Tailoring mRNA Vaccine to Balance Innate/Adaptive Immune Response

Linares-Fernández, Sergio; Lacroix, Céline; Exposito, Jean-Yves; Verrier, Bernard

doi:10.1016/j.molmed.2019.10.002

Cited by 376Immunotherapy and Immune ResponsesRNA Interference and Gene DeliveryImmune Response and Inflammation

Tailoring mRNA Vaccine to Balance Innate/Adaptive Immune Response

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Linares-Fernández, Sergio, Lacroix, Céline, Exposito, Jean-Yves, Verrier, Bernard·2020·Trends in Molecular Medicine

DOI 10.1016/j.molmed.2019.10.002

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Abstract

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.

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Crossref · 10.1016/j.molmed.2019.10.002

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UTRs can influence mRNA translation efficiency and resistance to degradation by interacting with RNA-binding proteins and microRNAs.
“It is known that UTRs are associated with processes of mRNA translation, and by interacting with RNA-binding proteins (RBPs) and microRNAs, UTRs can influence mRNA’s translation efficiency and resistance to degradation [3,4,5,6,7].”
From Untranslated Region Sequences and the Efficacy of mRNA Vaccines against Tuberculosis (2024) · cites this paper as [4]
The use of CleanCap® cap analogs reduces the probability of reverse capped, uncapped, and cap0 intermediates, and the co-transcribed mRNA only possesses a cap1 structure, therefore capping rate can be 90% or higher.
“The use of CleanCap® cap analogs reduces the probability of reverse capped, uncapped, and cap0 intermediates, and the co-transcribed mRNA only possesses a cap1 structure, therefore capping rate can be 90% or higher.52,126”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [52]
The vaccinia capping enzyme (VCE) integrates the enzymatic activity of RTPase, GTase, and G-N7 MTase, which can be capped to generate a cap0 structure, and then 2′-O-MTase can be used to generate a methylated cap1 structure, thus reaching a capping efficiency of 100%.
“The vaccinia capping enzyme (VCE) integrates the enzymatic activity of RTPase, GTase, and G-N7 MTase, which can be capped to generate a cap0 structure, and then 2′-O-MTase can be used to generate a methylated cap1 structure, thus reaching a capping efficiency of 100%.52”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [52]
dsRNA can activate PRR such as TLR3, whereas ssRNA activates TLR7 and TLR8 to produce IFN-I, thus inducing inflammation in the host and interrupting mRNA translation.
“dsRNA can activate PRR such as TLR3,52,156 whereas ssRNA activates TLR7 and TLR8 to produce IFN-I, thus inducing inflammation in the host and interrupting mRNA translation.157,158”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [52]
Currently, nucleoside-modified mRNA vaccines employ 100% chemically modified nucleosides replacing natural nucleosides, and m1ψ is often used to replace uridine during IVT to improve the safety and stability of mRNA vaccines.
“Currently, nucleoside-modified mRNA vaccines employ 100% chemically modified nucleosides replacing natural nucleosides, and m1ψ is often used to replace uridine during IVT to improve the safety and stability of mRNA vaccines.52,134,172”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [52]

Uridine depletion to reduce counterproductive immune reactions can be achieved by replacement of uridine by codon optimization, but this must be balanced with regard to transfer RNA abundance.
“Uridine depletion to reduce counterproductive immune reactions can be achieved by the replacement of uridine by codon optimization, but this must be balanced with regard to transfer RNA abundance.120, 121, 122”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [120]
Optimization of mRNA constructs, including the coding sequence, can regulate immunogenicity without incorporation of modified nucleosides.
“The optimization of mRNA constructs, including the coding sequence, can regulate immunogenicity without incorporation of modified nucleosides.”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [120]
The 5′ cap protects mRNA sterically from degradation by exonucleases and works synergistically with the poly(A) tail, poly(A) binding proteins and translation initiation factor proteins to circularize mRNA and recruit ribosomes for initiating translation.
“Further, the 5′ cap protects the mRNA sterically from degradation by exonucleases, and it works synergistically with the poly(A) tail at the 3′ end, poly(A) binding proteins and translation initiation factor proteins to circularize mRNA and recruit ribosomes for initiating translation10,11.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [11]
A sufficiently long poly(A) tail (100-150 bp) is necessary to interact with poly(A) binding proteins that form complexes necessary for initiating translation and protecting the cap from degradation by decapping enzymes.
“A sufficiently long tail (100–150 bp) is necessary to interact with poly(A) binding proteins that form complexes necessary for initiating translation11,12 and protecting the cap from degradation by decapping enzymes13.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [11]
Engineered UTR sequences minimize mRNA degradation by excluding miRNA-binding sites and AU-rich regions in the 3′ UTR.
“These engineered UTR sequences minimize mRNA degradation by excluding miRNA-binding sites11 and AU-rich regions in the 3′ UTR19.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [11]

