Vaccine adjuvants: the good, the bad and the
ugly
Professor Nikolai PetrovskyDirector of Endocrinology, Flinders Medical Centre
Research Director, Vaxine Pty LtdEditor-in-Chief, Journal of Vaccines and Vaccination
What are adjuvants?
•Any substance that increases the memory immune response to a co-administered antigen
•Discovered by trial and error, e.g. alum, oil emulsions, saponins
•Common feature – induction of inflammation – encapsulated in danger-hypothesis
•Postulated to work via innate immune cell activation, inflammatory cytokine production and APC activation leading to co-stimulation of memory T- and B-cell responses
Why do we need adjuvants
•Enhance antibody titers
•Generate CTL responses
•Improve cross-protective responses
•Antigen-sparing
•Speed kinetics of protection
•Decrease no. vaccine doses
•Extend immune memory
•Improve protection in neonates and the elderly
“After 2 doses of an H7N9 formulation containing 15 µg of hemagglutinin given without adjuvant, with AS03 adjuvant, or with MF59 adjuvant, the proportion achieving an HIA titer of 40 or higher was 2% without adjuvant, 84% with AS03 adjuvant, and 57% with MF59 adjuvant”
Potential adverse effects
LOCALpain bruisingswellingtenderness granuloma abscessulcer
SYSTEMICfever headachemyalgia/arthralgia fatigueLymphadenopathyeosinophilia allergy/anaphylaxisautoimmunity
Potential to trigger or exacerbate autoimmunity
Can we avoid adjuvant toxicity?
LOCAL•pain •bruising•swelling•tenderness •abscess
SYSTEMIC•fever •headaches•myalgia/arthralgia •fatigue•autoimmunity
REACTOGENICITY/TOXICITY
INFLAMMATION
Traditional adjuvants work via induction of inflammation
Delta inulin (Advax™) adjuvant breaks the
danger-signal paradigm
Soluble form –kidney testing
Particulate form –
Vaccine adjuvant
β-D-(2→1) polyfructofuranosyl α-D-glucose (inulin)
Advax enhances H5N1 influenza vaccine protection
in ferret model
Vaccine. 2011 Aug 26;29(37):6242-51.
Advax enhances JEV vaccine heterologous protection against
West Nile virus
Advax enhances neonatal influenza vaccine
protection
Advax provides influenza protection in adult B-cell deficient mice (uMT mice)
Nonsegmented negative-stranded RNA genome containing 7 structural and regulatory genes. )
Family: FiloviridaeFilamentous form with diameter ~80 nm and
variable length.
DoD VLP vaccine based on VP40 and glycoprotein (GP) expressed in
HEK293 cells
Ebola vaccine project with USAMRIID
VLP+Advax2 CD8 T-cell responses 2x PolyICLC
Preclinical models confirming efficacy of Advax delta inulin
adjuvant
Human clinical trials confirming efficacy of Advax
delta inulin adjuvant
• Trivalent inactivated seasonal Influenza
vaccine
• Recombinant HA pandemic influenza
(H1N1/2009pdm) vaccine
• T cell fluropeptide-based influenza vaccine
• Hepatitis B vaccine
• Insect venom allergy immunotherapy vaccine
Next-generation pandemic influenza vaccine project with Protein Sciences Corporation (Meriden, CT)
21 April 2009 - new H1N1/2009 virus isolated
and sequenced
Haemagglutinin gene cloned into baculovirus
Insect cellexpression
GMP cell culture and protein purification
Formulation with Advax adjuvant
17
Human trial commenced
Adelaide – 18 July 2009
Animal study
confirms need for adjuvant
Vaccine 2012 Aug 3;30(36):5407-16
Advax enhances human T-cell IFNresponses to influenza
peptide vaccine
Confidential slide
Human trials of Advax
HBVvaccine
Seasonal inactivated influenza vaccine
Bee sting anaphylaxisImmuno-therapy
rH1N1/2009pdm vaccine
Peptide-based universal influenza
Totalsubjects
>30 >1400 >20 271 80
Proportionreceiving Advax
2:1 2:1 2:1 1:1 1:1
Number of immunizations
3 1-4 >30 2 2
Why is Advax different to other
adjuvants?
