Advancing mRNA technologies for therapies and vaccines: An African context
Open accessAbstract
Synthetic mRNA technologies represent a versatile platform that can be used to develop advanced drug products. The remarkable speed with which vaccine development programs designed and manufactured safe and effective COVID-19 vaccines has rekindled interest in mRNA technology, particularly for future pandemic preparedness. Although recent R&D has focused largely on advancing mRNA vaccines and large-scale manufacturing capabilities, the technology has been used to develop various immunotherapies, gene editing strategies, and protein replacement therapies. Within the mRNA technologies toolbox lie several platforms, design principles, and components that can be adapted to modulate immunogenicity, stability, in situ expression, and delivery. For example, incorporating modified nucleotides into conventional mRNA transcripts can reduce innate immune responses and improve in situ translation. Alternatively, self-amplifying RNA may enhance vaccine-mediated immunity by increasing antigen expression. This review will highlight recent advances in the field of synthetic mRNA therapies and vaccines, and discuss the ongoing global efforts aimed at reducing vaccine inequity by establishing mRNA manufacturing capacity within Africa and other low- and middle-income countries.
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The current understanding of the field is that incorporating modified NTPs into saRNA abrogates downstream efficacy.
“However, the current understanding of the field is that incorporating modified NTPs into saRNA abrogates downstream efficacy, as reported by multiple independent groups5,19–28.”
From Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency (2025) · cites this paper as [19]
Section 2.4 says modified nucleotides may be unsuitable for saRNA because its replication relies on stable RNA structures, and that their compatibility needs evaluation. It does not say incorporating modified NTPs abrogates saRNA efficacy; the citing sentence turns a qualified concern into a categorical conclusion. (LLM, conf=0.87)
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“IFITs bind to eIF3 to prevent formation of the pre-initiation complex that is required for translation, and binds to mRNAs that lack a cap 1 moiety to prevent its translation (reviewed in (31)).”
BackgroundControl of mammalian translation by mRNA structure near caps
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A modular platform for targeted RNAi therapeutics
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“Kedmi and colleagues overcame this issue by designing a modular platform, referred to as anchored secondary scFv enabling targeting or ASSET, which can incorporate any antibody onto the surface of an LNP (97).”
BackgroundThe use of viral vectors in vaccine development
Travieso, T., Li, J., Mahesh, S., Mello, J. D. F. R. E., & Blasi, M. (2022) · npj Vaccines · doi:10.1038/s41541-022-00503-y · Cited by 314 · cited 2× · see citing works
“Recombinant viruses are very efficient at delivering vaccine and therapeutic sequences for expression within target cells and as a consequence their use is being actively explored in these fields (reviewed in (3, 4)).”
BackgroundEfficient generation of human iPSCs by a synthetic self-replicative RNA
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“Alternatively, incorporation of an IRES may be used to produce multi-cistronic synthetic mRNA (22).”
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“A further modification, in the form of 2’-Omethylation of the first ribose, generates the cap 1 structure which functions to abolish recognition of endogenous mRNAs by RIG-I and IFIT1 (55, 57).”
BackgroundInfluentialCell specific delivery of modified mRNA expressing therapeutic proteins to leukocytes
Veiga, N., Goldsmith, M., Granot, Y., Rosenblum, D., Dammes, N., Kedmi, R., Ramishetti, S., & Peer, D. (2018) · Nature Communications · doi:10.1038/s41467-018-06936-1 · Cited by 308 · cited 2× · see citing works
“It could also deliver mRNA encoding therapeutic interleukin 10 (IL10) to treat IBS (100), again using anti-Ly6C antibodies with reduced toxicity and immunogenicity.”
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Systemic delivery of factor IX messenger RNA for protein replacement therapy
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“Antibody conjugation has recently shown promise for CD4+ T cell targeting (94) albeit with leaky liver expression.”
BackgroundGenomics of disease risk in globally diverse populations
Gurdasani, D., Barroso, I., Zeggini, E., & Sandhu, M. S. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0144-0 · Cited by 299 · see citing works
Elimination of large tumors in mice by mRNA-encoded bispecific antibodies
Stadler, C. R., Bähr-Mahmud, H., Celik, L., Hebich, B., Roth, A. S., Roth, R. P., Karikó, K., Türeci, Ö., & Sahin, U. (2017) · Nature Medicine · doi:10.1038/nm.4356 · Cited by 290 · see citing works
An Update on Self-Amplifying mRNA Vaccine Development
Blakney, A. K., Ip, S., & Geall, A. J. (2021) · Vaccines · doi:10.3390/vaccines9020097 · Cited by 288 · cited 2× · see citing works
“While the majority of clinical trials have focused on conventional mRNA candidate vaccines, recent first-in human SARS-CoV-2 and Rabies saRNA vaccine studies will prove useful in determining the clinical potential this platform (5, 7).”
