A Pioneering DNA Origami Vaccine Platform Emerges as a Potent Alternative to mRNA Technology, Promising Enhanced Stability and Global Accessibility

The COVID-19 pandemic irrevocably propelled messenger RNA (mRNA) vaccines into the global consciousness, showcasing an unprecedented speed and efficacy in vaccine development. Following the swift completion of rigorous clinical trials, the world witnessed the administration of the first COVID-19 mRNA vaccine on December 8, 2020. This pivotal moment marked a new era in immunology, and subsequent epidemiological modeling by researchers, including studies published in The Lancet Infectious Diseases and supported by the World Health Organization, later estimated that these innovative vaccines prevented at least 14.4 million deaths worldwide during their crucial first year of deployment alone. This profound impact underscored the transformative potential of mRNA technology, galvanizing scientists to extend its application beyond SARS-CoV-2.

The mRNA Revolution and Its Persistent Challenges

The success against COVID-19 quickly spurred extensive research and development into mRNA vaccines for a myriad of other infectious diseases, many of which continue to pose significant global health threats. Ongoing clinical trials are now targeting pathogens responsible for influenza virus, Respiratory Syncytial Virus (RSV), Human Immunodeficiency Virus (HIV), Zika virus, Epstein-Barr virus (EBV), and tuberculosis bacteria. The promise is immense: to develop highly effective vaccines more rapidly than traditional methods, potentially addressing long-standing public health challenges like the elusive HIV vaccine or the annual burden of influenza.

However, the rapid deployment and extensive real-world data collection during the COVID-19 pandemic also illuminated important limitations inherent to the current generation of mRNA vaccine strategies, pointing to an urgent need for new approaches that can overcome these hurdles.

One significant challenge revolves around the variability and durability of the immune protection generated by COVID-19 mRNA vaccines. Protection levels can differ widely from person to person, influenced by factors such as age, underlying health conditions, and individual immune responses. Moreover, this protection is not indefinite, necessitating booster shots as immunity wanes over time. This issue is compounded by the relentless evolution of SARS-CoV-2, which continuously produces new variants capable of partially evading existing immune defenses. The emergence of variants like Delta and Omicron demonstrated the virus’s capacity for antigenic drift, requiring vaccines to be updated frequently to maintain efficacy, a process that is both resource-intensive and time-consuming.

Beyond immunological considerations, practical and logistical challenges have also become apparent. Manufacturing mRNA vaccines is a highly complex and expensive endeavor, involving intricate processes for synthesizing the mRNA molecule and encapsulating it within lipid nanoparticles (LNPs). Controlling the precise number of mRNA molecules packaged into these LNPs remains a difficult feat, impacting consistency and potentially efficacy. Furthermore, these vaccines famously require ultra-cold storage temperatures—as low as -70°C for Pfizer-BioNTech’s vaccine and -20°C for Moderna’s—creating significant cold-chain logistical nightmares, particularly in low-income countries or remote regions lacking advanced infrastructure. The associated costs of specialized freezers, transportation, and monitoring can be prohibitive. Finally, while generally safe, mRNA vaccines can cause reactogenicity (temporary, localized side effects) and, in rare instances, may lead to unintended off-target inflammatory effects, such as myocarditis, underscoring the need for platforms with improved safety profiles. Overcoming these multifaceted limitations is paramount for improving global preparedness and response capabilities for future infectious disease threats.

Introducing DoriVac: A DNA Origami Vaccine Platform Offering a Novel Alternative

In response to these critical issues, a multidisciplinary team of scientists from the Wyss Institute for Biologically Inspired Engineering at Harvard University, Dana-Farber Cancer Institute (DFCI), and their partner institutions embarked on exploring a fundamentally different approach. Their innovation centers on a DNA origami nanotechnology platform dubbed DoriVac, which ingeniously functions as both a vaccine antigen carrier and an intrinsic immune-stimulating adjuvant. This dual functionality represents a significant departure from many traditional vaccine designs that require separate adjuvant components.

