Lipid Nanoparticle Delivery Alters the Adjuvanticity of the TLR9 Agonist CpG by Innate Immune Activation in Lymphoid Tissue

Abstract

Pharmacological strategies to activate innate immune cells are of great relevance in the context of vaccine design and anticancer immune therapy, to mount broad immune responses able to clear infection and malignant cells. Synthetic CpG oligodeoxynucleotides (CpG‐ODNs) are short single‐stranded DNA molecules containing unmethylated CpG dinucleotides and a phosphorothioate backbone. Class B CpG ODNs activate robust innate immune responses through a TLR9‐dependent NF‐κB signaling pathway. This feature is attractive to exploit in the context of vaccine design and cancer immunotherapy. Soluble CpG‐ODNs cause hepatic toxicity, which reduces its therapeutic applicability. The formulation of class B CpG ODN1826 in lipid nanoparticles (LNPs) containing an ionizable cationic lipid that complexes CpG through electrostatic interaction is reported. Upon local administration, LNP‐formulated CpG drains to lymph nodes and triggers robust innate immune activation. Unformulated, soluble, CpG, by contrast, is unable to induce robust innate activation in draining lymph nodes and is distributed systemically. In a vaccination setting, LNP‐formulated CpG, admixed with a protein antigen, induces higher antigen‐specific antibody titers and T cell responses than antigen admixed with unformulated soluble CpG.

Lipid nanoparticle composition for adjuvant formulation modulates disease after influenza virus infection in QIV vaccinated mice

“…Nevertheless, these vaccines still need multiple booster doses to be sufficiently effective against emerging virus strains and therefore are limited in inducing an antigenically broader immune responses. Therefore, the LNPs doses and composition need to be tailored together with the vaccine and/or adjuvant combinations, in order to get the desired vaccination outcomes in terms of both humoral and cellular responses, besides providing protection against viral infections 22,25 .…”

“…Moreover, LNPs can also be used for formulating molecular adjuvants, such as RIG-I or TLR agonists, and facilitate uptake by actively phagocytosing innate immune cell subsets 25 . Nevertheless, the composition of LNP is crucial to achieve the optimal uptake by innate immune cells and efficient humoral responses.…”

“…The PEG lipids prolong the circulation of LNPs consisting of vaccines/adjuvants in circulation by increasing their half-life. Additionally, the surface molecules of LNPs can also be modified to target specific innate immune cells and facilitate uptake for efficient antigen presentation 23,[25][26][27] . Overall, LNPs present as an efficient in vivo vaccine-adjuvant delivery system.…”

“…These mRNA vaccine-LNP formulations have also successfully demonstrated the role of LNP-based vaccine platform for an efficient induction of humoral and cell-mediated immunity. Moreover, LNPs can also be used for formulating molecular adjuvants, such as RIG-I or TLR agonists, and facilitate uptake by actively phagocytosing innate immune cell subsets 25 . Nevertheless, the composition of LNP is crucial to achieve the optimal uptake by innate immune cells and efficient humoral responses.…”

Lipid nanoparticle composition for adjuvant formulation modulates disease after influenza virus infection in quadrivalent influenza vaccine vaccinated mice

“…These mRNA vaccine–LNP formulations have also successfully demonstrated the role of an LNP-based vaccine platform for an efficient induction of humoral and cell-mediated immunity. Moreover, LNPs can also be used for formulating molecular adjuvants, such as RIG-I or TLR agonists, and facilitate uptake by actively phagocytosing innate immune cell subsets ( 25 ). Nevertheless, the composition of LNP is crucial to achieve the optimal uptake by innate immune cells and efficient humoral responses.…”