TABLE 2.
Toll-like receptor agonists as vaccine adjuvants in COVID-19 vaccine formulation.
| TLR agonists | Platform | Adjuvant | Antigen | Formulation | Immunological response |
Route | Animal model or clinical trial | References | ||
| Nab | sIgA | T-cell response | ||||||||
| TLR 1/2 | Peptide vaccine | XS15 | T-cell epitopes from viral protein | Montanide ISA 51 VG | Weak | NA | CD4+ T and IFN-γ response | SC | Phase II trial | Rammensee et al., 2021; Heitmann et al., 2022 |
| TLR 1/2 and TLR3 | Subunit vaccine | L-pampo | RBD and S1 antigens | NA | Strong | NA | IFN-γ response | IM | BALB/c and ferret | Jeong et al., 2021 |
| TLR3 | Adenovirus-based vaccine | dsRNA | SARS-CoV-2 S and N gene | Adenovirus | Strong | Moderate | NA | Oral | Hamsters and phase I trial | Tiboni et al., 2021 |
| TLR3 | Subunit vaccine | PIKA | Trimeric S antigen | NA | Strong | NA | Balanced Th1/Th2 and IFN-γ response | IM | Rabbits, mice, and non-human primates | Liu Y. et al., 2021 |
| TLR3 and TLR9 | Subunit vaccine | CpG ODN + poly I:C + IL-15 | S1 protein | PLGA or DOTAP | Weak | Strong | CD4+ T response | IM, IN | Rhesus macaques | Sui Y. et al., 2021 |
| TLR4 | Subunit vaccine | MPLA + PUUC | S1 protein | Polymer nanoparticles | Strong | Strong | Memory T-cell response | IN, IM | BALB/c | Atalis et al., 2022 |
| TLR-4 | Subunit vaccine | MPLA + GM-CSF | SARS-CoV-2 N/S1/S2 proteins | MSRs | Strong | NA | CD4+ and CD8+ T response | SC | BALB/c | Langellotto et al., 2021 |
| TLR7/8 | Subunit vaccine | Alhydroxiquim-II | Trimeric spike antigen | NA | Strong | NA | CD4+ T | IM | C57BL/6, rabbits, horses | Counoupas et al., 2022 |
| TLR7/8 | Subunit vaccine | R848 | S1 protein | Nanoparticle decorated erythrocytes | Strong | NA | CD4+ T response | IV | C57BL/6 | Wang et al., 2021 |
| TLR7/8 | Inactivated vaccine | Chemisorbed Algel | Inactivated antigen | NA | Strong | NA | CD4+ T and Th1-biased responses | IM | Mice, rats, and rabbits | Ganneru et al., 2021 |
| TLR-7 or TLR-9 | Subunit vaccine | AS37-Alum or CpG 1018-Alum | RBD antigen | Self-assembling protein nanoparticle | Strong | NA | CD4+ T response | IM | Rhesus macaques and phase II trial | Arunachalam et al., 2021; Richmond et al., 2021 |
| TLR9 | mRNA vaccine | CpG SD-101 | RBD mRNA | CART | Strong | NA | CD4+ and CD8+ T | IV, IM | BALB/c | Haabeth et al., 2021 |
| TLR-9 | Subunit vaccine | CpG 7909-Alum | Trimeric S antigen | NA | Strong | NA | CD4+ T response | IM | BALB/c and monkeys | Liu H. et al., 2021 |
NA, not available; Nab, naturalization antibody; SC, subcutaneous; IM, intramuscular; IV, intravenous; IN, intranasal; PUUC, RIG-I agonist; PLGA, poly(lactic-co-glycolic acid); DOTAP, 1,2-dioleoyl-3-trimethylammonium-propane; CART, charge-altering releasable transporters.