Due to the novel coronavirus disease (COVID-19) pandemic, messenger RNA (mRNA) vaccines have attracted worldwide attention. After clinical trials were completed, the first COVID-19 mRNA vaccine was administered on December 8, 2020. Researchers later estimated through modeling that these vaccines prevented at least 14.4 million deaths worldwide in the first year.
Because of its strong impact, scientists have begun developing mRNA vaccines for other infectious diseases. Ongoing clinical trials target influenza virus, respiratory syncytial virus (RSV), HIV, Zika virus, Epstein-Barr virus, and Mycobacterium tuberculosis. At the same time, research into COVID-19 vaccines has revealed important limitations, pointing to the need for new vaccine strategies.
Challenges of mRNA vaccine performance and production
The immune protection provided by COVID-19 mRNA vaccines can vary widely from person to person, and protection may not last indefinitely. This problem is made even more difficult by the constant evolution of SARS-CoV-2, producing new variants that can partially escape immune defenses. As a result, vaccines must be updated frequently.
There are also practical challenges. The production of mRNA vaccines is complex and expensive, and it remains difficult to control the number of mRNA molecules encapsulated in lipid nanoparticles. These vaccines also require refrigeration, which can cause unintended off-target effects. Overcoming these limitations could improve how the world prepares for and responds to future infectious disease threats.
DNA Origami vaccine platform offers an alternative
To address these issues, an interdisciplinary team from Harvard University’s Wyss Institute, Dana-Farber Cancer Institute (DFCI), and partner institutions considered a different approach. They used a DNA origami nanotechnology platform called DoriVac, which acts as both a vaccine and an adjuvant.
Researchers designed the DoriVac vaccine to target a peptide region (HR2) in the spike protein of several viruses, including SARS-CoV-2, HIV, and Ebola. In mice, the SARS-CoV-2 HR2 vaccine elicited a strong immune response that included antibody-driven (humoral) and T-cell-driven (cellular) activity.
The research team also tested the vaccine in preclinical human models using the Wyss Institute’s microfluidic human organ chip technology, which simulates human lymph nodes in vitro. In this system, the SARS-CoV-2 HR2 vaccine also elicited a strong antigen-specific immune response in human cells.
In direct comparison with a SARS-CoV-2 mRNA vaccine delivered via lipid nanoparticles, the DoriVac vaccine carrying the same spike protein variant caused similarly strong immune activation in human models. However, DNA origami vaccines had advantages in terms of stability and were easy to store and manufacture. These findings show that natural biomedical engineering.
“With the DoriVac platform, we have developed a highly flexible chassis with many important advantages, including unprecedented control over vaccine composition and the ability to program immune recognition of target immune cells at the molecular level to achieve better responses,” said co-corresponding author Dr. William Shih, a Wyss Institute core faculty member who is pioneering the new vaccine concept. “Our study demonstrates the versatility and potential of DoriVac by taking a closer look at the immune changes needed to fight infectious viruses.” Shih is also a professor at Harvard Medical School and DFCI.
How is a DNA origami vaccine made?
In 2024, Shi’s team at the Wyss Institute and Dana-Farber introduced DoriVac as a DNA nanotechnology-based vaccine platform with broad application potential. Yang (Claire) Zeng, MD, who led this effort with collaborators, showed that DoriVac can precisely present immune-stimulating adjuvant molecules to cells at the nanoscale.
Previous studies using tumor-bearing mice demonstrated that these vaccines elicited stronger immune responses than versions without the DNA origami structure. The DoriVac vaccine is made from small self-assembled square DNA nanostructures. One side displays adjuvant molecules positioned at carefully controlled nanometer distances, and the other side displays a selected antigen, such as a peptide or protein from a tumor or pathogen.
“While we were developing our platform for oncology applications, the COVID-19 pandemic was still raging. “The question immediately arose: “Can we do this?” said Zeng, first and co-lead author of the new study and currently co-founder, CEO and CTO of DoriNano, who is leading the technology’s introduction into clinical applications.
