DNA Origami Vaccine Platform Shows Promise as Next-Generation Alternative to mRNA Vaccines
Key Insights
Researchers at Harvard's Wyss Institute developed DoriVac, a DNA origami vaccine platform that functions as both vaccine and adjuvant, targeting conserved peptide regions in viral spike proteins including SARS-CoV-2 (search), HIV (search), and Ebola (search).
In preclinical studies, DoriVac vaccines produced comparable immune responses to current mRNA vaccines (search) while offering superior stability, easier manufacturing, and elimination of cold-chain storage requirements.
The platform demonstrated strong humoral and cellular immune activation in both mouse models and human lymph node-on-chip systems, with significantly increased numbers of antibody-producing B cells and protective T cell populations.
A multidisciplinary research team at Harvard University's Wyss Institute has developed a novel DNA origami vaccine platform called DoriVac that could address key limitations of current mRNA vaccines (search) while maintaining comparable efficacy. The findings, published in Nature Biomedical Engineering, demonstrate the platform's potential as a next-generation vaccine technology for infectious diseases.
Addressing mRNA Vaccine Limitations
While mRNA vaccines (search) prevented at least 14.4 million deaths from COVID-19 (search) in their first year according to mathematical models, research has revealed significant shortcomings. The immune responses produced by COVID-19 mRNA vaccines vary considerably between people, and their duration is limited. Additional challenges include complex and costly manufacturing, poor control over mRNA molecule loading into lipid nanoparticles, cold-storage requirements, and potential off-target effects.
"With the DoriVac platform, we have developed an extremely flexible chassis with a number of critical advantages, including an unprecedented control over vaccine composition, and the ability to program immune recognition in targeted immune cells on a molecular level to achieve better responses," said co-corresponding author William Shih, Ph.D., Wyss Institute (search) Core Faculty member and Professor at Harvard Medical School and Dana-Farber Cancer Institute.
DNA Origami Technology Design
DoriVac vaccines consist of tiny self-folding and assembling square block-shaped nanostructures. On one face, they present immune-boosting adjuvant molecules with optimized nanometer spacing, while the opposite face displays antigens of choice, such as pathogen-derived peptides and proteins. The researchers designed vaccines targeting HR2 peptides (search), which function as highly conserved antigens within spike proteins from multiple viruses including SARS-CoV-2 (search), HIV (search), and Ebola (search).
Preclinical Efficacy Results
In mouse studies, the SARS-CoV-2 (search) HR2 vaccine produced potent antigen-specific antibody-mediated and T cell-mediated responses. The analysis revealed significantly greater and broader activation of humoral and cellular immunity compared to origami-free antigens and adjuvants.
"We found that the numbers of antibody-producing B cells, activated antigen-presenting dendritic cells (DCs), and antigen-specific memory and cytotoxic T cell types that are vital for long-term protection were all increased, especially in the case of the SARS-CoV-2 (search) HR2," explained Yang (Claire) Zeng, M.D., Ph.D., first and co-corresponding author and now cofounder and CEO/CTO of DoriNano (search).
Human Model Validation
To bridge the gap between mouse and human immune responses, the team tested DoriVac vaccines using a human lymph node-on-chip system. The SARS-CoV-2 (search)-HR2 DoriVac vaccine activated human dendritic cells and increased their production of inflammatory cytokine molecules to much higher levels than origami-free vaccine components. The numbers of CD4+ and CD8+ T cells with multiple protective functions were also increased.
"The predictive capabilities of human LN Chips gave us an ideal testing ground for DoriVac vaccines and the induced, antigen-specific immune cell profiles and activities very likely reflect those that would occur in human recipients of the vaccines," said co-corresponding author Donald Ingber, M.D., Ph.D., Judah Folkman Professor of Vascular Biology at Harvard Medical School.
Head-to-Head Comparison with mRNA Vaccines
In a direct comparison with Moderna and Pfizer/BioNTech (search) mRNA lipid nanoparticle vaccines, a DoriVac vaccine presenting the complete SARS-CoV-2 (search) spike protein (search) produced comparable anti-viral T cell and antibody-producing B cell responses using a common booster protocol in mice.
Manufacturing and Distribution Advantages
DoriVac vaccines offer several practical advantages over current mRNA platforms. They don't require the same cold-chain storage as mRNA-LNP vaccines, enabling more effective distribution especially in under-resourced regions. The platform could also overcome manufacturing complexities associated with LNP-formulated vaccines. Recent studies at DoriNano (search) have demonstrated that DoriVac exhibits a promising safety profile.
The research was funded by multiple sources including the Wyss Institute (search), National Institutes of Health, National Research Foundation of Korea, Korea Institute of Science and Technology, and the Bill and Melinda Gates Foundation. The study represents a convergence of DNA nanotechnology, microfluidic organ chip systems, and vaccine development that could reshape infectious disease preparedness strategies.