BackgroundReversal of Diabetes Insipidus in Brattleboro Rats: Intrahypothalamic Injection of Vasopressin mRNA
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“Although messenger RNA (mRNA) was first investigated as a therapeutic in 1992 (1), complications including stability and”
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The Critical Contribution of Pseudouridine to mRNA COVID-19 Vaccines
Morais, P., Adachi, H., & Yu, Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.789427 · Cited by 274 · cited 3× · see citing works
“It is not surprising that m1Y has been favored for the development of mRNA vaccines against Zika, Influenza, HIV-1 (Human Immunodeficiency Virus), and Ebola, and more recently, against SARS-CoV-2 [reviewed in (16)].”
BackgroundInfluentialVaidyanathan, S., Azizian, K. T., Haque, A. K. M. A., Henderson, J. M., Hendel, A., Shore, S., Antony, J. S., Hogrefe, R. I., Kormann, M. S. D., Porteus, M. H., et al. (2018) · Molecular Therapy Nucleic Acids · doi:10.1016/j.omtn.2018.06.010 · Cited by 262 · cited 1× · see citing works
“Thanks to the degeneracy of the genetic code, rare codons can be replaced by more abundant synonymous codons to increase the rate of translation which has also been shown to delay deadenylation of the polyA tail and mRNA decay (reviewed in (8) (9);).”
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Polyethylene glycol (PEG) is a cause of anaphylaxis to the Pfizer/BioNTech mRNA COVID‐19 vaccine
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“However, iLNPs would benefit from further optimization to improve targeted delivery (79) and reduce the likelihood of unwanted side effects such as anaphylaxis (80) and myocarditis (81).”
BackgroundAdvances in Lipid Nanoparticles for mRNA-Based Cancer Immunotherapy
Guevara, M. L., Persano, F., & Persano, S. (2020) · Frontiers in Chemistry · doi:10.3389/fchem.2020.589959 · Cited by 257 · see citing works
mRNA Vaccines in the COVID-19 Pandemic and Beyond
Hogan, M. J., & Pardi, N. (2021) · Annual Review of Medicine · doi:10.1146/annurev-med-042420-112725 · Cited by 252 · cited 1× · see citing works
“gov/) and numerous candidates in clinical trials (reviewed in (13)) • Influenza (NCT05052697) • HIV (NCT05001373) • Zika (NCT04917861) • Tuberculosis (NCT05537038) • Chikungunya virus (NCT03829384) • Anti-claudin 18.”
BackgroundPollard, C., Rejman, J., De Haes, W., Verrier, B., Van Gulck, E., Naessens, T., De Smedt, S., Bogaert, P., Grooten, J., Vanham, G., et al. (2013) · Molecular Therapy · doi:10.1038/mt.2012.202 · Cited by 248 · cited 1× · see citing works
“For vaccine applications, induction of interferons and pro-inflammatory cytokines may improve adaptive immune responses but could also prematurely inhibit translation of the antigen which can result in sub-optimal adaptive immunity (6).”
BackgroundGenome Editing with mRNA Encoding ZFN, TALEN, and Cas9
Zhang, H., Zhang, Y., & Yin, H. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.01.014 · Cited by 248 · see citing works
A multi-cohort study of the immune factors associated with M. tuberculosis infection outcomes
Chowdhury, R. R., Vallania, F., Yang, Q., Angel, C. J. L., Darboe, F., Penn‐Nicholson, A., Rozot, V., Nemes, E., Malherbe, S. T., Ronacher, K., et al. (2018) · Nature · doi:10.1038/s41586-018-0439-x · Cited by 243 · see citing works
Dendrimers in Medicine: Therapeutic Concepts and Pharmaceutical Challenges
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“Dendrimers are uniform molecules consisting of a core which is surrounded by highly branched sidechains terminating in functional groups (88).”
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“A further modification, in the form of 2’-Omethylation of the first ribose, generates the cap 1 structure which functions to abolish recognition of endogenous mRNAs by RIG-I and IFIT1 (55, 57).”
