Table 2.
Vaccine adjuvants used in pre-clinical and clinical development against infectious disease pathogens.
| Adjuvant Class | Immune Response(s) | Experimental Vaccine Details | Development Stage | Ref. |
|---|---|---|---|---|
| Mineral Adjuvants | ||||
| Aluminium salt (phosphate or hydroxide, Alum) | Enhanced cytokine, chemokine, antibody, and Th2 immune response | PiCoVacc (NCT04456595) | Phase 3 | [38] |
| BG505 SOSIP.664 gp140 (NTC04177355) | Phase 1 | [39] | ||
| Respiratory syncytial virus (RSV) (NCT01905215) | Phase 1 | [40] | ||
| RSV F vaccine (NCT01704365) | Phase 2 | [41] | ||
| RSV F vaccine (NCT02247726) | Phase 3 | [42] | ||
| HIV AIDSVAX B/E (NCT00006327) | Phase 3 | [43] | ||
| SCB-2019 (NCT04405908) | Phase 1 | [44] | ||
| Calcium salt | Herpes simplex virus (HSV)-2 vaccine | Pre-clinical | [45,46] | |
| Human enterovirus-71 virus (HEV-71) | [47] | |||
| Newcastle disease virus (RDVF) vaccine | [48] | |||
| Foot and mouth disease virus (FMDV) DNA vaccine | [49] | |||
| Microbial/Bacterial Products—Flagellin | ||||
| Flagellin | Enhanced Th1 and Th2 immune responses (toll-like receptor [TLR] 5 agonist); pattern recognition receptor (PRR) activation; strong mucosal IgA/Th2/Th17 responses | VAX-102 (NCT00603811); | Phase 1 | [25,50] |
| VAX-125 (NCT00966238 and NCT00730457) | Phase 1 | [51,52] | ||
| VAX2012Q (NCT02015494) | Phase 1 | [53] | ||
| VAX2012Q (NCT02434276) | Phase 2 | [25] | ||
| Plague the flagellin-F1-V recombinant fusion protein (NCT01381744) | Phase 1 | [54] | ||
| Microbial/Bacterial Products—Lipopolysaccharides | ||||
| Glucopyranosyl lipid adjuvant-aqueous formulation (GLA-AF) |
Enhanced Th1 immune responses (TLR1/2 agonist) | Influenza H5-VLP vaccine (NCT01657929) | Phase 1 | [55] |
| Microbial/Bacterial Products—Cholera toxin | ||||
| Cholera toxin (CT) | Enhanced Th1 and Th2 immune response | Recombinant Naegleria fowleri (rNfa1) protein-based vaccine | Pre-clinical | [56] |
| Malaria (Plasmodium vivax) ookinete surface protein (OSP), Pvs25 (AdPvs25) | [57] | |||
| HIV Envelope (Env) | [58] | |||
| Microbial/Bacterial Products—Bacillus Calmette-Guérin (BCG) | ||||
| Bacillus Calmette-Guérin (BCG) | Enhanced Th1 immune responses | Tuberculosis AERAS-404 and BCG revaccination with recombinant protein vaccines (H4:IC31 and H56:IC31) (NCT02378207; NCT02075203) | Phase 1/2 | [59,60,61] |
| COVID-19 vaccine (NCT04384549; NCT04328441; NCT04327206) | Phase 3 | [62,63] | ||
| Emulsion—Freund’s Complete/Incomplete Adjuvants | ||||
| Incomplete Freund’s adjuvant (IFA) | Enhanced Th1-or mixed Th1/Th17 and Th1/Th2 type immune responses | HIV-1 immunogen emulsified in IFA adjuvant, which was conducted on 25 participates (NCT00381875) | Phase 1 | [64] |
| Emulsion—Montanide | ||||
| ISA-51 | Enhanced antigen uptake by antigen-presenting cells and potent stimulator of adjuvant core response genes, and cytokine, chemokine and Th2 (antibody) responses | Mosquito borne disease anopheles gambiae saliva vaccine (NCT03055000) | Phase 1 | [65] |
| Emulsion—MF59® | ||||
| Squalene in oil-in-water emulsion (Squalene + Tween 80 + Span 85) | Enhanced Th1-or mixed Th1/Th17 and Th1/Th2-type immune responses | Seasonal influenza aIIV3; Fluad® (NCT04576702) | Phase 2 | [66] |
| SARS-CoV-2 Sclamp antigen combined with MF59® (NCT04495933) | Phase 1 | [67] | ||
| Emulsion—GLA-SE | ||||
| Glucopyranosyl lipid adjuvant (GLA) in combination with squalene (SE) | Strong Th1 immune response | Schistosoma Sm14 antigen combined with GLA-SE adjuvant (NCT01154049) | Phase 1 | [68] |
| Tuberculosis ID93 antigen combined with GLA-SE adjuvant (NCT01599897) | [69] | |||
| Emulsion—TiterMax | ||||
