Co-Delivery of Novel Synthetic TLR4 and TLR7/8 Ligands Adsorbed to Aluminum Salts Promotes Th1-Mediated Immunity against Poorly Immunogenic SARS-CoV-2 RBD
Despite the availability of effective vaccines against COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide, pressing the need for new vaccines with improved breadth and durability. We developed an adjuvanted subunit vaccine against SARS-CoV-2 using th...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-12-01
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| Series: | Vaccines |
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| Online Access: | https://www.mdpi.com/2076-393X/12/1/21 |
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| author | Karthik Siram Stephanie K. Lathrop Walid M. Abdelwahab Rebekah Tee Clara J. Davison Haley A. Partlow Jay T. Evans David J. Burkhart |
| author_facet | Karthik Siram Stephanie K. Lathrop Walid M. Abdelwahab Rebekah Tee Clara J. Davison Haley A. Partlow Jay T. Evans David J. Burkhart |
| author_sort | Karthik Siram |
| collection | DOAJ |
| description | Despite the availability of effective vaccines against COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide, pressing the need for new vaccines with improved breadth and durability. We developed an adjuvanted subunit vaccine against SARS-CoV-2 using the recombinant receptor–binding domain (RBD) of spikes with synthetic adjuvants targeting TLR7/8 (INI-4001) and TLR4 (INI-2002), co-delivered with aluminum hydroxide (AH) or aluminum phosphate (AP). The formulations were characterized for the quantities of RBD, INI-4001, and INI-2002 adsorbed onto the respective aluminum salts. Results indicated that at pH 6, the uncharged RBD (5.73 ± 4.2 mV) did not efficiently adsorb to the positively charged AH (22.68 ± 7.01 mV), whereas it adsorbed efficiently to the negatively charged AP (−31.87 ± 0.33 mV). Alternatively, pre-adsorption of the TLR ligands to AH converted it to a negatively charged particle, allowing for the efficient adsorption of RBD. RBD could also be directly adsorbed to AH at a pH of 8.1, which changed the charge of the RBD to negative. INI-4001 and INI-2002 efficiently to AH. Following vaccination in C57BL/6 mice, both aluminum salts promoted Th2-mediated immunity when used as the sole adjuvant. Co-delivery with TLR4 and/or TLR7/8 ligands efficiently promoted a switch to Th1-mediated immunity instead. Measurements of viral neutralization by serum antibodies demonstrated that the addition of TLR ligands to alum also greatly improved the neutralizing antibody response. These results indicate that the addition of a TLR7/8 and/or TLR4 agonist to a subunit vaccine containing RBD antigen and alum is a promising strategy for driving a Th1 response and neutralizing antibody titers targeting SARS-CoV-2. |
| first_indexed | 2024-03-08T09:44:34Z |
| format | Article |
| id | doaj.art-5588703beb6d4da48c23ab455bcdd91b |
| institution | Directory Open Access Journal |
| issn | 2076-393X |
| language | English |
| last_indexed | 2024-03-08T09:44:34Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj.art-5588703beb6d4da48c23ab455bcdd91b2024-01-29T14:25:17ZengMDPI AGVaccines2076-393X2023-12-011212110.3390/vaccines12010021Co-Delivery of Novel Synthetic TLR4 and TLR7/8 Ligands Adsorbed to Aluminum Salts Promotes Th1-Mediated Immunity against Poorly Immunogenic SARS-CoV-2 RBDKarthik Siram0Stephanie K. Lathrop1Walid M. Abdelwahab2Rebekah Tee3Clara J. Davison4Haley A. Partlow5Jay T. Evans6David J. Burkhart7Center for Translational Medicine, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USACenter for Translational Medicine, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USACenter for Translational Medicine, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USACenter for Translational Medicine, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USACenter