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.

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.

Publication date: Dec 23, 2023

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.

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Concepts Keywords
Agonist adju-phos
Aluminum adjuvants
Mice alhydrogel
Tlr4 COVID-19
Vaccines SARS-CoV-2
TLR4
TLR7/8

Semantics

Type Source Name
drug DRUGBANK Aluminium
disease VO effective
disease MESH COVID-19
disease VO Severe acute respiratory syndrome coronavirus 2
disease VO subunit vaccine
drug DRUGBANK Aluminum hydroxide
drug DRUGBANK Aluminium phosphate
disease VO efficient
disease VO vaccination
disease VO USA
disease MESH infection
disease IDO immune response
drug DRUGBANK Spinosad
disease VO storage
drug DRUGBANK Coenzyme M
disease IDO host
drug DRUGBANK Angiotensin II
disease VO vaccine
disease VO vaccine adjuvant
disease IDO pathogen
disease VO dose
disease MESH PRRs
disease IDO cell
disease VO Shingrix
disease VO Cervarix
disease VO Tir
disease IDO history
disease MESH influenza
drug DRUGBANK Glycerin
drug DRUGBANK Tromethamine
drug DRUGBANK Tretamine
drug DRUGBANK Copper
drug DRUGBANK Activated charcoal
disease MESH Arc
drug DRUGBANK 3 7 11 15-Tetramethyl-Hexadecan-1-Ol
drug DRUGBANK Water
drug DRUGBANK Riboprine
drug DRUGBANK Flunarizine
disease VO protocol
drug DRUGBANK Pentaerythritol tetranitrate
disease VO vaccinated
disease VO volume
disease IDO blood
disease VO injection
drug DRUGBANK L-Glutamine
drug DRUGBANK Streptomycin
drug DRUGBANK Human Serum Albumin
drug DRUGBANK Phosphate ion
disease IDO assay
disease VO ANOVA
drug DRUGBANK Sulfate ion
disease VO efficiency
drug DRUGBANK Trestolone
disease VO titer
disease VO antibody titer
disease IDO production
disease MESH viral infection
disease VO Glycoprotein
disease VO ineffective
drug DRUGBANK Tropicamide
disease MESH lung inflammation
disease VO unvaccinated
disease VO tertiary vaccination
disease MESH Allergy
disease MESH Infectious Diseases
disease IDO country
disease VO boost vaccination
disease IDO replication
disease VO vaccine candidate
disease VO vaccine antigen
disease VO Influenza virus vaccine
disease VO COVAXIN
drug DRUGBANK (S)-Des-Me-Ampa
drug DRUGBANK Guanosine
drug DRUGBANK Silicon dioxide
drug DRUGBANK Diphenylpyraline
disease MESH Asthma
pathway KEGG Asthma
drug DRUGBANK Squalene
drug DRUGBANK Tocopherol
disease MESH Seroconversion
disease VO Toll-like receptor

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