| TiterMax® | Enhanced Th2 immune response | Schistosoma mansoni venom allergen-like protein with TiterMax adjuvant | Pre-clinical | [12] |
| Emulsion—RIBI Adjuvant System | ||||
| RIBI adjuvant system (RAS) | Enhanced Th2 immune response | Recombinant influenza viral nucleoprotein combined with RAS® system | Pre-clinical | [70] |
| Mycobacterium paratuberculosis 85B antigen of MPT combined with RIBI adjuvant system | [71] | |||
| Immunostimulatory Complexes—Cytokines | ||||
| Granulocyte-macrophage colony-stimulating factor (GM-CSF) | Enhanced Th1/Th2/CD8+ T and mucosal IgA responses; immune responses, activation of dendritic cells; increased migration and antigen presentation to CD4+ T cells; cross-priming of CD8+ T cells; generation of Th1-biased CD4+ T cells | BRII-179 combined with IFN-α (ACTRN12619001210167). | Phase 1 | [72] |
| HIV Vacc-C5, containing residues 489–511 from the HIV-1 virus C5 domain, with GM-CSF adjuvant (NCT01627678) | Phase 1/2 | [73] | ||
| Dendritic cells loaded with S-protein from SARS-CoV-2 alongside GM-CSF (NCT04386252) | Phase 1 | [74] | ||
| Type 1 interferon (IFN) | BRII-179 combined with IFN-α (NCT04749368) | Phase 2 | [72] | |
| Interleukins (IL-1, IL-15, IL-2, and Il-18) | Influenza A viruses (H1N1 and H3N2) adjuvanted with INF-α (NCT00436046). | Phase 1 | [75] | |
| Immunostimulatory Complexes—Chemokines | ||||
| Chemokine CCL3 | Secretion of mucosal IgA and CTL | HIV-1 Gag antigen with murine chemokine CCL3 | Pre-clinical | [76] |
| Particulate—Imidazoquinolines | ||||
| Resiquimod (R-848) | Enhanced Th1 and Th2 immune responses (TLR7/8 agonist) and secretion of Type 1 IFN, pro-inflammatory cytokines, antibodies, and CD8+ T cells | Influenza IPR8-R848 | Pre-clinical | [77] |
| Imidazoquinolines | HSV RSV vaccine candidate | [78] | ||
| Particulate—Virus-like Particles/Virosomes | ||||
| Virus-like particles (VLPs) | Enhanced Th1, Th2, and CD8+ T cell immune response | Nine-valent human papilloma virus vaccine (V503-020) (NCT02114385) | Phase 3 | [79] |
| Chikungunya virus VRC-CHKVLP059-00-VP (NCT02562482) | Phase 2 | [80] | ||
| Recombinant hemagglutinin trivalent nanoparticle vaccine (tNIV) produced in Sf9 insect cell-recombinant baculovirus platform containing wide-type virus sequences composed of conserved H3N2 epitope, as an influenza vaccine candidate (NCT03293498). | Phase 1/2 | [81] | ||
| Virosomes | Enhanced Th1, Th2, and CD8+ T cell immune response | Combined HIV-1 virulence peptide antigens (gp41, p1) adjuvanted with virosomes (NCT04553016). | Phase 1 | [82] |
| Anti-malaria peptide vaccine derived from the circumsporozoite protein and apical antigen-1 (AMA-1) adjuvanted with virosomes (NCT00408668). | Phase 2 | [83] | ||
| Double stranded (ds)-RNA (e.g., Poly I:C; PolyI:C12U (Ampligen®) | Type I IFN induction; pro-inflammatory cytokine/chemokine/antibody/CD4+/CD8+ T cell responses; mucosal adjuvant inducing Th1 and Th17 immune responses | H5N1 influenza antigen was a formalin-inactivated whole virus (NIBRG14) derived from a recombinant avian virus from H1N5 combined with Poly I: Poly C12 U (Ampligen®) adjuvant (NCT00711295) | Phase 3 | [84] |
| Combined plasma HIV-1 RNA with the TLR-3 agonist Poly-ICLC adjuvant as an HIV vaccine (NCT00207195). | Phase 1 | [85] | ||
| RNA cyclic di-GMP oligodeoxynucleotide (CpG ODN) (e.g., unmethylated CpG DNA, CpG ODN; CpG 1018; CpG 7909; IC31) | PRR activation; potent inducer of ‘adjuvant core response genes’ | Anthrax AVA vaccine (NCT01263691) | Phase 1 | [86] |
| Malaria vaccine (NCT00344539) | Phase 1 | [87] | ||
| Tuberculosis H4:IC31(ASERAS-404) (NCT02066428 and NCT02074956) | Phase 1/2 | [88] | ||
| Particulate—Liposomes | ||||
