close
Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Nov;41(11):1417-1429.
doi: 10.1016/j.tibtech.2023.05.007. Epub 2023 Jun 14.

Rise of the RNA machines - self-amplification in mRNA vaccine design

Jerome D G Comes  1 , Gorben P Pijlman  2 , Tessy A H Hick  1
Affiliations
Review

Rise of the RNA machines - self-amplification in mRNA vaccine design

Jerome D G Comes et al. Trends Biotechnol. 2023 Nov.

Abstract

mRNA vaccines have won the race for early COVID-19 vaccine approval, yet improvements are necessary to retain this leading role in combating infectious diseases. A next generation of self-amplifying mRNAs, also known as replicons, form an ideal vaccine platform. Replicons induce potent humoral and cellular responses with few adverse effects upon a minimal, single-dose immunization. Delivery of replicons is achieved with virus-like replicon particles (VRPs), or in nonviral vehicles such as liposomes or lipid nanoparticles. Here, we discuss innovative advances, including multivalent, mucosal, and therapeutic replicon vaccines, and highlight novelties in replicon design. As soon as essential safety evaluations have been resolved, this promising vaccine concept can transform into a widely applied clinical platform technology taking center stage in pandemic preparedness.

Keywords: lipid nanoparticles; mRNA; platform technology; replicon; self-amplifying RNA; vaccines.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests No interests are declared.

Figures

Figure 1
Figure 1
Schematic representation of the protein of interest expression induced by a conventional mRNA and a replicon vaccine. Once released in the cell, the mRNA is translated to produce the protein of interest. In contrast to mRNA, replicon RNA encodes alongside the protein of interest, self-amplifying genes (depicted in blue) that amplify the replicon RNA. This intracellular amplification will subsequently result in higher expression levels of the protein of interest.
Figure I
Figure I
Schematic overview of (viral) nucleic acid vectors. (A) An mRNA molecule contains the coding sequence of the gene of interest (GOI) flanked by a 5′ m7G cap-analog and a 3′ poly-A-tail. Similar to the mRNA vector, (B) virus-based replicons encode the GOI but also self-amplification genes, allowing RNA amplification. Both mRNA and replicon vectors are propagation-deficient as they do not encode a complete structural gene cassette. This is in contrast to (C) chimeric and (D) recombinant virus vectors that encode a complete (heterologous) structural gene cassette. These genes facilitate viral propagation, not limiting transduction of the viral vector to a single cell.
Figure 2
Figure 2
Schematic overview of replicon delivery vehicles. (A) In trans coexpression of replicon RNA and helper RNAs in a mammalian production cell line enables encapsulation of replicon RNA in virus-like replicon particles. Delivery vehicles can also be based on nonviral carriers that encapsulate the replicon RNA in (B) liposomes, (C) lipid nanoparticles, or (D) nanostructured lipid carriers in a cell-free manufacturing process. The delivery vehicles protect the replicon RNA and allow efficient delivery to target cells upon immunization.
Figure 3
Figure 3
Schematic overview of heterologous gene expression using a liposomal-delivered DNA-launched RNA replicon (DREP). (A) Upon liposomal delivery to a cell, (B) the DREP migrates to the nucleus where (C) it serves as a template for the RNA polymerase II-mediated transcription of replicon RNA. (D) Subsequently, the replicon RNA is transported to the cytoplasm where the self-amplification, mediated by replicase proteins, occurs. (E) During amplification, cellular sensors recognize amplification intermediates (double-stranded RNA), enhancing host immunity. (F) At the same time, translation of the replicon RNA produces the protein of interest (POI). (G) This will induce an antigen-specific immune response.
See this image and copyright information in PMC

References

    1. World Health Organization Status of COVID-19 vaccines within WHO EUL/PQ evaluation process. 2021. https://extranet.who.int/pqweb/sites/default/files/documents/Status_COVI... Published online January 20, 2021.
    1. Vogel A.B., et al. Self-amplifying RNA vaccines give equivalent protection against influenza to mRNA vaccines but at much lower doses. Mol. Ther. 2018;26:446–455. - PMC - PubMed
    1. de Alwis R., et al. A single dose of self-transcribing and replicating RNA-based SARS-CoV-2 vaccine produces protective adaptive immunity in mice. Mol. Ther. 2021;29:1970–1983. - PMC - PubMed
    1. Voigt E.A., et al. A self-amplifying RNA vaccine against COVID-19 with long-term room-temperature stability. NPJ Vaccines. 2022;7:136. - PMC - PubMed
    1. Lundstrom K. Self-amplifying RNA viruses as RNA vaccines. Int. J. Mol. Sci. 2020;21:1–29. - PMC - PubMed