Innate immune mechanisms of mRNA vaccines

Abstract

The lipid nanoparticle (LNP)-encapsulated, nucleoside-modified mRNA platform has been used to generate safe and effective vaccines in record time against COVID-19. Here, we review the current understanding of the manner whereby mRNA vaccines induce innate immune activation and how this contributes to protective immunity. We discuss innate immune sensing of mRNA vaccines at the cellular and intracellular levels and consider the contribution of both the mRNA and the LNP components to their immunogenicity. A key message that is emerging from recent observations is that the LNP carrier acts as a powerful adjuvant for this novel vaccine platform. In this context, we highlight important gaps in understanding and discuss how new insight into the mechanisms underlying the effectiveness of mRNA-LNP vaccines may enable tailoring mRNA and carrier molecules to develop vaccines with greater effectiveness and milder adverse events in the future.

Keywords: SARSCoV- 2 vaccine; T cell; adjuvant; dendritic cell; germinal center; innate immunity; ionizable lipid; lipid nanoparticle; mRNA vaccine; neutralizing antibody; nucleoside modification.

Figure 1

Biodistribution and innate immune cell dynamics upon administration of mRNA-iLNP vaccines (A) Intramuscular administration of nucleoside-modified mRNA-iLNP vaccines results in local inflammation, which recruits neutrophils, monocytes, and various dendritic cell (DC) subsets from the blood to the injection site by production of chemokines and other inflammatory mediators contributing to the extravasation of immune cells. (B) mRNA-iLNPs and/or antigen-expressing cells are transported to the draining lymph node. The size and surface properties of the particles can impact biodistribution, protein absorption (opsonization), and cellular uptake. (C) DCs and monocytes/macrophages contribute to antigen presentation and priming of T cells. (D) T follicular helper (Tfh) cells provide help to B cells in germinal center (GC) reactions in the presence of follicular DCs, leading to affinity maturation. In mice, an important role for iLNP-induced IL-6 was found in the induction of Tfh and GC B cell responses, while type I IFNs promoted CTL responses. Abbreviations: m1Ψ: N1-methylpseudouridine, iLNP: ionizable lipid nanoparticle, IL: interleukin, IFN: interferon, ISG: interferon-stimulated gene, CXCL10: C-X-C motif chemokine ligand 10, CD86: cluster of differentiation 86, FDC: follicular dendritic cell, CTL: cytotoxic T lymphocyte, Th1: T helper 1.

Figure 2

Working model of the innate immune mechanisms that contribute to the immunogenicity and reactogenicity of mRNA-iLNP vaccines (A) Uptake of empty iLNPs by innate immune cells and other cell types is sufficient to induce local and systemic inflammation, characterized by the release of pro-inflammatory cytokines such as IL-1β and IL-6. (B) The incorporation of modified uridines and stringent IVT mRNA purification drastically lowers the recognition of IVT mRNA by TLR3/7/8 and other RNA sensors. These modifications are important to minimize the negative effects of type I IFN-stimulated RNA sensors on protein expression from the antigen-encoding mRNA and to avoid dose-limiting toxicities. The role of the MDA5-IFN-α signaling pathway in inducing CTLs to BNT162b2 in mice suggests residual type I IFN activity of the current generation of mRNA vaccines. (C) After administration of a second vaccine dose, there is a strong boost in the T cell responses, which is associated with higher IFN-γ production. The enhanced activation of myeloid cells and T cells following boosting may reflect a crosstalk between lymphocytes and myeloid cells. Abbreviations: IVT, in vitro transcribed; iLNP, ionizable lipid nanoparticle; m1Ψ, N1-methylpseudouridine; NF-κB, nuclear factor-κB; IL-1R, interleukin-1 receptor; IL-1ra, interleukin-1 receptor antagonist; MYD88, myeloid differentiation primary response protein 88; dsRNA, double-stranded RNA; MDA5, melanoma differentiation-associated protein 5; RIG-I, retinoic acid-inducible gene I; PRR, pattern recognition receptor; IRF, interferon regulatory factor; IFN-I, type I interferon; IFNAR, interferon-α/β receptor; TYK1, leukocyte receptor tyrosine kinase; JAK, janus kinase; STAT, signal transducer and activator of transcription; ISRE, interferon-sensitive response element; PKR, protein kinase R; OAS, 2’-5’-oligoadenylate synthetase; IFNGR, interferon gamma receptor; GAS, gamma interferon activation site; ISG, interferon-stimulated gene; NK, natural killer; CTL, cytotoxic T lymphocyte; Tfh, T follicular helper; GC, germinal center; TLR, toll-like receptor; CXCL10, C-X-C motif chemokine ligand 10; TNF, tumor necrosis factor.