increased risk for >30 auto-immune and neurological

diseases (except narcolepsy) in Swedish cohort of >3.3 million

Pandemrix vaccinated individuals2

1. Isai et al. Vaccine. 2012;30(49):7123-9

2. Persson et al. J Intern Med. 2014 Feb;275(2):172-90

See also: Vaughn et al. Hum Vaccin Immunother (2014) pooled analysis of H1N1 and H5N1 clinical trials

10

(AS04) human papillomavirus vaccine

Cervarix™

• Theoretical risk of pIMDs: in addition to clinical data, pooled safety

analysis and post-marketing experience do not support increased risk of

autoimmune diseases

• GSK study in the UK CPRD: no significantly increased risk of

ophthalmic/neuro-inflammatory and other AD1

• Pregnancy outcomes in line with published literature. GSK study in the UK

CPRD: no evidence of increased risk of spontaneous abortions2

• Enhanced surveillance in national immunisation programmes (UK,

Netherlands) confirm acceptable safety profile

• Post-licensure data confirm favorable benefit–risk profile in women

of all ages

11

1. Baril et al. Vaccine 2015

2. Rosillon et al., ICPE abstract (PDS 2014); Willame et al., ICPE abstract (PDS 2015)

See also: Angelo et al. Pharmacoepidemiology & Drug Safety (2014)

CPRD: Clinical Practice Research Datalink

Understanding the Mode of action of adjuvanted

vaccines to support the evaluation of their safety

protection

Key scientific questions- Translational research is needed

Link

innate-adaptive Link

Innate-reacto

Biomarkers of inflammation

Correlate of protection

role of

pre-existing immunity

Clinical

research

Mechanistic

models

13

Les adjuvants induisent une réponse innée nécessaire pour

augmenter la réponse contre l’antigène

Cytokines Antigène Granulocyte

Garçon N, et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam: Elsevier; 2011; chapter 4: p89-113 14

Réponse innée (0-72 h) Réponse adaptative (jour 1 à plusieurs

semaines)

Confidentiel

Sang

Stimulation

du système

inné local

Recrutement

de cellules

immunitaires

innées

Réponse immunitaire adaptative Réponse

locale de

cytokine

Les cellules présentatrices d’antigènes transfèrent les

messages issus de l'immunité innée aux cellules T et B

Ganglion

lymphatique

drainant Site de l'infection/injection

What are the key signalling pathways implicated in the

adjuvant effect of adjuvants?

TLR

adaptator

Kinase

activation

Transcription

factors

Ag+ adjuvant

Sensors?

Stress

platforms

MPL, CpG Alum, emulsions

ER stress Metabolic

stress

Inflammasome Hypoxia

Danger

molecules

Transcription

factors

saponins

16

Duthie et al. ; Immunological Reviews 2011

Vol. 239: 178–196

These pathways also operate in other “classical” vaccines

Early Clinreseach-002: Head-to-head comparison

of different Adjuvant Systems in humans

• Aim: Head to head comparison of Adjuvants Systems

AS01B, AS01E (AS01B 1/2 dose), AS03, AS04

using the same antigen (HBs Ag model antigen) vs

Alum-adjuvanted antigen, in HBV naïve adults (18-45y)

• Design: Phase II, randomized, multicenter, observer-blind, N~140 subjects/group

• Vaccine schedule: 2 doses (0, 1 month), intramuscular injection

• Objectives:

• To compare the adaptive immune response induced by AS

• To evaluate the innate immune response and, potential correlations with

the reactogenicity and with the adaptive immune response

• To evaluate the safety and reactogenicity

AS Composition

Formulation Immunostimulants

AS01 Liposomes MPL, QS-21

AS03 O/W emulsion Alpha tocopherol

AS04 Aluminium salt MPL

Confidential 51

Anti-HBs Antibodies (mIU/mL)

Specific CD4+

T cells (CD40L+ per

1.10e6 cells)

The « adaptive signature » of different AS in humans

Technical Cut-off

Seropositivity

Cut-off

AS

01

Marchant & Leroux, submitted

Higher antigen-specific CD4 T cell is associated with a higher

prevalence of reactogenicity symptoms

SW

RE

PAFA

MA

GA

MYHA

FE

SW

RE

PAFA

MA

GA

MYHA

FE

SW

RE

PAFA

MA

GA

MYHA

FE

SW

RE

PAFA

MA

GA

MYHA

FE

AS01

Alum

AS04

AS03

100%

100%

100%

100%

Ag-

spec

ific

CD

40L+

CD

4+T

-cel

ls

per

mill

ion

CD

4+T

cel

ls

Ag-specific antibody

concentrations, (EU/ml)

Alum

AS01AS03

AS04

100 102 104

104

103

102

101

Symptom

PA Pain

RE Redness

SW Swelling

FE Fever

HA Headache

MY Myalgia

GA Gastrointestinal

MA Malaise

FA Fatigue

Loca

lS

yste

mic

Intensity

Grade ≥1

Grade 3

A B

Marchant & Leroux, submitted

No vaccine-related SAE

reported in the study

Confidential 53

PA

RE

SW

FE

FAHE

MY

MA

GI

Grade . 1 2 any

1

48

95

26.4

Any

Grade 1 (mild)

Grade 2 (moderate)

The effect of the adjuvant is localized at the site of injection

and draining lymph node (macaque data)

Collignon et al. Manuscript in preparation

D0

VZV gE Ag

+/- AS01 or AS03

3h 24h 72h 7d

Confidential 55

Adjuvant effect of AS01 is local and transient

1st injection

AS01 (1/10 HD)

2nd injection

gE (5 µg) 2nd injection

gE (5 µg)

n=16

Immunizations Antibody and T cell

response d0 d28 d58

(§)

Didierlaurent et al. J. Immunol, 2014

conclusions

Study of the MOA helps to define the nature and kinetics of the inflammation Link to the formulation and vaccine response (reacto vs adaptive)

Now can be done in humans- Biomarkers could be used for association with reacto and

safety

Help to define the best predictive models to study safety signals

Difference between adjuvanted vaccines and other vaccines/infections

However, models do not account for variability of the human population can only do risk assessment based on profile of the response observed (ex: risk of

auto-immune diseases)

Best assessment still remains through clinical safety evaluation and pharmacovigilance

Understanding relationship between baseline status pre-vaccination and

vaccine response will be key to assess risk of rare events

Confidential

Acknowledgments

• GSK R&D

– Catherine Collignon

– Margherita Coccia

– Caroline Hervé

– Aurélie Chalon

– Cedric Vanderhaegen

– Viviane Bechtold

– Sandra Morel

– Nathalie Garçon (Now at Bioaster)

– Marcelle Van Mechelen

– Robert Van Den Berg

– Robbert Van Der Most

• GSK Clinical RD

– Fernanda Tavares

– Catherine Cohet

– Pascale Van Belle

– Wivine Burny

– ECR-002 Study Participants and clinical

investigators