BackgroundInfluentialParhiz, H., Shuvaev, V. V., Pardi, N., Khoshnejad, M., Kiseleva, R. Y., Brenner, J. S., Uhler, T., Tuyishime, S., Mui, B. L., Tam, Y. K., et al. (2018) · Journal of Controlled Release · doi:10.1016/j.jconrel.2018.10.015 · Cited by 233 · cited 1× · see citing works
“The same group targeted lung and inflamed brain endothelial cells using anti-PECAM-1 (95) and -VCAM (96) antibodies conjugated to iLNPs and cLNPs respectively.”
BackgroundLong-term storage of lipid-like nanoparticles for mRNA delivery
Zhao, P., Hou, X., Yan, J., Du, S., Xue, Y., Li, W., Xiang, G., & Dong, Y. (2020) · Bioactive Materials · doi:10.1016/j.bioactmat.2020.03.001 · Cited by 233 · see citing works
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“The various CleanCap® analogs function by complementary base-pairing to the first two initiating nucleotides following the T7 promoter sequence, a factor that needs to be taken into consideration during initial template design (10, 18).”
BackgroundInduction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires
Tian, M., Cheng, C., Chen, X., Duan, H., Cheng, H.-L., Dao, M. N., Sheng, Z., Kimble, M. T., Wang, L., Lin, S. G., et al. (2016) · Cell · doi:10.1016/j.cell.2016.07.029 · Cited by 228 · see citing works
An origin of the immunogenicity of in vitro transcribed RNA
Mu, X., Greenwald, E., Ahmad, S., & Hur, S. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky177 · Cited by 218 · see citing works
Sequestration by IFIT1 Impairs Translation of 2′O-unmethylated Capped RNA
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“A further modification, in the form of 2’-Omethylation of the first ribose, generates the cap 1 structure which functions to abolish recognition of endogenous mRNAs by RIG-I and IFIT1 (55, 57).”
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“for mRNA and saRNA vaccine development (84).”
Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines
Xia, X. (2021) · Vaccines · doi:10.3390/vaccines9070734 · Cited by 201 · see citing works
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“N6-methyladenosine (m6A), a natural modification of adenosine, is known to reduce the thermodynamic stability of dsRNA structures (49).”
BackgroundTheoretical basis for stabilizing messenger RNA through secondary structure design
Wayment-Steele, H. K., Kim, D. S., Choe, C. A., Nicol, J. J., Wellington-Oguri, R., Watkins, A. M., Parra Sperberg, R. A., Huang, P.-S., Participants, E., & Das, R. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab764 · Cited by 197 · see citing works
Cancer in Africa: The Untold Story
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Lessons from miR-143/145: the importance of cell-type localization of miRNAs
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“Efficacy of these UTRs in other cell types may vary though as miRNAs are known to be differentially expressed between different cell types (reviewed in (40)).”
BackgroundLipopolyplex potentiates anti-tumor immunity of mRNA-based vaccination
Persano, S., Guevara, M. L., Li, Z., Mai, J., Ferrari, M., Pompa, P. P., & Shen, H. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.02.019 · Cited by 187 · see citing works
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“The same group targeted lung and inflamed brain endothelial cells using anti-PECAM-1 (95) and -VCAM (96) antibodies conjugated to iLNPs and cLNPs respectively.”
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“However, translation of the downstream gene in bi-cistronic constructs are often less efficient and certain upstream mRNA sequences, such as mRNA encoding Firefly luciferase (Fluc), can hinder IRES-dependent translation (23, 24).”
BackgroundRacial Differences in Cancer Susceptibility and Survival: More Than the Color of the Skin?
Özdemir, B. C., & Dotto, G. P. (2017) · Trends in cancer · doi:10.1016/j.trecan.2017.02.002 · Cited by 178 · see citing works
Priming HIV-1 broadly neutralizing antibody precursors in human Ig loci transgenic mice
Sok, D., Briney, B. S., Jardine, J. G., Kulp, D. W., Menis, S., Pauthner, M. G., Wood, A. L., Lee, E.-C., Le, K. M., Jones, M., et al. (2016) · Science · doi:10.1126/science.aah3945 · Cited by 176 · see citing works
mRNA-Based Protein Replacement Therapy for the Heart
Magadum, A., Kaur, K., & Zangi, L. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2018.11.018 · Cited by 176 · see citing works
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“These nanoparticles can be engineered to mimic components of cell membranes by conjugating sugars to their hydrophobic region, and this, along with their ionizable properties and versatility of potential structure, make them excellent candidates for efficient mRNA delivery (90).”
