The COVID-19 pandemic brought messenger RNA (mRNA) vaccines into the global spotlight. After completing clinical trials, the first COVID-19 mRNA vaccine was given on December 8, 2020. Researchers later estimated through modeling that these vaccines prevented at least 14.4 million deaths worldwide during their first year.
Because of their strong impact, scientists began developing mRNA vaccines for other infectious diseases. Ongoing clinical trials are targeting influenza virus, Respiratory Syncytial Virus (RSV), HIV, Zika, Epstein-Barr virus, and tuberculosis bacteria. At the same time, studies of COVID-19 vaccines have revealed important limitations, pointing to the need for new vaccine strategies.
Challenges With mRNA Vaccine Performance and Production
The immune protection generated by COVID-19 mRNA vaccines can differ widely from person to person, and the protection does not last indefinitely. This issue is made more difficult by the constant evolution of SARS-CoV-2, which produces new variants that can partially escape immune defenses. As a result, vaccines often need to be updated.
There are also practical challenges. Manufacturing mRNA vaccines is complex and expensive, and controlling how many mRNA molecules are packaged into lipid nanoparticles remains difficult. These vaccines also require cold storage and may 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, a multidisciplinary team from the Wyss Institute at Harvard University, Dana-Farber Cancer Institute (DFCI), and partner institutions explored a different approach. They used a DNA origami nanotechnology platform called DoriVac, which functions as both a vaccine and an adjuvant.
The researchers designed DoriVac vaccines to target a peptide region (HR2) found in the spike proteins of several viruses, including SARS-CoV-2, HIV, and Ebola. In mice, the SARS-CoV-2 HR2 vaccine triggered strong immune responses, including antibody-driven (humoral) and T cell-driven (cellular) activity.
The team also tested the vaccine in a preclinical human model using the Wyss Institute’s microfluidic human Organ Chip technology, which simulates a human lymph node in vitro. In this system, the SARS-CoV-2 HR2 vaccine also generated strong antigen-specific immune responses in human cells.
When directly compared with SARS-CoV-2 mRNA vaccines delivered through lipid nanoparticles, a DoriVac vaccine carrying the same spike protein variant produced a similarly strong immune activation in human models. However, the DNA origami vaccine showed advantages in stability and was easier to store and manufacture. These findings were reported in Nature Biomedical Engineering.
“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 and Wyss Institute Core Faculty member William Shih, Ph.D., whose group pioneered the new vaccine concept. “Our study demonstrates DoriVac’s versatility and potential by taking a close look at the immune changes that are required to fight infectious viruses.” Shih is also Professor at the Harvard Medical School and DFCI.
How DNA Origami Vaccines Are Built
In 2024, Shih’s team at the Wyss Institute and Dana-Farber introduced DoriVac as a DNA nanotechnology-based vaccine platform with broad potential applications. Yang (Claire) Zeng, M.D., Ph.D., who led the effort with collaborators, showed that DoriVac can precisely present immune-stimulating adjuvant molecules to cells at the nanoscale.
Earlier studies in tumor-bearing mice demonstrated that these vaccines produced stronger immune responses than versions without the DNA origami structure. DoriVac vaccines are built from tiny, self-assembling square DNA nanostructures. One side displays adjuvant molecules arranged at carefully controlled nanometer distances, while the opposite side presents selected antigens such as peptides or proteins from tumors or pathogens.
“While we were developing the platform for cancer applications, the COVID-19 pandemic was still moving with full force. So, the question quickly arose whether DoriVac’s superior adjuvant activity could also be leveraged in infectious disease settings,” said Zeng as a first and co-corresponding author on the new study, and now cofounder and CEO/CTO of DoriNano, leading the translation of this technology into clinical applications.
To explore this idea, Zeng and co-first author Olivia Young, Ph.D., a former graduate student in Shih’s group, collaborated with Donald Ingber’s team at the Wyss Institute. Ingber’s group focuses on antiviral innovation using AI-driven and multiomics approaches alongside microfluidic human Organ Chip systems. Together with co-first author Longlong Si, Ph.D., a former postdoctoral researcher in Ingber’s lab, the researchers developed DoriVac vaccines targeting SARS-CoV-2, HIV, and Ebola. These vaccines present HR2 peptides, which act as conserved antigens within viral spike proteins.
“Our analysis of the immune responses provoked by these first DoriVac vaccines in mice led to several encouraging observations, including significantly greater and broader activation of humoral and cellular immunity across a range of relevant immune cell types than what the origami-free antigens and adjuvants could produce,” said Zeng. “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 HR2,” explained Zeng.
From Mouse Studies to Human Models
One challenge 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 better predict human outcomes, the team tested DoriVac vaccines using a human lymph node-on-a-chip (human LN Chip), which mimics aspects of the human immune system.
This system, advanced by co-first author Min Wen Ku and co-corresponding author Girija Goyal, Ph.D., Director, Bioinspired Therapeutics at the Wyss Institute, showed that the SARS-CoV-2-HR2 DoriVac vaccine activated human DCs and significantly increased their production of inflammatory cytokines compared with origami-free components. It also increased the number of CD4+ and CD8+ T cells with multiple protective functions, further supporting the platform’s potential for human use.
“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. This convergence of technologies enabled us to dramatically raise the chances of success for a new class of vaccines and create a new testbed for future vaccine developments,” said co-corresponding author Ingber, M.D., Ph.D. who 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 John A. Paulson School of Engineering and Applied Sciences.
Head to Head Comparison With mRNA Vaccines
The researchers also evaluated a DoriVac vaccine that presents the full SARS-CoV-2 spike protein. Led by Zeng and co-author Qiancheng Xiong, the team compared it directly 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 produced similar antiviral T cell and antibody-producing B cell responses.
“This underscored DoriVac’s potential as a DNA nanotechnology-enabled, self-adjuvanted vaccine platform. But DoriVac vaccines have a number of other advantages: they don’t have the same cold-chain requirements as mRNA-LNP vaccines do and thus could be distributed much more effectively, especially in under-resourced regions; and they could overcome some of the enormous manufacturing complexities of LNP-formulated vaccines, to name two major ones,” said Shih. Recent studies at DoriNano have also demonstrated that DoriVac exhibits a promising safety profile.
Other authors on the study are Sylvie Bernier, Hawa Dembele, Giorgia Isinelli, Tal Gilboa, Zoe Swank, Su Hyun Seok, Anjali Rajwar, Amanda Jiang, Yunhao Zhai, LaTonya Williams, Caleb Hellman, Chris Wintersinger, Amanda Graveline, Andyna Vernet, Melinda Sanchez, Sarai Bardales, Georgia Tomaras, Ju Hee Ryu, and Ick Chan Kwon. The study has been funded by the Director’s Fund and Validation Project program of the Wyss Institute; Claudia Adams Barr Program at DFCI; 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); and Bill and Melinda Gates Foundation (INV-002274).