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mRNA Vaccines: The Dawn of a New Era of Cancer Immunotherapy
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Manganese-coordinated mRNA vaccines with enhanced mRNA expression and immunogenicity induce robust immune responses against SARS-CoV-2 variants
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mRNA Vaccine Development for Emerging Animal and Zoonotic Diseases
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mRNA nanodelivery systems: targeting strategies and administration routes
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A comprehensive comparison of DNA and RNA vaccines
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Circular RNA vaccines with long-term lymph node-targeting delivery stability after lyophilization induce potent and persistent immune responses
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Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial
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mRNA vaccines: the most recent clinical applications of synthetic mRNA
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Nanoparticles as Adjuvants and Nanodelivery Systems for mRNA-Based Vaccines
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mRNA Cancer Vaccines: Construction and Boosting Strategies
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Chemical modification of uridine modulates mRNA-mediated proinflammatory and antiviral response in primary human macrophages
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Influenza and Universal Vaccine Research in China
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Mucosal immunity and vaccination strategies: current insights and future perspectives
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In vivo fate and intracellular trafficking of vaccine delivery systems
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Towards the future exploration of mucosal mRNA vaccines against emerging viral diseases; lessons from existing next-generation mucosal vaccine strategies
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Fluoroalkane modified cationic polymers for personalized mRNA cancer vaccines
Li, J., Wu, Y., Xiang, J., Wang, H., Zhuang, Q., Wei, T., Cao, Z., Gu, Q., Liu, Z., & Peng, R. (2022) · Chemical Engineering Journal · doi:10.1016/j.cej.2022.140930 · Cited by 64 · see citing works
mRNA vaccines: a new opportunity for malaria, tuberculosis and HIV
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Authors: Linares-Fernández, S., Lacroix, C., Exposito, J.-Y., & Verrier, B.
Affiliations: Lyon 1 Université (FR)
Corresponding author: Verrier, Bernard
ORCID: Linares-Fernández, Sergio
Lacroix, Céline
Exposito, Jean-Yves
Verrier, Bernard
Venue: Trends in Molecular Medicine
Publisher: Elsevier BV
Published: 2020-03
Volume: 26
Issue: 3
Pages: 311-323
ISSN: 1471-4914 (ISSN-L)
DOI: 10.1016/j.molmed.2019.10.002
OpenAlex: W2986812831
Cited by: 376
References: 92
Citations by year: 2026: 43 · 2025: 67 · 2024: 65 · 2023: 69 · 2022: 76 · 2021: 47 · 2020: 9
FWCI: 2.84
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (am, 362 d)
Locations: Trends in Molecular Medicine (acceptedVersion)
PubMed (publishedVersion)
HAL (submittedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: mRNA vaccines, innate immune response, adaptive immune response, pattern recognition receptors, antigen-presenting cells, 5' cap, poly(A) tail, mRNA translation inhibition, vaccine formulation
MeSH terms: mRNA Vaccines, Animals, Humans, Immunity, Innate, RNA, Messenger, Vaccines, Synthetic, Receptors, Pattern Recognition, Adaptive Immunity

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Tailoring mRNA Vaccine to Balance Innate/Adaptive Immune Response

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