Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Karthik Siram
ORCID logo ,
Stephanie K. Lathrop
,
Walid Abdelwahab
,
Rebekah Tee
,
Clara J. Davison
,
Haley A. Partlow
,
Jay T. Evans
ORCID logo ,
David J. Burkhart
*
Version 1 : Received: 18 November 2023 / Approved: 22 November 2023 / Online: 22 November 2023 (14:34:17 CET)

A peer-reviewed article of this Preprint also exists.

Siram, K.; Lathrop, S.K.; Abdelwahab, W.M.; Tee, R.; Davison, C.J.; Partlow, H.A.; Evans, J.T.; Burkhart, D.J. 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 2024, 12, 21. Siram, K.; Lathrop, S.K.; Abdelwahab, W.M.; Tee, R.; Davison, C.J.; Partlow, H.A.; Evans, J.T.; Burkhart, D.J. 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 2024, 12, 21.

Abstract

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 recombinant receptor-binding domain (RBD) of spike 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.

Keywords

toll-like receptor (TLR) agonist; TLR4; TLR7/8; adjuvants; alhydrogel; adju-phos; SARS-CoV-2; COVID-19

Subject

Medicine and Pharmacology, Immunology and Allergy

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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