Researchers at Harvard’s Wyss Institute and Dana-Farber Cancer Institute report that a DNA origami-based vaccine platform called DoriVac generated robust immune responses in mice and in a human lymph node “Organ Chip” model. The team says the approach could be easier to store and manufacture than lipid nanoparticle–delivered mRNA vaccines, though the work remains preclinical. The results were published in Nature Biomedical Engineering.
mRNA vaccines played a central role in the COVID-19 response. After clinical trials, the first COVID-19 mRNA vaccine dose was administered on December 8, 2020. Researchers later estimated via mathematical modeling that COVID-19 vaccination prevented at least 14.4 million deaths worldwide during the first year of the global vaccination program (Dec. 8, 2020, to Dec. 8, 2021), using officially reported COVID-19 deaths as the outcome.
Even as mRNA platforms expanded, studies of COVID-19 vaccination have highlighted practical and biological constraints that can complicate ongoing use. The Wyss Institute notes that protection can vary among individuals and does not last indefinitely, and that the continual emergence of SARS-CoV-2 variants can reduce vaccine effectiveness enough to necessitate updates. The institute also points to manufacturing complexity and cost, challenges in controlling how much mRNA is packaged into lipid nanoparticles, and cold-storage requirements; it also cites potential unintended “off-target” effects.
Against that backdrop, a multidisciplinary team from the Wyss Institute for Biologically Inspired Engineering at Harvard University, Dana-Farber Cancer Institute (DFCI) and partner institutions tested an alternative concept based on DNA origami nanotechnology. The platform, called DoriVac, is designed to function as both a vaccine and an adjuvant by precisely arranging immune-stimulating components on folded DNA nanostructures.
The researchers built DoriVac from tiny, self-assembling square DNA structures. According to the Wyss Institute description of the work, one face of the structure presents adjuvant molecules at carefully controlled nanometer spacing, while the opposite face displays selected antigens, including a conserved peptide region known as heptad repeat 2 (HR2) found in spike proteins of multiple viruses.
In mouse studies, a DoriVac vaccine targeting SARS-CoV-2 using an HR2 antigen triggered strong immune activity, including both antibody-driven (humoral) and T cell-driven (cellular) responses. The team reported increases in antibody-producing B cells, activated antigen-presenting dendritic cells, and antigen-specific memory and cytotoxic T cell populations.
To better approximate human immune biology, the group also tested the approach in a preclinical human model using the Wyss Institute’s microfluidic Organ Chip technology configured to simulate a human lymph node (a “human LN Chip”). In that system, the SARS-CoV-2 HR2 DoriVac vaccine activated human dendritic cells and increased inflammatory cytokine production compared with “origami-free” components, while also increasing the number of CD4+ and CD8+ T cells with multiple protective functions.
The study also evaluated a DoriVac formulation presenting the full SARS-CoV-2 spike protein. In mice, using a booster-style approach, the researchers compared it with Moderna and Pfizer/BioNTech mRNA vaccines delivered via lipid nanoparticles that encode the same spike protein, and reported similar antiviral T cell and antibody-producing B cell responses.
William Shih, a Wyss Institute Core Faculty member and co-corresponding author, said the platform provides “unprecedented control over vaccine composition” and can be programmed to shape immune recognition in targeted immune cells. Yang (Claire) Zeng, a first and co-corresponding author, said the team observed broader activation of humoral and cellular immunity than could be achieved with comparable components not arranged on the DNA origami structure. Donald Ingber, another co-corresponding author, said the human lymph node chip offered a testing ground whose induced antigen-specific immune profiles and activities are likely to reflect what would occur in human recipients.
The researchers argued that DNA origami vaccines could offer practical advantages for distribution and production, including reduced reliance on cold-chain storage and the potential to avoid some manufacturing challenges associated with lipid nanoparticle–formulated mRNA vaccines. Still, the findings are based on mouse experiments and a preclinical human Organ Chip system, and clinical studies in people would be needed to establish safety, durability of protection, and effectiveness against disease.
