Figure 1.

Technological approaches to reduce innate immune activation by mRNA-based vaccines. (a) After entering the cell, IVT mRNA and certain IVT-related impurities (such as dsRNA and ssRNA fragments) can be recognized by a variety of innate immune receptors, including endosomal TLR3 or TLR7/8 and cytosolic sensors MDA5 or RIG-I, ultimately resulting in robust type-1 interferon signaling and proinflammatory cytokine induction. (b) Manufacture of IVT mRNA has been steadily advanced to limit innate immune activation, including by replacing uridine-5′-triphosphate with N1-methyl-pseudouridine-5′-triphosphate within the IVT mRNA, and removing or reducing the amount of short dsRNA and loopback dsRNA produced during the IVT process. MDA5, melanoma differentiation-associated protein 5; RIG-1, retinoic acid-inducible gene I; ssRNA, single-strand RNA.