Next-Generation Vaccines Build On mRNA’s Breakthrough

The next generation of vaccines crashed into public awareness during the COVID-19 pandemic, when rapidly formulated mRNA-based vaccines against SARS-CoV-2 proved more effective than anyone could have hoped. These represented the first instance of lipid nanoparticles (LNPs) in vaccines approved for human use. As tiny hydrophobic bubbles encapsulating the mRNA vaccine, LNPs shield it from the body’s attempt to degrade it until delivered to cells, which are stimulated to mount an immune response. Quick on the heels of successes like the SARS-CoV-2 vaccine are emerging RNA technologies for longer-lasting antigen expression and stronger immune responses. Here’s a look at how next-generation vaccines are doing just that.

Molecules for advanced vaccine delivery

Advances in RNA molecules designed for antigen delivery are proving successful. Innovations such as self-amplifying RNA (saRNA) and circular RNA (circRNA) “provide the same inherent sequence flexibility as mRNA vaccines but may offer improved expression and stability in vivo,” notes Jonathan Mitchell, Senior Research Scientist at Promega. “Consequently, they could enable lower dosing and therefore reduce costs relative to conventional mRNA.” Self-amplifying RNA enables intracellular RNA amplification, which promotes strong antigen expression at lower vaccine doses. Circular RNA—as opposed to standard linear mRNA—exists as a continuous closed loop, lacking ends vulnerable to degradation by intracellular enzymes.

New quality control tools can also help to speed up workflows in mRNA vaccine manufacturing. “Historically, assays like LC-MS and capillary electrophoresis have provided the precision needed to measure critical quality attributes, but they’re labor-intensive, slow and require specialized expertise, thereby creating bottlenecks in release timelines,” says Mitchell. Promega’s Lumit^® dsRNA Detection Assay can more quickly detect dsRNA contamination of in vitro transcribed mRNA samples, facilitating quality control and the overall manufacturing process.

Enzymatic DNA synthesis

Until recently, most vaccine researchers relied on ordering chemically synthesized DNA from commercial suppliers. New enzymatic DNA synthesis methods are faster, more ecologically friendly, and more accurate, and can create oligos that are longer and more complex than previous chemical synthesis methods. In addition, it is now possible for researchers to synthesize their own single-stranded DNA oligos in less than 24 hours, mostly hands-free.

Enzymatic DNA synthesis may further support the design and manufacturing of personalized, mRNA-based cancer vaccines. “DNA synthesis is required to generate the in vitro transcription templates used to produce personalized cancer vaccines and can be a bottleneck,” says Dan Lin-Arlow, Chief Scientific Officer and Co-founder of Ansa Biotechnologies. “New methods for the rapid construction of these templates could meaningfully accelerate treatment timelines.”

DNA Script’s SYNTAX platform gives researchers the ability to synthesize ssDNA oligos in-house, mainly overnight. This makes it possible to generate in vitro transcription templates for mRNA vaccine manufacturing in less time, which in turn facilitates faster testing of vaccine candidates. “The persistent gating step [in personalized medicine and cancer vaccines] has been the upstream production of the DNA template,” says Thomas Ybert, CSO and Co-founder of DNA Script. “On-demand enzymatic DNA synthesis condenses template generation from a multi-week, often outsourced process into a daily, on-site operation.”

AI-based mRNA design

The advent of enzymatic methods to synthesize DNA is, in turn, supporting advances in mRNA design assisted by artificial intelligence. “A challenge is that many of the sequences generated by these AI tools contain features such as repeats, hairpins, and variations in GC content that are difficult to produce using established gene synthesis methods for generating in vitro transcription templates,” says Lin-Arlow. “Fortunately, new enzymatic DNA synthesis methods are now available that can efficiently build these challenging sequences.”

Enzymatic DNA synthesis supports the iterative testing process used to identify AI-designed antigen candidates, leading to quicker vaccine development. “Designing and testing ‘super antigens’ or broad antigen libraries means generating, expressing, and screening very large numbers of candidate sequences, then closing the design-build-test-learn loop as quickly as possible,” says Ybert. “The build side—rapidly turning a designed sequence into physical DNA and then into testable antigen—is where throughput is most often lost.”

AI-based mRNA design is showing great promise when it comes to increasing vaccine effectiveness. “AI-based mRNA design tools can have a significant impact on the performance of mRNA-based vaccines and therapeutics,” says Lin-Arlow. “For example, the latest tools for codon optimization and UTR design can improve both the expression level and the duration of expression of encoded proteins, leading to more efficacious therapeutics.”

Incorporating AI into the mRNA design process is also showing promise in identifying new types of effective antigens. The idea of a “super antigen” —an unchanging region common to all viruses of a particular family—is building hope for vaccines that remain effective despite natural viral mutations; in other words, “future-proofed.” Recently, researchers at the University of Cambridge and DIOSynVax used AI to design a “universal” vaccine against the Sarbeco family of coronaviruses,¹ which includes SARS-CoV-2 among others. In an initial clinical trial by the UK’s National Institute for Health and Care Research, the vaccine was found to be safe and well-tolerated, and will progress to a larger Phase II trial. The vaccine is administered intradermally via needle-free microfluidic jet, which makes it simpler and faster to vaccinate larger numbers of people—especially in areas of the world with less technological infrastructure and/or fewer trained healthcare workers.

Even with AI helping to broaden vaccine coverage, “it’s important to acknowledge the ‘evolutionary arms race’ that exists between viruses and our immune systems,” notes Mitchell. Humans haven’t won the race. Recent advances may help us get further ahead of viral mutations, but we’ll probably still need to keep adapting our vaccines. “AI-designed antigens won’t circumvent that need entirely, but they should give us a leg-up.”

Reference

1. Munro A PS et al. A phase I, needle free, dose escalation clinical trial of pEVAC-PS, a candidate pan-Sarbecovirus Vaccine. J Infect. 2026; DOI:10.1016/j.jinf.2026.106759.