place de l’inflammation dans la réponse aux vaccins adjuvantés · 2019. 5. 19. · as01 alum...
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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 Sci Transl Med. 2011 (MF59); unpublished (AS03) 4 Nolan et al, J Infect Dis 2014 5 Moris et al.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