The DoriVac platform leverages the principles of DNA nanotechnology, where synthetic DNA strands are programmed to self-assemble into precise, predetermined two- or three-dimensional nanostructures. This precise control at the nanoscale allows for an unparalleled level of engineering over vaccine composition and antigen presentation. In 2024, William Shih, Ph.D., a co-corresponding author and Wyss Institute Core Faculty member whose group pioneered the DoriVac concept, along with his team at the Wyss Institute and Dana-Farber, formally introduced DoriVac as a DNA nanotechnology-based vaccine platform with broad potential applications, initially explored in cancer research.

Yang (Claire) Zeng, M.D., Ph.D., who led the initial development effort with collaborators, demonstrated that DoriVac could precisely present immune-stimulating adjuvant molecules to cells at carefully controlled nanometer distances. Earlier studies in tumor-bearing mice had already shown that these DNA origami vaccines produced stronger immune responses compared to versions lacking the DNA origami structure, highlighting the intrinsic adjuvant activity of the platform itself. DoriVac vaccines are meticulously built from tiny, self-assembling square DNA nanostructures. One side is engineered to display adjuvant molecules arranged at precise nanometer distances, while the opposite side presents selected antigens, which can be peptides or proteins derived from tumors or pathogens.

"While we were developing the platform for cancer applications, the COVID-19 pandemic was still moving with full force," said Zeng, a first and co-corresponding author on the new study, and now cofounder and CEO/CTO of DoriNano, a company leading the translation of this technology into clinical applications. "So, the question quickly arose whether DoriVac’s superior adjuvant activity could also be leveraged in infectious disease settings."

To explore this compelling idea, Zeng and co-first author Olivia Young, Ph.D., a former graduate student in Shih’s group, initiated a collaboration with Donald Ingber’s team at the Wyss Institute. Ingber’s group is renowned for its work in antiviral innovation, employing AI-driven and multiomics approaches alongside advanced 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 highly conserved peptide regions from SARS-CoV-2, HIV, and Ebola viruses. Specifically, they focused on the HR2 peptide region found in the spike proteins of these viruses. This strategy of targeting conserved regions is critical for developing broad-spectrum vaccines that are less susceptible to viral mutation and could offer protection against multiple variants or even different strains of a virus.

Rigorous Preclinical Validation: From Mouse Models to Human Organ Chips

The initial evaluation of the DoriVac platform began with comprehensive studies in mouse models. The researchers designed DoriVac vaccines to target the HR2 peptide region found in the spike proteins of several viruses, including SARS-CoV-2, HIV, and Ebola. In mice, the SARS-CoV-2 HR2 vaccine triggered exceptionally strong immune responses. These responses encompassed both antibody-driven (humoral) and T cell-driven (cellular) activity. Humoral immunity, mediated by antibodies, is crucial for neutralizing viruses before they infect cells, while cellular immunity, driven by T cells, is essential for clearing infected cells and providing long-term protection.

Zeng elaborated on these encouraging findings: "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." She added, "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." These detailed observations underscore DoriVac’s potential to elicit robust and comprehensive immune protection.

A significant challenge in vaccine development has historically been the translation gap between animal models and human responses. Immune reactions observed in mice often do not fully reflect what occurs in the human body, leading to many promising treatments failing during later clinical trials. To bridge this critical gap and better predict human outcomes, the team ingeniously tested DoriVac vaccines using a sophisticated preclinical human model: the Wyss Institute’s microfluidic human Organ Chip technology, specifically a human lymph node-on-a-chip (human LN Chip). This innovative system simulates crucial aspects of a human lymph node in vitro, providing a more physiologically relevant environment for assessing immune responses.

This advanced system, further refined by co-first author Min Wen Ku and co-corresponding author Girija Goyal, Ph.D., Director of Bioinspired Therapeutics at the Wyss Institute, demonstrated that the SARS-CoV-2-HR2 DoriVac vaccine effectively activated human dendritic cells (DCs) within the chip. Furthermore, it significantly increased their production of inflammatory cytokines—key signaling molecules that orchestrate immune responses—when compared with control experiments using origami-free components. Crucially, the system also showed an increase in the number of CD4+ and CD8+ T cells, which are vital for multiple protective functions, including helping B cells produce antibodies and directly killing infected cells. These findings provided strong additional support for the platform’s potential for human use.

