Table 1.

Overview of inflammasome-activating adjuvants.

Adjuvant	Description	Targeted Inflammasome	References
Al(OH)3, AlPO4	Al-hydroxide, Al-phosphate individually or as part of AS04	NLRP3	[6,7,8,9,10] [11,12,13,14,15] 1
MF59	Squalene O/W emulsion	NLRP3	[16,17] 2 [15,18] 3
AS01 AS02	QS-21 + MPL + liposomes QS-21 + MPL + O/W emulsion	NLRP3	[19,20,21] 4
AS03	Squalene O/W emulsion + vitamin E	NLRP3	5
AS04	MPL adsorbed onto Al(OH)3 or AlPO4	NLRP3	[6,7,8,9,10] 6 [22] 7
GLA-SE	GLA + squalene O/W emulsion	NLRP3, Non-canonical	[23]
QS-21	Triterpene saponin fraction purified from Quillaja saponaria	NLRP3	[19,20,21]
ISCOM, IMX	Immunostimulating complex containing saponins, phospholipids and cholesterol	NLRP3	[24,25]
CpG-ODN	TLR9 agonist (putative inflammasome-activator)	NLRP3	[26]
Ca3(PO4)2	Calcium phosphate	NLRP3	[27,28]
TDB	Synthetic trehalose-6,6′-dibehenate (an analogue of mycobacterial cord factor trehalose-6,6′-dimycolate)	NLRP3	[29,30]
PLGA	Poly(lactic-co-glycolic acid) microparticles	NLRP3	[31]
Vault NPs	Large cytoplasmic ribonucleoprotein particles	NLRP3	[32]
Chitosan	Biodegradable cationic polymer obtained from chitin	NLRP3	[10,33,34,35,36]
Silica particles	Biocompatible particles	NLRP3	[37,38]
Gold NPs	Gold nanoparticles	NLRP3	[39]
Flagellin	Used as recombinant protein, or encoded in virus replicon or DNA plasmid	NLRC4	[40,41,42,43,44]
DNA vaccines	DNA plasmids or Aim2 encoded in vector as immunopotentiator	AIM2	[45,46,47]
CTB	Cholera toxin B from Vibrio cholerae, added to an Ag, or as a DNA vaccine	NLRP3, Pyrin	[48,49,50]
oxPAPC	Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (generated during tissue damage)	Non-canonical	[51,52,53]

¹ These studies suggest that the NLRP3 inflammasome is dispensable for the adjuvanticity of Al salts. ² These studies found indications that NLRP3 might be involved in the MoA of MF59 (induction of expression of caspase-1, IL-1β, and IL-1R1). ³ These studies suggest that the NLRP3 inflammasome is dispensable for the adjuvanticity of MF59. ⁴ These studies used components of AS01/AS02: QS-21 + MPL [20]; QS-21 formulated in liposomes [19,21]. ⁵ AS03 is listed as a putative activator of NLRP3, since other squalene O/W emulsions (MF59, GLA-SE) have been suggested as potential inflammasome activators. ⁶ These studies used components of AS04 (Al salts). ⁷ This study showed enhanced adjuvanticity of AS04 compared to Al salts (increased NLRP3 activation through MPL mediated TLR4 priming is a potential explanation). Abbreviations: aluminium (Al), oil-in-water (O/W), adjuvant system (AS), antigen (Ag), glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE), nano particles (NPs), immunostimulating complex (ISCOM), ISCOMATRIX (IMX), poly(lactic-co-glycolic acid) (PLGA), trehalose-6,6′-dibehenate (TDB), cholera toxin B (CTB), oxidized phospholipids (oxPAPC), absent in melanoma 2 (AIM2), nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing protein 3 (NLRP3), NLR family CARD domain-containing protein 4 (NLRC4), CpG oligodeoxynucleotide (CpG-ODN); 3-O-desacyl-4′-monophosphoryl lipid A (MPL); Quillaja Saponaria fraction 21 (QS-21).