mRNA vaccines: a new opportunity for malaria, tuberculosis and HIV

Abstract

The success of the first licensed mRNA-based vaccines against COVID-19 has created a widespread interest on mRNA technology for vaccinology. As expected, the number of mRNA vaccines in preclinical and clinical development increased exponentially since 2020, including numerous improvements in mRNA formulation design, delivery methods and manufacturing processes. However, the technology faces challenges such as the cost of raw materials, the lack of standardization, and delivery optimization. MRNA technology may provide a solution to some of the emerging infectious diseases as well as the deadliest hard-to-treat infectious diseases malaria, tuberculosis, and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), for which an effective vaccine, easily deployable to endemic areas is urgently needed. In this review, we discuss the functional structure, design, manufacturing processes and delivery methods of mRNA vaccines. We provide an up-to-date overview of the preclinical and clinical development of mRNA vaccines against infectious diseases, and discuss the immunogenicity, efficacy and correlates of protection of mRNA vaccines, with particular focus on research and development of mRNA vaccines against malaria, tuberculosis and HIV.

Keywords: HIV; RNA vaccines; infectious diseases; malaria; tuberculosis.

Figure 1

Structure, function and in vitro synthesis of vaccine mRNA. (A) mRNA are single stranded nucleic acids composed of an open reading frame (ORF) encoding the gene of interest, flanked by untranslated regions (UTRs) implicated in translation regulation, a cap at the 5’ end consisting of a N7-methylated guanosine residue, important for translation initiation and immune detection, and a poly(A) tail at the 3’ end, participating in the stability of the mRNA, as well as the stabilisation of the translation initiation complex. (B) In vitro synthesis of mRNA is often performed from a linearised plasmid template. The gene of interest is encoded in the plasmid template downstream of a promoter sequence. E. coli are transformed with the plasmid and cultured in liquid medium containing an antibiotic for which the plasmid encodes a resistance gene, thereby allowing the selection of bacteria that express the plasmid. The plasmid is then purified from the culture and digested using restriction enzymes to obtain a linear DNA template. In vitro transcription of mRNA is performed in the presence of the DNA template, an RNA polymerase and nucleotides triphosphates (NTPs). The capping can be performed by directly adding a cap analogue in the IVT reaction mix (1-step reaction), or alternatively by an enzymatic capping reaction after the IVT. If the poly(A) tail is not encoded in the plasmid, an additional step of polyadenylation is required. Created with BioRender.com.

Figure 2

Mechanism of action and immune response induced by mRNA vaccines. 1) mRNA vaccines enter the cells through different mechanisms depending on the nature and size of the nanoparticles, such as clathrin-, caveolin- and receptor-mediated endocytosis, micropinocytosis, phagocytosis or diffusion across the cell membrane (47). 2) After reaching the cytoplasm, mRNAs are translated by the ribosomes into the encoded protein. 3) The protein is processed by the proteasome into small antigenic peptides. 4) The peptides are presented at the surface of the antigen presenting cell by major histocompatibility complex (MHC) molecules to prime CD4+ and CD8+ T cells through, respectively, MHC-II or MHC-I interaction with the T cell receptor (TCR), to activate humoral and cellular adaptive responses. 5) Exogenous mRNAs can be detected by the innate immune system through binding to pattern recognition receptors (PRRs) localised at the endosomal membrane or in the cytosol, inducing the transcription and translation (6) of proinflammatory factors, such as type 1 interferons (IFN-I), IFN-stimulated genes (ISGs) and RNases. NF-κB, nuclear factor κB. Created with BioRender.com.