An Ionizable Lipid Material with a Vitamin E Scaffold as an mRNA Vaccine Platform for Efficient Cytotoxic T Cell Responses

Oct 10, 2023ACS nano

An Ionizable Lipid with a Vitamin E Base for mRNA Vaccines that Boost Killer T Cell Responses

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Abstract

An RNA vaccine using with a vitamin E scaffold induced OVA-specific cytotoxic T cell responses and showed an antitumor effect against an E.G7-OVA tumor model.

The vaccine demonstrated an enhanced ability to induce cellular immunity through a novel ionizable lipid.
Vaccination conferred protection against lethal infection using the TgPF antigen.
Type I interferon response, dependent on the vitamin E scaffold, was crucial for the differentiation of effector CD8 T cells.
Conventional dendritic cells were essential for eliciting CD8 T cell responses from the mRNA-lipid nanoparticles.
The cDC2 subset of dendritic cells, rather than cDC1, selectively transfected by the mRNA-lipid nanoparticles, facilitated antigen presentation.

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RNA vaccines based on (LNPs) withtranscribed mRNA (IVT-mRNA) encapsulated are now a currently successful but still evolving modality of vaccines. One of the advantages of RNA vaccines is their ability to induce CD8T-cell-mediated cellular immunity that is indispensable for excluding pathogen-infected cells or cancer cells from the body. In this study, we report on the development of LNPs with an enhanced capability for inducing cellular immunity by using an ionizable lipid with a vitamin E scaffold. An RNA vaccine that contained this ionizable lipid and an IVT-mRNA encoding a model antigen ovalbumin (OVA) induced OVA-specific cytotoxic T cell responses and showed an antitumor effect against an E.G7-OVA tumor model. Vaccination with the LNPs conferred protection against lethal infection byusing its antigen TgPF. The vitamin E scaffold-dependent type I interferon response was important for effector CD8T cell differentiation induced by the mRNA-LNPs. Our findings also revealed that conventional dendritic cells (cDCs) were essential for achieving CD8T cell responses induced by the mRNA-LNPs, while the XCR1-positive subset of cDCs, cDC1 specialized for antigen cross-presentation, was not required. Consistently, the mRNA-LNPs were found to selectively transfect another subset of cDCs, cDC2 that had migrated from the skin to lymph nodes, where they could make vaccine-antigen-dependent contacts with CD8T cells. The findings indicate that the activation of innate immune signaling by the adjuvant activity of the vitamin E scaffold and the expression of antigens in cDC2 are important for subsequent antigen presentation and the establishment of antigen-specific immune responses. in vitro Toxoplasma gondii + + + +

Key numbers

Higher than control

OVA-specific Increase

induced superior compared to conventional vectors.

10 of 10 mice

Survival Rate

Mice immunized with mTgPF- showed full survival after challenge.

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An Ionizable Lipid Material with a Vitamin E Scaffold as an mRNA Vaccine Platform for Efficient Cytotoxic T Cell Responses

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