| Cationic liposomes (e.g., CAF01) | Immunostimulatory depot effect; strong antigen-specific antibody and Th1/Th2 cell responses | COVID-19 mRNA-1273 vaccine—lipid nanoparticle-encapsulated with nucleoside-modified mRNA which encodes the SARS-CoV-2 spike (s) glycoprotein (NCT04470427) | Phase 3 | [89] |
| Reformed liposomes | Tuberculosis hybrid 1(H1) fusion protein adjuvanted with CAF01 liposome (NCT00922363) | Phase 1 | [90] | |
| Chlamydia trachomatis recombinant protein subunit CTH 522 adjuvanted with CAF01 liposome (NCT02787109) | Phase 1 | [91] | ||
| Particulate—Polysaccharides | ||||
| Chitosan | Enhanced Th1 and Th2 immune response and mucosal immune response; site-directed delivery of antigens; source of DAMP (chitosan); mucosal (chitosan); induction of pro-inflammatory cytokines and secretory antibody responses; Th2 and mucosal IgA responses; PRR activation; upregulation of co-stimulatory molecules; activation of complement pathways. | Norwalk virus MPL/chitosan-VLP vaccine (NCT00973284) |
Phase 2 | [92] |
| AdvaxTM | Hepatitis B surface antigen (HBsAg) combined with Advax (ACTRN12607000598482) | Phase 1 | [93] | |
| HIV-1 vaccine candidate plus Advax adjuvant (NCT00249106) | Phase 1 | [94] | ||
| Particulate—Polymeric nanoparticles | ||||
| Polymeric nanoparticles e.g., PLA: poly (lactic acid); PLGA: poly (lactic-co-glycolic acid) | Enhanced Th1 and Th2 immune response; depot effect; mucoadhesive; strong antigen specific Th1/Th2, CD8+ T cell a and antibody responses | MPL/chitosan-VLP HIV vaccine (NCT00973284) | Phase 2 | [92,95] |
| HBV antigen (HBsAg) has been conducted into healthy adults (ACTRN12607000598482). | Phase 1 | [93] | ||
| HIV-1 vaccine candidate plus Advax adjuvant (NCT00249106) | Phase 1 | [94] | ||
| Particulate—Glycosphingolipids | ||||
| Glycosphingolipids (α-GalCer) | Pattern recognition receptor activation; Th1/CTL and mucosal IgA responses | Combined HBV protein antigen with synthetic α-GalCer (KRN 7000), intravenously administrated into participants against HBV (NCT00363155). | Phase 2 | [96] |
| Tensoactive—Saponin | ||||
| Matrix-MTM | Induction of cytokines and cellular influx; induction of Th1- or mixed Th1/Th17-, Th1/Th1-type as well as strong antibody (CD8+ T cell) responses | Matrix-M adjuvant combined with the full-length SARS-CoV-2 spike (S) glycoprotein (NCT04368988) | Phase 1/2 | [97] |
| COVID-19 NVX-CoV2373 (EudraCT number, 2020-004123-16) | Phase 3 | [98] | ||
| Immune-stimulating complexes (ISCOMs) | ||||
| QS-21 | H7N9 influenza (NCT01897701) | Phase 1 | [99] | |
| Protease—Papain-like Cysteine Proteases | ||||
| Papain-like cysteine proteases | Enhanced T helper (Th) 1 and Th17 immune responses | Schistosomiasis glyceraldehyde 3-phosphate dehydrogenase (SG3PDH), peroxiredoxin (TPX), and other larval excretory–secretory products (ESP) with Papain | Pre-clinical | [100] |
| Combination Adjuvant Systems | ||||
| AS01(MPL, QS-21 and liposome) | Transient induction of cytokines at the site of injection; increased influx of antigen-loaded monocytes in draining lymph nodes (dLNs) | RTS, S/AS01 malaria (NCT00866619) | Phase 3 | [101] |
| AS02 (3-O-desacyl-4′-monophosphoryl lipid A [MPL] and QS-21) | Malaria FMP2.1/AS02A vaccine (NCT00460525) | Phase 2 | [102] | |
| AS03 (Squalene, polysorbate 80 and α-tocopherol) | SK SARS-CoV-2 recombinant protein nanoparticle vaccine (GBP 510) combined with AS03 (NCT04742738) and (NCT04750343) | Phase 1/2 | [103,104] | |
| Influenza A (H1N1) pdm09 vaccines combined with AS03 (NCT00616928) | Phase 3 | [105,106] | ||
| AS04 (MPL adsorbed onto aluminium hydroxide or aluminium phosphate) | HPV-16/-18 VLP adjuvanted with AS04 (NCT00128661) | Phase 3 | [107] | |