Delta inulin is non-reactogenic
and targets mDC
Holden Maecker, Stanford Uni
Advax provides single-dose anthrax vaccine
protection
Clin Vaccine Immunol. 2014 Apr;21(4):580-6.
Advax induces minimal reactogenicity
Clin Vaccine Immunol. 2014 Apr;21(4):580-6.
Adjuvant reactogenicity comparison study in camels
Enhanced immunogenicity Enhanced immunogenicity versus reactogenicityversus reactogenicity
• Positive-stranded RNA virus• Spike protein mediates target cell
entry via ACE2• Alum-adjuvanted vaccine induces
lung eosinophilic pathology
SARS coronavirus vaccine
J. Virol. 2014 Dec 17.
Alzheimer’s vaccine• Abeta and p-tau proteins play
pathogenic role• Monoclonal Ab. can work but
expensive & inconvenient
1
10
100
1000
10000
Montanide ISA51
Montanide ISA720
MPLA Alhydrogel®
Quil-A AdvaxMT
Abeta Multitep vaccine
Con
c. o
f an
ti-A
Ab
s (µ
g/m
l)β
Abeta
P-tau
Abeta pTau
How does Advax enhance humoral
and cellular immunity without reactogenicity?
Traditional adjuvants
Advax is effective in innate immune knockout models
•MYD88/TRIF•TLR4, TLR9 •NALP3•IL1 receptor•Complement C3, Factor B •IL12, IL33•IFNR1•NSAID treatment•NFkB inhibition
Advax is effective in MYD88/TRIF double knockouts
Advax is the first non-inflammatory
adjuvant
CD4T cell
CD8T cell
Advax
Advax
Chemokines/Chemokine receptors
(MCP1, IL-8 CCR1, CCR2)
Antigen presentation (MHC1, MHC2,
CD40, CD40L, CD80, CD86)
Inflammatory cytokines
(TNFa, IL1, IL6)
TLR agonist
MyD88/TRIF
TRAF6
NFkB
MHC 1MHC 2
Monocyte/mDC differentiation
(CD11c, CD71)
Advax mechanisms of action
Advax
Advax
CD71
CD11c
CD86
B cellB cellMCP1
IL-8MIP1b
TLRsMF59QS21Alum
Opsonisation
Endosomalregulation
Chemotaxis
DC differentiation
Co-stimulation
Adaptive adjuvant
Inflammation
Innate adjuvants
Antigen presentation NALP3
A new way to think about adjuvants?
NIH Adjuvant Discovery Program
TLR9 ECD
Advax combined adjuvants for mTB
vaccines
Triccas, unpublished data
Alternative immunization routes
Lung immunization with Advax
Enhanced neonatal immunization
Y. Honda-Okuba Vaccine, in press
Adjuvant evolutionAdjuvant evolution
1st Generation (CFA, oil emulsions, bacterial extracts) • Emulsions/bacterial extracts generate danger signals by
inducing tissue damage– high reactogenicity• Induce autoimmunity in animal models
2nd Generation (alum, MPL, CpG, squalene, QS21) • Better characterised – stimulate TLR or inflammasome• Induce inflammatory cytokines (IL-1, TNF-a)• Can cause pyrexia• Remaining potential for autoimmunity
Next generation adjuvants (Advax)• Non-inflammatory • Don’t induce autoimmunity• Don’t induce pyrexia• Specific enhancement adaptive immunity
AcknowledgementsVaxinePeter CooperSu HeinzelBruce LyonsY. Honda-OkubaFadi SaadeSamay TrecLei LiHarinda R.
Mario LobigsDavid GordonDimitar Sajkov
Manon Cox, Protein Sciences
John Morrey and Dale Barnard, Utah State University
Fred Coster, Lovelace Respiratory Research Institute
Tod Merkel, CBER, FDA
Kitasato Institute, Japan
Dr Uli KinniCVRL Dubai
NIH ContractsU01AI061142 HHSN272200800039CHHSN272201400053C
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