Table 1.

Summary of adjuvant strategies in human TB vaccine clinical trials or in preclinical animal testing. MPLA:3-O-desacyl-4′-monophosphoryl lipid A; DDA:dimethyldioctadecyl-ammonium; TDB:trehalose 6,6-dibehenate; GLA:glucopyranosyl lipid adjuvant; KLK:KLKL₅KLK; TLR:toll-like receptor.

Adjuvant/Delivery System	Components	Antigen	Proposed Mechanism of Action	Immune Readout	Testing Status	References
Advax	Delta inulin particles	Ag85B, CysD (CysVac2)	Enhanced phagocytosis, immune cell recruitment, low reactogenicity	Th1, Th17	Preclinical	[12,14]
AS01	MPLA and QS21	Mtb32, Mtb 39 (M72)	TLR4 activation (MPLA), liposomal disruption and Syk activation, CD2 activation on T-cells, NLRP3 inflammasome (QS21)	Th1	Phase IIb (54% efficacy)	[40,71,72]
B. subtilis spores		MPT64; Acr-Ag85B	Mucoadhesive, resistant to enzymatic degradation, suitable for mucosal administration	Th1, IgA, low Th17	Preclinical	[73,74]
CAF01	DDA and TDB	Ag85B, ESAT-6 (H1)	TDB activates Mincle, MyD88-dependent Th1/Th17 polarising cytokines. DDA forms cationic liposomes that are stabilised by TDB.	Th1, Th17	Phase I	[49,52,75,76]
Chitosan and derivatives		Ag85B, ESAT-6 (H1)	Activates cGAS-STING pathway, mucoadhesive and mucosal epithelial penetration properties, suitable for mucosal administration	Th1, low Th17	Preclinical	[77,78]
Cyclic dinucleotides	Synthetic dinucleotide analogue of cyclic diguanylate	Ag85B, ESAT-6, Rv1733c, Rv2626c, RpfD (5Ag)	STING activation (IRF-3 type I IFN production, NFkB, STAT-6 chemokine expression)	Th17, low Th1	Preclinical	[26]
Dextran		Ag85A, ESAT-6-CFP10	Activates DC-SIGN receptor family, mannose receptor, langerin	Th1/Th2	Phase I	[64,65]
GLA-SE	GLA in squalene emulsion	Rv2608, Rv3619, Rv3620, Rv18183 (ID93)	GLA is a synthetic TLR4 agonist, in squalene in water emulsion activates NLRP3 inflammasome	Th1	Phase IIa	[56,57,58,79]
IC31	KLK and ODN1a	Ag85V, ESAT-6 (H1); Ag85B, ESAT-6 and Rv2660c (H56) and Ag 85B, TB10.4 (H4)	ODN1a binds TLR9, KLK forms aggregates with ODN1a and enhances translocation into cells	Th1	Phase IIa (H56:IC31; 30.5% efficacy)	[46,59,80,81]
ISCOMs	Immune stimulatory complexes (saponin, cholesterol and phospholipid)	Ag85B, ESAT-6 (H1); Ag85A	TLR independent, may be inflammasome mediated (under investigation)	Th1/Th2	Preclinical	[82,83,84]
Lipokel	PamCys2 and 3NTA	Culp 1, Culp 6	PamCys2 is a TLR2 ligand and 3NTA is a chelating entity that allows antigen binding	Th1	Phase I	[85]
Nanoemulsion	Soybean oil phase mixed into aqueous phase	ESAT-6, Ag85B	Mucoadhesive, highly tolerated, suitable for mucosal administration	Th17, Th1	Preclinical	[86,87]
PLGA (poly(lactic-co-glycolic acid))	Microsphere delivery system	Ag85B, ESAT-6 (H1); MPT83	Antigen protection, depot formation, controlled release, enhanced phagocytosis, biodegradable, suitable for mucosal administration	Th1, Th17	Preclinical	[88,89]
PolyI:C	dsRNA	BCG; Ag85B, HspX	TLR3 agonist	Th1, Th2	Preclinical	[90,91]
Yellow carnauba wax nanoparticles	Incorporated with heparin-binding hemagglutinin adhesion (HBHA) protein	Ag85B	Enhanced adherence to alveolar epithelium (HBHA), highly tolerated (particles), suitable for mucosal administration	Th1	Preclinical	[92]