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“Post-transcriptional purification of synthetic mRNAs is necessary to remove immunogenic dsDNA templates and dsRNA by-products, aborted transcripts, excess reagents, and other chemical by-products to obtain full-length mRNA transcripts which would then be acceptable as pharmaceutical grade therapeutics and vaccines (re…”
Background“Janus” dendrimers: syntheses and properties
Caminade, A., Laurent, R., Delavaux‐Nicot, B., & Majoral, J. (2011) · New Journal of Chemistry · doi:10.1039/c1nj20458k · Cited by 155 · cited 1× · see citing works
“In this case, amphiphilic molecules were synthesized, allowing for nanoparticles to self-assemble (89).”
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Immunity to CRISPR Cas9 and Cas12a therapeutics
Chew, W. L. (2017) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1408 · Cited by 146 · see citing works
Immune Response and Evasion Mechanisms of Plasmodium falciparum Parasites
Belachew, E. B. (2018) · Journal of Immunology Research · doi:10.1155/2018/6529681 · Cited by 143 · see citing works
A network analysis of COVID-19 mRNA vaccine patents
Gaviria, M. A., & Kilic, B. (2021) · Nature Biotechnology · doi:10.1038/s41587-021-00912-9 · Cited by 143 · see citing works
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Engineered mRNA-expressed antibodies prevent respiratory syncytial virus infection
Tiwari, P. M., Vanover, D. A., Lindsay, K. E., Bawage, S. S., Kirschman, J. L., Bhosle, S. M., Lifland, A. W., Zurla, C., & Santangelo, P. J. (2018) · Nature Communications · doi:10.1038/s41467-018-06508-3 · Cited by 139 · see citing works
Synthesis of low immunogenicity RNA with high-temperature in vitro transcription
Wu, M. Z., Asahara, H., Tzertzinis, G., & Roy, B. (2020) · RNA · doi:10.1261/rna.073858.119 · Cited by 135 · cited 10× · see citing works
“This convenient adaptation to the IVT protocol, when used in combination with polyA-encoding templates, has been shown to be just as effective at reducing the interferon response as compared to purification using high performance liquid chromatography (HPLC).”
BackgroundMethodInfluentialPolymeric and lipid nanoparticles for delivery of self-amplifying RNA vaccines
Blakney, A. K., McKay, P. F., Hu, K., Samnuan, K., Jain, N., Brown, A., Thomas, A. M., Rogers, P., Polra, K., Sallah, H., et al. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.08.029 · Cited by 135 · cited 2× · see citing works
“1 μg saRNA could produce strong SARS-CoV-2 specific IgG and neutralizing antibodies, as well as cellular immune responses (86).”
BackgroundVerbeke, R., Lentacker, I., Wayteck, L., Breckpot, K., Van Bockstal, M., Descamps, B., Vanhove, C., De Smedt, S. C., & Dewitte, H. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.09.041 · Cited by 132 · see citing works
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RNA Modifications Modulate Activation of Innate Toll-Like Receptors
Freund, I., Eigenbrod, T., Helm, M., & Dalpke, A. H. (2019) · Genes · doi:10.3390/genes10020092 · Cited by 119 · cited 1× · see citing works
“A key function of eukaryotic PTMs is to assist the innate immune system to distinguish between self and non-self (reviewed in (48)).”
BackgroundErasmus, J. H., Archer, J., Fuerte-Stone, J., Khandhar, A. P., Voigt, E., Granger, B., Bombardi, R. G., Govero, J., Tan, Q., Durnell, L. A., et al. (2020) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2020.06.011 · Cited by 118 · see citing works
Delivery of mRNA Therapeutics for the Treatment of Hepatic Diseases
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It is not too late to achieve global covid-19 vaccine equity
Yamey, G., Garcia, P., Hassan, F., Mao, W., McDade, K. K., Pai, M., Saha, S., Schellekens, P., Taylor, A., & Udayakumar, K. (2022) · BMJ · doi:10.1136/bmj-2022-070650 · Cited by 114 · see citing works
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mRNA: Fulfilling the Promise of Gene Therapy
Weissman, D., & Karikó, K. (2015) · Molecular Therapy · doi:10.1038/mt.2015.138 · Cited by 111 · cited 2× · see citing works
“immunogenicity limited the feasibility of the technology for further drug development, leading to the prioritization of DNA-based platforms (2).”
