Advancing mRNA technologies for therapies and vaccines: An African context

Abstract

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.

Production, Characterization, and Assessment of Permanently Cationic and Ionizable Lipid Nanoparticles for Use in the Delivery of Self-Amplifying RNA Vaccines

“…The ability of mRNA vaccines to confer a protective immune response against SARS-CoV-2 has reignited the field of vaccinology and has brought the mRNA platform to the forefront of infectious disease vaccine development. This has been facilitated by the multiple iterations and recent advancements that synthetic RNA has undergone resulting in improved stability and translatability of mRNA vaccines and therapies [3]. A key advancement has been the use of modified nucleotides to prevent the recognition of synthetic exogenous mRNAs and induction of an innate immune response, leading to improved antigen expression.…”

“…The World Health Organization, together with international and local collaborators, has taken the first steps to establish an mRNA technology transfer program which is intended to enable African countries to produce and supply mRNA-based vaccines to the continent. The benefits of this vaccine platform have been recently showcased with the rapid development of multiple, highly effective vaccines against SARS-CoV2 and numerous other pathogens [3]. mRNA vaccines enable in situ translation of antigens ensuring that antigens are folded in their native conformations and bear the correct post-translational modifications.…”

Complete substitution with modified nucleotides suppresses the early interferon response and increases the potency of self-amplifying RNA

“…A hypothesis for this observed incompatibility is the alteration of vital saRNA secondary structures [16, 21]. saRNAs traditionally utilize alphavirus sequences, replacing the structural genes with the genes encoding the cargo(s) of interest [22].…”

“…The best tools for such improvements are modNTPs. However, the current understanding of the field is that the incorporation of modNTPs into saRNA abrogates downstream efficacy, as reported by multiple independent groups [5,[16][17][18][19][20]. Thus, modified nucleotides are not currently viewed as a viable strategy to decrease immunogenicity.…”

Biodrug Delivery Systems: Do mRNA Lipid Nanoparticles Come of Age?

“…Although recent research and development approaches have largely focused on advancing mRNA vaccines and large-scale manufacturing capabilities, the technology has also been used to develop various immunotherapies, gene editing strategies, and protein replacement therapies. 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].…”