for Translational Medicine, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USACenter for Translational Medicine, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USACenter for Translational Medicine, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USACenter for Translational Medicine, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USADespite the availability of effective vaccines against COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide, pressing the need for new vaccines with improved breadth and durability. We developed an adjuvanted subunit vaccine against SARS-CoV-2 using the recombinant receptor–binding domain (RBD) of spikes with synthetic adjuvants targeting TLR7/8 (INI-4001) and TLR4 (INI-2002), co-delivered with aluminum hydroxide (AH) or aluminum phosphate (AP). The formulations were characterized for the quantities of RBD, INI-4001, and INI-2002 adsorbed onto the respective aluminum salts. Results indicated that at pH 6, the uncharged RBD (5.73 ± 4.2 mV) did not efficiently adsorb to the positively charged AH (22.68 ± 7.01 mV), whereas it adsorbed efficiently to the negatively charged AP (−31.87 ± 0.33 mV). Alternatively, pre-adsorption of the TLR ligands to AH converted it to a negatively charged particle, allowing for the efficient adsorption of RBD. RBD could also be directly adsorbed to AH at a pH of 8.1, which changed the charge of the RBD to negative. INI-4001 and INI-2002 efficiently to AH. Following vaccination in C57BL/6 mice, both aluminum salts promoted Th2-mediated immunity when used as the sole adjuvant. Co-delivery with TLR4 and/or TLR7/8 ligands efficiently promoted a switch to Th1-mediated immunity instead. Measurements of viral neutralization by serum antibodies demonstrated that the addition of TLR ligands to alum also greatly improved the neutralizing antibody response. These results indicate that the addition of a TLR7/8 and/or TLR4 agonist to a subunit vaccine containing RBD antigen and alum is a promising strategy for driving a Th1 response and neutralizing antibody titers targeting SARS-CoV-2.https://www.mdpi.com/2076-393X/12/1/21toll-like receptor (TLR) agonistTLR4TLR7/8adjuvantsalhydrogeladju-phos |
| spellingShingle | Karthik Siram Stephanie K. Lathrop Walid M. Abdelwahab Rebekah Tee Clara J. Davison Haley A. Partlow Jay T. Evans David J. Burkhart Co-Delivery of Novel Synthetic TLR4 and TLR7/8 Ligands Adsorbed to Aluminum Salts Promotes Th1-Mediated Immunity against Poorly Immunogenic SARS-CoV-2 RBD Vaccines toll-like receptor (TLR) agonist TLR4 TLR7/8 adjuvants alhydrogel adju-phos |
| title | Co-Delivery of Novel Synthetic TLR4 and TLR7/8 Ligands Adsorbed to Aluminum Salts Promotes Th1-Mediated Immunity against Poorly Immunogenic SARS-CoV-2 RBD |
| title_full | Co-Delivery of Novel Synthetic TLR4 and TLR7/8 Ligands Adsorbed to Aluminum Salts Promotes Th1-Mediated Immunity against Poorly Immunogenic SARS-CoV-2 RBD |
| title_fullStr | Co-Delivery of Novel Synthetic TLR4 and TLR7/8 Ligands Adsorbed to Aluminum Salts Promotes Th1-Mediated Immunity against Poorly Immunogenic SARS-CoV-2 RBD |
| title_full_unstemmed | Co-Delivery of Novel Synthetic TLR4 and TLR7/8 Ligands Adsorbed to Aluminum Salts Promotes Th1-Mediated Immunity against Poorly Immunogenic SARS-CoV-2 RBD |
| title_short | Co-Delivery of Novel Synthetic TLR4 and TLR7/8 Ligands Adsorbed to Aluminum Salts Promotes Th1-Mediated Immunity against Poorly Immunogenic SARS-CoV-2 RBD |
| title_sort | co delivery of novel synthetic tlr4 and tlr7 8 ligands adsorbed to aluminum salts promotes th1 mediated immunity against poorly immunogenic sars cov 2 rbd |
| topic | toll-like receptor (TLR) agonist TLR4 TLR7/8 adjuvants alhydrogel adju-phos |
| url | https://www.mdpi.com/2076-393X/12/1/21 |
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