BackgroundZhang, D., Atochina‐Vasserman, E. N., Lu, J., Maurya, D. S., Xiao, Q., Liu, M., Adamson, J., Ona, N. A., Reagan, E. K., Ni, H., et al. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c00273 · Cited by 111 · cited 1× · see citing works
“Recently, Zhang and colleagues described ionizable dendrimers as single component nanoparticles, bypassing the need for cholesterol, phospholipids, and a PEGylated lipid (87).”
BackgroundA general method for rapid and cost-efficient large-scale production of 5′ capped RNA
Fuchs, A.-L., Neu, A., & Sprangers, R. (2016) · RNA · doi:10.1261/rna.056614.116 · Cited by 106 · see citing works
The 5′ and 3′ ends of alphavirus RNAs – Non-coding is not non-functional
Hyde, J., Chen, R., Trobaugh, D. W., Diamond, M., Weaver, S. C., Klimstra, W. B., & Wilusz, J. (2015) · Virus Research · doi:10.1016/j.virusres.2015.01.016 · Cited by 105 · cited 3× · see citing works
“In contrast to the variety of UTRs that are available for use in conventional non-replicating mRNAs, saRNAs depend on structured alphaviral genomic and subgenomic 5’ UTRs, referred to as CSEs for RNA replication, translation, and innate immune system evasion (reviewed in (26)).”
BackgroundInfluentialInnate Inhibiting Proteins Enhance Expression and Immunogenicity of Self-Amplifying RNA
Blakney, A. K., McKay, P. F., Bouton, C. R., Hu, K., Samnuan, K., & Shattock, R. J. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2020.11.011 · Cited by 105 · cited 1× · see citing works
“To ensure that innate inhibiting proteins co-localize with the therapeutic protein or antigen, the genes can be encoded within the same transcript, although in the case of saRNAs, this will increase manufacturing complications (47).”
BackgroundRecent Developments in mRNA-Based Protein Supplementation Therapy to Target Lung Diseases
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Chemical Stability of Nucleic Acid–Derived Drugs
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Special focus on challenges and opportunities for the development and use of vaccines in Africa
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BackgroundAnother HIV vaccine strategy fails in large-scale study
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Covid-19 and mRNA technology are helping Africa fix its vaccine problems
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“However, the current understanding of the field is that incorporating modified NTPs into saRNA abrogates downstream efficacy, as reported by multiple independent groups 5,19–28 .”
BackgroundThe translational gap for gene therapies in low- and middle-income countries
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Biodrug Delivery Systems: Do mRNA Lipid Nanoparticles Come of Age?
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“Within the mRNA technology toolbox lie several platforms, design principles, and components that can be adapted to modulate immunogenicity, stability, in situ expression, and delivery [3].”
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“The frontier of personalized medicine, enabled by mRNA technology, also holds promise for Africa, as the ability to create individualized Immunotherapeutics based on unique genetic and immunological profiles represents a significant leap forward in treatment efficacy [50, 51].”
Advances in Biotechnology and the Development of Novel Human Vaccines
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Incorporating mRNA therapeutics into biological treatments of hematologic malignancies
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“DNA vaccines are also an interesting platform with a good prospect of pandemic response and chronic infections, given the ongoing rapid advancements in delivery technologies and vector engineering [36].”
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Africa is an Essential Partner in the Research and Development of an HIV Vaccine
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LNP-mRNA immunogenicity and toxicity
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Nanotechnology-based self-amplifying RNA
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- Authors
- Kairuz, D., Samudh, N., Ely, A., Arbuthnot, P., & Bloom, K.
- Affiliations
- South African Medical Research Council (ZA)
- Corresponding author
- Bloom, Kristie
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2022-10-24
- Volume
- 13
- Pages
- 1018961-1018961
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC9637871
- OpenAlex
- W4307271772
- Cited by
- 25
- References
- 190
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 5 · 2023: 3
- FWCI
- 0.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Research Foundation (120383)
- South African Medical Research Council (120383)
- Poliomyelitis Research Foundation (120383)
- Medical Research Council
- Division of Research Capacity Development
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- mRNA vaccines, mRNA therapeutics, COVID-19 vaccines, vaccine production capacity, vaccine inequity, low- and middle-income countries, Africa, modified nucleotides, self-amplifying RNA, immunotherapy, genome editing, protein replacement therapy, pandemic preparedness
- MeSH terms
- COVID-19, COVID-19 Vaccines, Humans, RNA, Messenger, Technology, Vaccines
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