mRNA vaccines: a new era in vaccine development

Abstract

The advent of RNA therapy, particularly through the development of mRNA cancer vaccines, has ushered in a new era in the field of oncology. This article provides a concise overview of the key principles, recent advancements, and potential implications of mRNA cancer vaccines as a groundbreaking modality in cancer treatment. mRNA cancer vaccines represent a revolutionary approach to combatting cancer by leveraging the body's innate immune system. These vaccines are designed to deliver specific mRNA sequences encoding cancer-associated antigens, prompting the immune system to recognize and mount a targeted response against malignant cells. This personalized and adaptive nature of mRNA vaccines holds immense potential for addressing the heterogeneity of cancer and tailoring treatments to individual patients. Recent breakthroughs in the development of mRNA vaccines, exemplified by the success of COVID-19 vaccines, have accelerated their application in oncology. The mRNA platform's versatility allows for the rapid adaptation of vaccine candidates to various cancer types, presenting an agile and promising avenue for therapeutic intervention. Clinical trials of mRNA cancer vaccines have demonstrated encouraging results in terms of safety, immunogenicity, and efficacy. Pioneering candidates, such as BioNTech's BNT111 and Moderna's mRNA-4157, have exhibited promising outcomes in targeting melanoma and solid tumors, respectively. These successes underscore the potential of mRNA vaccines to elicit robust and durable anti-cancer immune responses. While the field holds great promise, challenges such as manufacturing complexities and cost considerations need to be addressed for widespread adoption. The development of scalable and cost-effective manufacturing processes, along with ongoing clinical research, will be pivotal in realizing the full potential of mRNA cancer vaccines. Overall, mRNA cancer vaccines represent a cutting-edge therapeutic approach that holds the promise of transforming cancer treatment. As research progresses, addressing challenges and refining manufacturing processes will be crucial in advancing these vaccines from clinical trials to mainstream oncology practice, offering new hope for patients in the fight against cancer.

Keywords: Cancer immunotherapy; Delivery system; Immune checkpoint; Preventive & therapeutic vaccine; mRNA.

Figure 1. RNA-based medications have the capacity to intervene at various stages of protein-coding and noncoding gene expression. Splicing manipulation is achievable through antisense oligonucleotides (ASOs), while mature messenger RNAs [9] can be targeted using ASOs or small interfering RNAs (siRNAs). Moreover, noncoding RNAs (ncRNAs), encompassing both small and long forms (lncRNAs), can be suppressed utilizing ASOs or siRNAs. Aptamer binding enables the modulation of protein function. Additionally, exogenous mRNAs can be employed to introduce specific proteins into cells, either to restore deficient enzymes or to serve as antigens, triggering a targeted immune response.

Figure 2. The distinctive forms of mRNA structures, non-replicating mRNA (NRM) and self-amplifying mRNA (SAM); The structure of SAM consists of an untranslated region (UTR) and coding sequence (CDS), like the structure depicted in the provided image. However, SAM is identified by the existence of a replica, which enables prompt intracellular amplification of mRNA. In the image, this progression is represented as follows: (1, 2) A lipid nanoparticle is employed to prevent degradation and facilitate cellular uptake. Through this delivery system, SAM utilizes the (3) endocytic pathway, (4) allowing the mRNA to be circulated into the cytosol. SAM’s unique structure leads it into the cytosol, where ribosomes translate the construct, guiding the expressed protein for post-translational modification. (5) SAM’s replicase machinery aids in the translation process by ribosomes, which is crucial for the self-amplification of RNA. The expressed proteins undergo (6) post-translational modification, and these proteins are subsequently sorted to either the (7) trans/intracellular membrane or (8) secreted. Both the innate and adaptive immune responses recognize these proteins.

Figure 3. Designing mRNA Vaccines to Equilibrate Innate and Adaptive Immune Responses. The figure illustrates the innate immune response associated with two categories of mRNA vaccines. Blue cogs represent RNA sensors; MDA-5, and LGP2, while blue blub shaped with black tails represent DC maturation factors. In the top right area, a lipid nanoparticle carrier is illustrated. On the left side, there is a list of key RNA sensors responsible for distinguishing double-stranded and unaltered single-stranded RNAs. The figure showcases two formats for mRNA vaccines: (a) Unmodified/purified and nucleoside-modified (b) fast protein liquid chromatography (FPLC)-refined.

Figure 4. Main delivery systems for carrying mRNA vaccines; the figure depicts frequently used delivery techniques with carrier molecules having specific diameters for mRNA vaccines. (A) Naked mRNA (B) Protamine (C) Cationic polymer (D) Cationic polymer liposome (E) Cationic Nanoemulsion (F) Polysaccharide particle (G) Viral recombinant particle (H) Dendritic cell-based mRNA vaccine.