DNA origami vaccines could be the next leap beyond mRNA

The groundbreaking emergence of messenger RNA (mRNA) vaccines during the COVID-19 pandemic irrevocably shifted the landscape of modern vaccinology. On December 8, 2020, the first COVID-19 mRNA vaccine was administered, marking a pivotal moment in public health. Through sophisticated modeling, researchers later concluded that these innovative vaccines were instrumental in preventing at least 14.4 million deaths worldwide during their inaugural year of deployment, underscoring their profound and rapid impact on a global health crisis. This unprecedented success not only validated a novel vaccine modality but also propelled scientists to explore mRNA technology for a wider array of infectious diseases, with ongoing clinical trials now targeting pathogens such as influenza virus, Respiratory Syncytial Virus (RSV), HIV, Zika, Epstein-Barr virus, and tuberculosis bacteria. Yet, even as mRNA vaccines demonstrated their life-saving potential, their rapid development and widespread deployment also illuminated critical limitations, signaling an urgent need for the evolution of next-generation vaccine strategies.

Navigating the Limitations of First-Generation mRNA Vaccines

Despite their monumental success in combating SARS-CoV-2, mRNA vaccines present several performance and logistical challenges that have become increasingly apparent. One significant issue is the variability in immune protection generated, which can differ widely among individuals. Furthermore, the longevity of this protection is not indefinite, often necessitating booster shots or updated formulations. This challenge is compounded by the relentless evolutionary pressure on SARS-CoV-2, leading to the emergence of new variants capable of partially evading existing immune defenses. The continuous emergence of variants like Alpha, Delta, and Omicron has meant a perpetual race for vaccine manufacturers to update their products, adding complexity and cost to the pandemic response.

Beyond immunological considerations, the practical hurdles associated with mRNA vaccine production and distribution are substantial. Manufacturing mRNA vaccines is an intricate and expensive process. Key challenges include precisely controlling the packaging of mRNA molecules into lipid nanoparticles (LNPs), which are crucial for delivery but difficult to standardize at scale. Perhaps the most significant logistical barrier is the stringent cold chain requirement; some mRNA vaccines, notably Pfizer-BioBioNTech’s Comirnaty, demand ultra-cold storage at temperatures as low as -70°C (-94°F), while Moderna’s Spikevax requires -20°C (-4°F). These extreme temperature requirements complicate global distribution, particularly in regions with limited infrastructure, hindering equitable access. Moreover, there have been observations of unintended off-target effects, though generally mild, which warrant continuous monitoring and improvement in vaccine design. Addressing these inherent limitations is paramount to enhancing the world’s preparedness and agility in responding to future infectious disease threats.

Introducing DoriVac: A DNA Origami Nanotechnology Breakthrough

In response to these multifaceted challenges, a multidisciplinary consortium of researchers from the Wyss Institute at Harvard University, Dana-Farber Cancer Institute (DFCI), and partner institutions has pioneered an innovative alternative: a DNA origami nanotechnology platform dubbed DoriVac. This platform represents a significant leap forward, functioning uniquely as both a vaccine and an intrinsic adjuvant, thereby streamlining the immune activation process. The core innovation lies in the precision of DNA origami, a technique that allows for the self-assembly of DNA strands into predefined nanoscale shapes, offering unparalleled control over the spatial arrangement of vaccine components.

The research team strategically designed DoriVac vaccines to target a specific peptide region, HR2, which is found in the spike proteins of several formidable viruses, including SARS-CoV-2, HIV, and Ebola. This conserved target offers the potential for broader protection against viral families, a key advantage over variant-specific approaches. Initial preclinical studies in mice yielded highly encouraging results, demonstrating that the SARS-CoV-2 HR2 DoriVac vaccine elicited robust immune responses. These responses encompassed both antibody-driven (humoral) activity, crucial for neutralizing viruses, and T cell-driven (cellular) activity, vital for clearing infected cells and establishing long-term immunity.

To bridge the critical gap between animal models and human physiology, the team leveraged the Wyss Institute’s cutting-edge microfluidic human Organ Chip technology. This advanced in vitro system accurately simulates a human lymph node, providing a more predictive platform for evaluating vaccine efficacy. In this sophisticated human preclinical model, the SARS-CoV-2 HR2 DoriVac vaccine again generated strong antigen-specific immune responses in human cells, further validating its potential. A direct comparison with existing SARS-CoV-2 mRNA vaccines, delivered via lipid nanoparticles, revealed that a DoriVac vaccine presenting the same spike protein variant produced a similarly potent immune activation in human models. Crucially, however, the DNA origami vaccine demonstrated significant advantages in terms of stability, ease of storage, and manufacturing simplicity. These pivotal findings, which signal a potential paradigm shift in vaccine development, were reported in the prestigious journal Nature Biomedical Engineering.

Precision Engineering at the Nanoscale: How DoriVac Works

The conceptual foundation of DoriVac was laid in 2024 by Dr. William Shih’s team at the Wyss Institute and Dana-Farber, introducing it as a DNA nanotechnology-based vaccine platform with expansive potential. Dr. Yang (Claire) Zeng, a co-corresponding author on the new study and now cofounder and CEO/CTO of DoriNano, spearheaded the effort. Her earlier work demonstrated DoriVac’s capacity to precisely present immune-stimulating adjuvant molecules to cells at the nanoscale, a level of control previously unattainable.

