Tailoring mRNA Vaccine to Balance Innate/Adaptive Immune Response

• Published in: Trends in molecular medicine Vol. 26; no. 3; pp. 311 - 323
• Main Authors: Linares-Fernández, Sergio, Lacroix, Céline, Exposito, Jean-Yves, Verrier, Bernard
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2020; Elsevier
• Subjects: adaptive immunity; Adaptive Immunity - immunology; Animals; Biochemistry, Molecular Biology; Humans; Immunity, Innate - immunology; innate immunity; Life Sciences; Molecular biology; mRNA design; mRNA Vaccines; Receptors, Pattern Recognition - immunology; RNA, Messenger - immunology; Vaccines, Synthetic - immunology; mRNA vaccines; mRNA design; innate immunity; adaptive immunity
• ISSN: 1471-4914; 1471-499X; 1471-499X
• DOI: 10.1016/j.molmed.2019.10.002

mRNA vaccine platforms present numerous advantages, such as versatility, rapid production, and induction of cellular and humoral responses. Moreover, mRNAs have inherent adjuvant properties due to their complex interaction with pattern recognition receptors (PRRs). This recognition can be either beneficial in activating antigen-presenting cells (APCs) or detrimental by indirectly blocking mRNA translation. To decipher this Janus effect, we describe the different innate response mechanisms triggered by mRNA molecules and how each element from the 5′ cap to the poly-A tail interferes with innate/adaptive immune responses. Then, we emphasize the importance of some critical steps such as production, purification, and formulation as key events to further improve the quality of immune responses and balance innate and adaptive immunity. mRNA-based vaccines enable the well-controlled design of on-demand transcript sequences and could be adapted to any pandemic crisis.In vitro-transcribed (IVT) mRNA used for formulation and subsequent administration has to be highly homogeneous with no DNA, dsRNA, or 5′ triphosphate transcripts in order to avoid any overstimulation of innate immunity.During the formulation process, mRNA–cargo interactions could unmask sequences leading to unexpected side effects. The intricate mechanisms of RNA sensing by PRRs, accounts for the unpredictability of in vitro assays.To date, there is no animal model for mRNA vaccines that matches perfectly human immune responses, underlying the importance of clinical trials. Moreover, innate immune activation by mRNA molecules is dependent on the route of administration and the species, hampering the interpretation of in vitro or preclinical data.