Advances in nucleic acid-based cancer vaccines

Abstract

Nucleic acid vaccines have emerged as crucial advancements in vaccine technology, particularly highlighted by the global response to the COVID-19 pandemic. The widespread administration of mRNA vaccines against COVID-19 to billions globally marks a significant milestone. Furthermore, the approval of an mRNA vaccine for Respiratory Syncytial Virus (RSV) this year underscores the versatility of this technology. In oncology, the combination of mRNA vaccine encoding neoantigens and immune checkpoint inhibitors (ICIs) has shown remarkable efficacy in eliciting protective responses against diseases like melanoma and pancreatic cancer. Although the use of a COVID-19 DNA vaccine has been limited to India, the inherent stability at room temperature and cost-effectiveness of DNA vaccines present a viable option that could benefit developing countries. These advantages may help DNA vaccines address some of the challenges associated with mRNA vaccines. Currently, several trials are exploring the use of DNA-encoded neoantigens in combination with ICIs across various cancer types. These studies highlight the promising role of nucleic acid-based vaccines as the next generation of immunotherapeutic agents in cancer treatment. This review will delve into the recent advancements and current developmental status of both mRNA and DNA-based cancer vaccines.

Keywords: Cancer vaccine; DNA vaccine; Neoantigen; mRNA vaccine.

Fig. 1

Molecular mechanisms of DNA and mRNA cancer vaccines. DNA is delivered to the cell nucleus and then transcribed to mRNA. The mRNA is translated to protein in the cytosol, and the protein is degraded via the proteasome into small peptides. These peptides are translated into the ER and bind to MHC class I molecules after fine-tuning. MHC class I/peptide complexes are present in CD8⁺ T cells to kill cancer cells. However, the mRNA was delivered into the cell cytosol and translated to the protein through the same mechanisms that activate CD8⁺ T cells. Alternatively, the extracellular proteins expressed by DNA or mRNA vaccines can be taken up by APCs and degraded by the endosome-lysosome pathway, which then binds to MHC class II molecules to present to CD4⁺ T cells. Activated CD4⁺ T cells induce antigen-specific B cells to secrete antibodies targeting tumor cells. In summary, DNA and mRNA cancer vaccines can induce both CD4⁺ and CD8⁺ T cells to clear cancer cells. (Figure created with Biorender)

Fig. 2

Key Design Elements for an Optimized DNA Vaccine Vector. Many factors need to be considered when designing a DNA vaccine. These elements collectively aim to optimize DNA vaccines for efficacy and safety. A Minimization of Plasmid Size: This involves removing unnecessary backbone sequences to facilitate large-scale production, enhance gene delivery efficiency, and decrease immune recognition. B Promoter Selection: The use of strong and ubiquitous promoters ensures transcription. Tissue-specific promoters are employed to enhance specificity, safety, and effectiveness. C Selectable Markers: Avoid markers that confer resistance to antibiotics used in human infections and ensure stable maintenance of the plasmid in bacterial hosts during large-scale production. D Origin of replication: providing high copy numbers of the plasmid without enabling replication in other hosts. E Using the leader sequence, signal peptides that direct proteins to the ER for efficient secretion and target antigens to MHC class I for cytotoxic T-cell responses. F Refinement of the ORF sequence: codon optimization to match the host tRNA abundance, increasing mRNA stability and removing mRNA secondary structures. G Polyadenylation signal: This signal ensures the termination of transcription, promotes mRNA export from the nucleus and increases the stability of the mRNA product. (Figure created with Biorender)

Fig. 3

Essential Components and Strategies for mRNA Vaccine Design. Illustration of the key structural and strategic elements in the design of an mRNA vaccine to optimize its stability and efficacy. The components include A 5' cap addition: aids in evading innate immune detection, protects mRNA from exonuclease degradation, and facilitates translation initiation. B 5' Untranslated Region (UTR): This region modulates ribosome binding to initiate translation, but stable secondary structures can negatively influence mRNA translation. C Coding sequence optimization involves replacing rare codons to match tRNA abundance in the host, using modified nucleotides to avoid immune detection and extend the mRNA half-life, and refining the sequence to reduce secondary structure. D 3' Untranslated Region (UTR): 3' UTR sequences were added in tandem to improve protein expression, and UTRs from highly expressed genes were used to increase overall mRNA effectiveness. E Poly(A) tail extension: poly(A) tails are added posttranscriptionally or encoded directly within the DNA template, with lengths generally between 100–250 nucleotides tailored to the target cell type to prevent mRNA decapping and exonuclease degradation. (Figure created with Biorender)