By Hendra Lukman 
The global scientific community, galvanized by the unprecedented success of messenger RNA (mRNA) vaccines against COVID-19, is now exploring innovative frontiers in vaccine development. While mRNA technology undeniably revolutionized pandemic response, ushering in the first authorized COVID-19 mRNA vaccine on December 8, 2020, and subsequently credited with preventing an estimated 14.4 million deaths worldwide in its inaugural year, researchers are keenly aware of its limitations. These challenges, ranging from variable immune responses and waning protection to complex manufacturing and stringent cold-chain requirements, have spurred a fervent search for next-generation vaccine platforms. Against this backdrop, a multidisciplinary team from the Wyss Institute at Harvard University, Dana-Farber Cancer Institute (DFCI), and partner institutions has unveiled a promising alternative: DoriVac, a DNA origami nanotechnology platform poised to redefine vaccine design and delivery.
The mRNA Revolution and Its Lingering Questions
The rapid deployment of mRNA vaccines, a testament to decades of foundational research, marked a paradigm shift in immunology and public health. These vaccines, by instructing cells to produce viral proteins, elicit a robust immune response. The staggering impact on mortality, as estimated through sophisticated modeling, underscores their significance. However, the very nature of mRNA vaccines presents inherent challenges. The immune protection they confer can vary considerably among individuals, and the duration of this protection is not indefinite. Compounding this, the relentless evolution of pathogens like SARS-CoV-2, the virus responsible for COVID-19, leads to the emergence of new variants that can partially evade existing immune defenses, necessitating frequent vaccine updates.
Beyond the biological complexities, practical hurdles persist. The manufacturing of mRNA vaccines is an intricate and costly process. Precisely controlling the encapsulation of mRNA molecules within lipid nanoparticles, a critical step for delivery, remains a technical challenge. Furthermore, the requirement for ultra-cold storage significantly complicates distribution, particularly in resource-limited settings. These limitations, while surmountable to a degree, highlight the imperative for alternative strategies that can enhance vaccine efficacy, accessibility, and stability, thereby bolstering global preparedness for future infectious disease threats.
DoriVac: A Novel Approach Through DNA Nanotechnology
In response to these challenges, the Wyss Institute team has pioneered the DoriVac platform, a sophisticated application of DNA origami nanotechnology. This innovative approach serves a dual purpose, functioning as both a vaccine and an adjuvant—a substance that enhances the immune system’s response to antigens. The researchers strategically designed DoriVac vaccines to target the conserved HR2 peptide region, a critical component found within the spike proteins of a range of viruses, including SARS-CoV-2, HIV, and Ebola. This conserved region offers a stable target less prone to viral mutation, potentially leading to broader and more durable immune protection.
Promising Preclinical Results in Mouse and Human Models
Initial studies in mice have demonstrated the remarkable efficacy of the DoriVac SARS-CoV-2 HR2 vaccine. It successfully triggered robust immune responses, characterized by both potent antibody-driven (humoral) immunity and targeted T cell-driven (cellular) immunity. These findings are crucial, as a comprehensive immune response involving both arms is often necessary for effective viral clearance and long-term protection.
To bridge the gap between animal models and human applicability, the researchers employed the Wyss Institute’s cutting-edge microfluidic human Organ Chip technology. This system simulates key aspects of a human lymph node in vitro, providing a more predictive model of human immune responses. In this advanced preclinical human model, the SARS-CoV-2 HR2 DoriVac vaccine similarly elicited strong antigen-specific immune responses in human cells, mirroring the success observed in mice.
Crucially, a direct head-to-head comparison with current SARS-CoV-2 mRNA vaccines delivered via lipid nanoparticles revealed compelling advantages for DoriVac. When carrying the same spike protein variant, the DoriVac vaccine induced comparably strong immune activation in human models. However, the DNA origami vaccine exhibited superior stability and demonstrated ease in both storage and manufacturing processes, addressing some of the most significant practical limitations of mRNA vaccines. These groundbreaking findings were recently published in the prestigious journal Nature Biomedical Engineering.
Precision Engineering of Immune Responses at the Nanoscale
William Shih, Ph.D., a co-corresponding author and a Wyss Institute Core Faculty member whose group pioneered the DoriVac concept, emphasized the platform’s versatility. "With the DoriVac platform, we have developed an extremely flexible chassis with a number of critical advantages, including unprecedented control over vaccine composition, and the ability to program immune recognition in targeted immune cells on a molecular level to achieve better responses," Dr. Shih stated. "Our study demonstrates DoriVac’s versatility and potential by taking a close look at the immune changes that are required to fight infectious viruses." Dr. Shih also holds professorships at Harvard Medical School and DFCI.
