DNA Origami Vaccine Matches mRNA Shots in Immune Response, Without the Cold Chain

Published in Nature Biomedical Engineering. Research by Wyss Institute at Harvard University, Dana-Farber Cancer Institute, and collaborating institutions.

The mRNA vaccines that helped end the acute phase of the COVID-19 pandemic were a scientific triumph. They also came with a list of practical headaches: ultra-cold storage, complex manufacturing, limited control over how much genetic material ends up in each dose, and immune responses that vary widely between recipients and fade over months.

Now a team at Harvard's Wyss Institute, Dana-Farber Cancer Institute, and collaborating institutions has built something designed from the ground up to address those problems. Their platform, called DoriVac, uses DNA origami -- tiny self-folding nanostructures -- to deliver vaccine components with a precision that lipid nanoparticles cannot match. In head-to-head testing against the Moderna and Pfizer COVID-19 vaccines, DoriVac produced comparable immune activation. The findings appear in Nature Biomedical Engineering.

Folding DNA into a vaccine chassis

DoriVac's architecture is deceptively simple in concept. Small square blocks of DNA self-assemble through the principles of DNA origami, a technique that uses the predictable base-pairing of DNA to fold strands into precise three-dimensional shapes. One face of each block presents adjuvant molecules -- immune-stimulating compounds -- with optimized nanometer spacing. The opposite face displays antigens: the viral fragments the immune system needs to recognize.

That spatial control is the key differentiator. In mRNA vaccines, the number of mRNA molecules packaged into each lipid nanoparticle varies. With DoriVac, the ratio of adjuvant to antigen is fixed at the molecular level. William Shih, the Wyss Institute faculty member who pioneered the platform, described it as an extremely flexible chassis with unprecedented control over vaccine composition.

The team tested DoriVac against a conserved peptide region called HR2, found in the spike proteins of SARS-CoV-2, HIV, and Ebola. Targeting a conserved region is strategic: it is less likely to mutate away, potentially offering broader protection than vaccines aimed at the rapidly evolving parts of a virus.

Mouse data, then a human lymph node on a chip

In mice, the SARS-CoV-2 HR2 DoriVac vaccine produced significantly greater activation across multiple immune cell types compared to the same antigens and adjuvants delivered without the DNA origami scaffold. Antibody-producing B cells, activated dendritic cells, and memory and cytotoxic T cells -- the cellular machinery of long-term protection -- were all increased.

But mouse immune responses often fail to predict human outcomes, a problem that has sunk many promising vaccine candidates in clinical trials. To address this, the team turned to a remarkable piece of bioengineering: a human lymph node-on-a-chip developed by Donald Ingber's group at the Wyss Institute. This microfluidic device contains human immune cells arranged to mimic the architecture of an actual lymph node, allowing researchers to observe human-relevant immune responses without a human trial.

In this system, the DoriVac SARS-CoV-2 HR2 vaccine activated human dendritic cells and boosted inflammatory cytokine production well beyond what the origami-free components could achieve. Human CD4+ and CD8+ T cells with multiple protective functions also increased. Girija Goyal, Director of Bioinspired Therapeutics at the Wyss Institute, noted that the predictive capabilities of human lymph node chips gave the team an ideal testing ground.

Going head-to-head with mRNA vaccines

The most striking experiment compared a DoriVac vaccine presenting the complete SARS-CoV-2 spike protein against Moderna and Pfizer mRNA vaccines encoding the identical spike protein. Using a standard booster protocol in mice, the team measured anti-viral T cell and antibody-producing B cell responses. The results were comparable.

That equivalence matters because it establishes DoriVac as a credible alternative, not just a laboratory curiosity. And where the immune activation was similar, the practical advantages diverge sharply. DoriVac does not require the deep-freeze cold chain that mRNA vaccines depend on. It could be stored and shipped at higher temperatures, a critical factor for reaching under-resourced regions where cold chain logistics have limited mRNA vaccine distribution.

Manufacturing is also simpler. The self-assembling nature of DNA origami structures avoids some of the complexities involved in formulating mRNA into lipid nanoparticles, a process that requires tight quality control and specialized equipment.

The distance still to travel

Several important caveats apply. The head-to-head comparison with mRNA vaccines was conducted in mice, not humans. Immune equivalence in rodents does not guarantee equivalence in people. The human lymph node chip data are encouraging but remain a model -- a sophisticated one, but still a proxy for what happens in a living human body over months and years.

DoriVac has not entered human clinical trials. The safety profile, while described as promising by recent studies at DoriNano (the startup translating the technology), has not been tested in the rigorous, large-scale format that mRNA vaccines underwent during the pandemic.

Long-term durability of immune responses -- one of the key weaknesses of mRNA vaccines -- has not been established for DoriVac either. Whether DNA origami vaccines can produce the lasting memory responses needed to avoid frequent boosters remains an open question.

Cost is another unknown. While the manufacturing process is theoretically simpler, the economics of producing DNA origami nanostructures at vaccine scale have not been validated commercially.

A platform, not just a vaccine

The broader significance may lie in DoriVac's versatility. The same chassis can present antigens from virtually any pathogen by swapping the molecules displayed on one face of the origami block. The team demonstrated this by building vaccines targeting conserved regions of HIV and Ebola spike proteins alongside SARS-CoV-2.

Yang (Claire) Zeng, who spearheaded the project and is now CEO of DoriNano, described the platform's ability to program immune recognition in targeted immune cells on a molecular level -- a degree of precision that current vaccine technologies cannot easily replicate.

If the technology delivers on its early promise, it could offer a rapid-response platform for future pandemics: swap in the antigens of a new pathogen, and the rest of the vaccine architecture remains the same. That modularity, combined with relaxed storage requirements, addresses two of the most significant bottlenecks exposed during COVID-19.

For now, DoriVac sits at the boundary between proof-of-concept and clinical reality. The science is solid. The engineering is elegant. The question is whether it can navigate the long road from a laboratory in Boston to a clinic in the communities that need it most.