Strategies for controlling the innate immune activity of conventional and self-amplifying mRNA therapeutics: Getting the message across

Adv Drug Deliv Rev. 2021 Sep:176:113900. doi: 10.1016/j.addr.2021.113900. Epub 2021 Jul 26.

Abstract

The recent approval of messenger RNA (mRNA)-based vaccines to combat the SARS-CoV-2 pandemic highlights the potential of both conventional mRNA and self-amplifying mRNA (saRNA) as a flexible immunotherapy platform to treat infectious diseases. Besides the antigen it encodes, mRNA itself has an immune-stimulating activity that can contribute to vaccine efficacy. This self-adjuvant effect, however, will interfere with mRNA translation and may influence the desired therapeutic outcome. To further exploit its potential as a versatile therapeutic platform, it will be crucial to control mRNA's innate immune-stimulating properties. In this regard, we describe the mechanisms behind the innate immune recognition of mRNA and provide an extensive overview of strategies to control its innate immune-stimulating activity. These strategies range from modifications to the mRNA backbone itself, optimization of production and purification processes to the combination with innate immune inhibitors. Furthermore, we discuss the delicate balance of the self-adjuvant effect in mRNA vaccination strategies, which can be both beneficial and detrimental to the therapeutic outcome.

Keywords: Immune evasion strategies; Innate immune stimulation; Self-amplifying mRNA (saRNA); Type I IFNs; mRNA; mRNA vaccination.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • COVID-19 / genetics
  • COVID-19 / immunology
  • COVID-19 / prevention & control
  • Gene Amplification / drug effects
  • Gene Amplification / immunology*
  • Humans
  • Immunity, Innate / drug effects
  • Immunity, Innate / immunology*
  • Immunotherapy / methods*
  • Immunotherapy / trends
  • RNA, Messenger / administration & dosage
  • RNA, Messenger / genetics
  • RNA, Messenger / immunology*
  • Vaccines, Synthetic / administration & dosage
  • Vaccines, Synthetic / genetics
  • Vaccines, Synthetic / immunology*
  • mRNA Vaccines

Substances

  • RNA, Messenger
  • Vaccines, Synthetic