The DoriVac platform, introduced by Shih’s team in 2024, leverages DNA nanotechnology to create a vaccine with broad potential applications. Yang (Claire) Zeng, M.D., Ph.D., who spearheaded the research alongside collaborators, explained that DoriVac precisely presents immune-stimulating adjuvant molecules to cells at the nanoscale. This precise arrangement is key to optimizing immune activation.
Earlier research focused on cancer applications had already demonstrated that DoriVac vaccines elicited stronger immune responses than versions lacking the DNA origami structure. The construction of DoriVac vaccines involves self-assembling, nanoscale square DNA structures. One surface is meticulously engineered to display adjuvant molecules at controlled nanometer distances, while the opposing surface presents specific antigens, such as peptides or proteins derived from tumors or pathogens.
From Cancer to Infectious Diseases: A Pandemic Pivot
"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 Dr. Zeng, the first and co-corresponding author on the new study, and now co-founder and CEO/CTO of DoriNano, an organization dedicated to translating this technology into clinical applications. This strategic pivot exemplifies the adaptability of scientific research in the face of urgent global health crises.
To explore this potential, Dr. Zeng and co-first author Olivia Young, Ph.D., a former graduate student in Dr. Shih’s group, collaborated with Donald Ingber’s team at the Wyss Institute. Dr. Ingber’s group specializes in antiviral innovation, employing artificial intelligence-driven and multiomics approaches, alongside microfluidic human Organ Chip systems. Together with co-first author Longlong Si, Ph.D., a former postdoctoral researcher in Dr. Ingber’s lab, the team developed DoriVac vaccines specifically targeting SARS-CoV-2, HIV, and Ebola. These vaccines utilize conserved HR2 peptides as antigens, providing a stable target across different viral strains.
"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," Dr. Zeng reported. "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," she further elaborated.
Bridging the Mouse-to-Human Gap with Organ Chip Technology
A persistent challenge in vaccine development is the frequent disconnect between immune responses observed in mice and those that occur in humans. This translational gap has historically led to the failure of numerous promising preclinical candidates during human clinical trials. To enhance the predictive accuracy of their findings, the team utilized the human lymph node-on-a-chip (human LN Chip) system, a sophisticated tool designed to mimic key aspects of the human immune system.
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. It also significantly boosted their production of inflammatory cytokines, a crucial signaling mechanism in immune responses, when compared to the effects of origami-free components. Furthermore, the vaccine increased the population of CD4+ and CD8+ T cells, which possess multiple protective functions, thereby reinforcing the platform’s strong potential for human application.
"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," stated co-corresponding author Dr. Ingber, M.D., Ph.D. Dr. Ingber holds distinguished positions including 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 the Harvard John A. Paulson School of Engineering and Applied Sciences. "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."
Direct Comparison: DoriVac Versus mRNA Vaccines
In a critical evaluation, the researchers also assessed a DoriVac vaccine engineered to present the full SARS-CoV-2 spike protein. Led by Dr. Zeng and co-author Qiancheng Xiong, the team conducted a direct comparison with commercially available Moderna and Pfizer/BioNTech mRNA lipid nanoparticle (LNP) vaccines that encode the identical spike protein.
Following a standard booster immunization protocol in mice, both vaccine types elicited comparable antiviral T cell and antibody-producing B cell responses. This finding suggests that DoriVac can achieve a similar level of immune activation as established mRNA vaccines.
"This underscored DoriVac’s potential as a DNA nanotechnology-enabled, self-adjuvanted vaccine platform," Dr. Shih remarked. "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." Recent studies conducted at DoriNano have further indicated a promising safety profile for DoriVac.
The groundbreaking research involved a collaborative effort by numerous scientists, including 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 received vital funding from 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).
Broader Implications for Global Health Security
The development of DoriVac represents a significant stride towards more robust and accessible vaccine technologies. The potential to overcome the cold-chain limitations of mRNA vaccines could democratize vaccine access, particularly in remote or economically disadvantaged areas, thereby enhancing global health equity. Furthermore, the streamlined manufacturing process holds the promise of reducing production costs and increasing the speed at which vaccines can be deployed during future health emergencies.
The platform’s inherent flexibility, allowing for the precise presentation of various antigens and adjuvants, opens doors for the development of vaccines against a wide spectrum of pathogens, including those for which current vaccine development has been challenging, such as HIV and tuberculosis. The successful targeting of conserved viral regions like HR2 also suggests a potential for creating vaccines that offer broader protection against multiple strains or even different viruses within the same family, a concept known as "universal vaccines."
As the world continues to grapple with the ongoing threat of infectious diseases and prepares for inevitable future pandemics, innovations like DoriVac offer a beacon of hope. By building upon the lessons learned from the mRNA revolution and embracing novel approaches like DNA nanotechnology, scientists are forging a path toward a future where effective, stable, and accessible vaccines are within reach for all. The journey from laboratory discovery to widespread clinical application is long and rigorous, but the early promise of DoriVac positions it as a critical contender in the ongoing global effort to safeguard public health.