To explore this idea, Zeng and co-lead author Dr. Olivia Young, a former graduate student in Shih’s group, collaborated with Donald Ingber’s team at the Wyss Institute. Ingber’s group focuses on antiviral innovations using AI-driven multi-omics approaches in parallel with microfluidic human organ chip systems. The researchers, along with co-lead author Dr. Longlong Si, a former postdoctoral fellow in Ingber’s lab, developed the DoriVac vaccine for SARS-CoV-2, HIV, and Ebola. These vaccines present the HR2 peptide, which acts as a conserved antigen within the virus’s spike protein.
“Our analysis of the immune responses elicited in mice by these first DoriVac vaccines yielded several encouraging observations, including a significantly broader activation of humoral and cell-mediated immunity across a range of relevant immune cell types than that produced by origami-free antigens and adjuvants,” Zeng said. “Specifically for SARS-CoV-2 HR2, we found that the numbers of antibody-producing B cells, activated antigen-presenting dendritic cells (DCs), antigen-specific memory cells essential for long-term protection, and cytotoxic T-cell types were all increased,” Zeng explained.
From mouse research to human models
One of the challenges in vaccine development is that immune responses in mice often do not fully reflect what happens in humans. This gap has caused many promising treatments to fail during clinical trials. To more accurately predict human outcomes, the team tested the DoriVac vaccine using human lymph nodes on a chip (human LN chips) that mimic aspects of the human immune system.
The system, advanced by co-lead author Min Wen Ku and co-corresponding author Dr. Girija Goyal, director of bioinspired therapeutics at the Wyss Institute, showed that the SARS-CoV-2-HR2 DoriVac vaccine activated human DCs and significantly increased the production of inflammatory cytokines compared to non-origami components. It also increased the number of CD4+ and CD8+ T cells with multiple protective functions, further increasing the potential for this platform to be used in humans.
“The predictive power of the human LN chip provides us with an ideal testing ground for the DoriVac vaccine, and the induced antigen-specific immune cell profiles and activities are very likely to mirror those that occur in human recipients of the vaccine. With this fusion of technologies, we have been able to dramatically increase the likelihood of success for a new class of vaccines and create a new test bed for future vaccine development,” said co-corresponding author Ingber, MD. He is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital and the Hansjörg Wyss Professor of Biologically Inspired Engineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences.
Direct comparison with mRNA vaccines
Researchers also evaluated the DoriVac vaccine, which presents the complete SARS-CoV-2 spike protein. The team led by Zeng and co-author Qiancheng Xiong made direct comparisons with Moderna and Pfizer/BioNTech mRNA lipid nanoparticle (LNP) vaccines that encode the same spike protein.
Using a standard booster approach in mice, both vaccine types elicited similar antiviral T-cell and antibody-producing B-cell responses.
“This highlighted the potential of DoriVac as a self-adjuvant vaccine platform leveraging DNA nanotechnology. However, the DoriVac vaccine has many other advantages. The same call as the mRNA-LNP vaccine The lack of chain requirements allows for more efficient distribution, especially in resource-poor regions, and overcomes some of the enormous manufacturing complexity of LNP-formulated vaccines, to name two key things,” Shih said. Recent studies at DoriNano also demonstrated that DoriVac exhibits a promising safety profile.
Other authors of the study are Sylvie Bernier, Hawa Dembélé, Giorgia Icinelli, Tal Gilboa, Zoe Swank, Hyun-seok Su, Anjali Rajwal, Amanda Jiang, Yunhao Zai, Latonya Williams, Caleb Hellman, Chris Wintersinger, Amanda Gravelin, Andina Bernette, Melinda Sanchez, Sarai Baldares, Georgia Tomaras, and Zhu. Hi Ryu and Ik Chang Kwon. This research was funded by the Wyss Institute’s Director’s Fund and Validation Project programs. DFCI’s Claudia Adams Barr Program. National Institutes of Health (U54 grant CA244726-01); US-Japan CRDF Global Fund (grant R-202105-67765). National Research Foundation of Korea (grants MSIT, RS-2024-00463774, RS-2023-00275456); Intramural Research Program of the Korea Institute of Science and Technology (KIST). Bill & Melinda Gates Foundation (INV-002274).