Co-corresponding author Donald 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, highlighted the importance of this approach: "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."

DoriVac vs. mRNA: A Head-to-Head Comparison and Distinct Advantages

To directly ascertain DoriVac’s comparative efficacy, the researchers conducted a head-to-head comparison with established mRNA vaccine technology. Led by Zeng and co-author Qiancheng Xiong, the team evaluated a DoriVac vaccine presenting the full SARS-CoV-2 spike protein and compared it directly with commercially available 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 similarly strong antiviral T cell and antibody-producing B cell responses. This critical finding, reported in Nature Biomedical Engineering, underscored DoriVac’s ability to achieve immune activation comparable to the leading mRNA vaccines, while simultaneously offering a suite of distinct advantages.

"This underscored DoriVac’s potential as a DNA nanotechnology-enabled, self-adjuvanted vaccine platform," stated Dr. Shih. He further elaborated on DoriVac’s key benefits: "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."

The enhanced stability of DNA, compared to the fragile mRNA molecule, means DoriVac vaccines are expected to have a significantly longer shelf life and require less stringent storage conditions, potentially allowing for storage at standard refrigeration temperatures or even room temperature for extended periods. This drastically simplifies logistics, reduces costs, and critically enhances vaccine accessibility in challenging environments globally. Furthermore, the manufacturing process for DNA origami structures, while sophisticated, presents a different set of challenges than LNP-mRNA production, potentially offering a pathway to greater scalability and cost-effectiveness once optimized. Recent studies at DoriNano have also reportedly demonstrated that DoriVac exhibits a promising safety profile, a crucial factor for broad public acceptance and regulatory approval.

Broader Impact and Future Implications

The emergence of the DoriVac platform holds profound implications for global health and future pandemic preparedness. Its unique combination of precise immune engineering, intrinsic adjuvant activity, and superior logistical profile positions it as a powerful contender in the next generation of vaccine technologies. By addressing the critical limitations of current mRNA vaccines—particularly cold-chain requirements and manufacturing complexity—DoriVac offers a pathway toward more equitable vaccine distribution worldwide. The ability to produce stable, potent vaccines that do not require ultra-cold storage could revolutionize vaccine access in low- and middle-income countries, which often bear the brunt of infectious disease outbreaks but struggle with advanced logistical infrastructure.

Moreover, the platform’s versatility in targeting conserved viral regions, demonstrated by its application to SARS-CoV-2, HIV, and Ebola, suggests its potential for developing pan-variant or even pan-species vaccines. Such broad-spectrum protection could significantly enhance the world’s ability to respond rapidly and effectively to novel pathogens, reducing the likelihood of future pandemics escalating to the scale of COVID-19. The underlying DNA origami nanotechnology itself opens doors for customization, allowing scientists to program immune recognition at a molecular level to achieve optimized responses against a diverse array of threats, including those previously intractable to vaccine development.

This groundbreaking research was supported by a consortium of funders, including the Director’s Fund and Validation Project program of the Wyss Institute; the Claudia Adams Barr Program at DFCI; the National Institutes of Health (U54 grant CA244726-01); the US-Japan CRDF global fund (grant R-202105-67765); the National Research Foundation of Korea (grants MSIT, RS-2024-00463774, RS-2023-00275456); the Intramural Research Program of the Korea Institute of Science and Technology (KIST); and the Bill and Melinda Gates Foundation (INV-002274). The robust funding signifies the widespread recognition of DoriVac’s transformative potential. As DoriNano, co-founded by Dr. Zeng, moves to translate this technology into clinical applications, the scientific community and global health organizations will keenly watch for the next steps, including human clinical trials, which will be crucial in validating DoriVac’s promise as a truly revolutionary vaccine platform. The collaboration between leading institutions and the dedication of a multidisciplinary team underscore a collective commitment to overcoming current vaccine limitations and building a more resilient global health future.