DoriVac vaccines are constructed from minuscule, self-assembling square DNA nanostructures. One side of these structures is meticulously engineered to display adjuvant molecules, arranged at carefully controlled nanometer distances. This precise spatial presentation is critical for optimal immune cell activation. The opposite side of the nanostructure is designed to present selected antigens, such as peptides or proteins derived from tumors or pathogens. This modular design allows for immense flexibility in vaccine composition. Earlier studies in tumor-bearing mice had already shown that these DNA origami-enhanced vaccines produced superior immune responses compared to versions lacking the DNA origami structure, indicating the intrinsic adjuvant effect of the platform.

"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," stated Dr. William Shih, co-corresponding author, Wyss Institute Core Faculty member, and Professor at Harvard Medical School and DFCI, whose group pioneered the novel 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."

From Cancer Research to Pandemic Preparedness: DoriVac’s Evolution

The genesis of DoriVac’s application in infectious diseases is rooted in its initial development for cancer immunology. "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," explained Dr. Zeng. To explore this promising avenue, Dr. Zeng and co-first author Dr. Olivia Young, a former graduate student in Dr. Shih’s group, initiated a crucial collaboration with Dr. Donald Ingber’s team at the Wyss Institute. Dr. Ingber’s laboratory is renowned for its innovative antiviral research, integrating AI-driven and multiomics approaches with advanced microfluidic human Organ Chip systems.

Working alongside co-first author Dr. Longlong Si, a former postdoctoral researcher in Dr. Ingber’s lab, the team successfully developed DoriVac vaccines specifically targeting SARS-CoV-2, HIV, and Ebola. These vaccines strategically present conserved HR2 peptides, which function as critical antigens within the respective viral spike proteins. This focus on conserved regions is a deliberate strategy to potentially circumvent the issue of rapidly mutating 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 elaborated. "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 findings underscore DoriVac’s capacity to orchestrate a comprehensive and robust immune response, a cornerstone for effective and enduring vaccine protection.

Validating Human Efficacy: The Role of Human Organ Chips

A persistent challenge in vaccine development has been the disparity between immune responses observed in animal models, particularly mice, and those in humans. This translational gap often leads to the failure of promising treatments during human clinical trials. To overcome this hurdle and improve the predictive accuracy of preclinical evaluations, the research team rigorously tested DoriVac vaccines using a human lymph node-on-a-chip (human LN Chip). This sophisticated in vitro system faithfully recapitulates key aspects of the human immune system, providing a more reliable proxy for human outcomes.

This advanced system, further refined by co-first author Min Wen Ku and co-corresponding author Dr. Girija Goyal, Director of Bioinspired Therapeutics at the Wyss Institute, yielded compelling results. The SARS-CoV-2-HR2 DoriVac vaccine effectively activated human dendritic cells (DCs) and significantly boosted their production of inflammatory cytokines, essential signaling molecules for immune coordination, when compared to origami-free components. Furthermore, the vaccine led to an increase in the number of CD4+ and CD8+ T cells, both critical for various protective immune functions, lending substantial support to the platform’s 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," commented Dr. Donald Ingber, co-corresponding author, 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. "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 Versus mRNA: A Head-to-Head Comparison

To firmly establish DoriVac’s competitive standing, the researchers undertook a direct comparison with established mRNA vaccine technologies. Led by Dr. Zeng and co-author Qiancheng Xiong, the team evaluated a DoriVac vaccine engineered to present the full SARS-CoV-2 spike protein, pitting it against commercially available Moderna and Pfizer/BioNTech mRNA lipid nanoparticle (LNP) vaccines encoding the identical spike protein. Utilizing a standard booster regimen in mice, both vaccine types elicited comparable antiviral T cell and antibody-producing B cell responses, demonstrating DoriVac’s equivalent immunological potency.

"This underscored DoriVac’s potential as a DNA nanotechnology-enabled, self-adjuvanted vaccine platform," Dr. Shih affirmed. "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 reduced reliance on ultra-cold storage, typically a logistical nightmare for mRNA vaccines, is a game-changer for global vaccine equity and rapid deployment in crisis scenarios. The inherent stability of DNA and the relatively simpler self-assembly process of DNA origami structures also promise to significantly reduce manufacturing costs and complexity compared to the highly sensitive LNP encapsulation process. Recent studies conducted at DoriNano have also provided encouraging data, indicating that DoriVac exhibits a promising safety profile, a critical factor for any new vaccine technology.

Broader Implications and the Future of Pandemic Preparedness

The development of the DoriVac platform carries profound implications for global health and future pandemic preparedness. Its ability to generate robust and broad immune responses, coupled with superior stability, ease of manufacturing, and reduced cold chain requirements, positions it as a formidable contender in the next generation of vaccine technologies. This platform’s versatility, evident from its origins in cancer research and its successful application to multiple infectious diseases, suggests a broad applicability that could address a wide range of public health challenges.

For under-resourced regions, DoriVac’s potential to eliminate the need for costly and complex cold storage infrastructure could revolutionize vaccine accessibility, ensuring that life-saving immunizations reach populations currently underserved. This could significantly democratize global health equity, a lesson painfully learned during the COVID-19 pandemic where vaccine distribution disparities exacerbated humanitarian crises. Economically, the anticipated reduction in manufacturing complexity and logistical overhead could lead to more affordable vaccines, further enhancing global access and sustainable public health initiatives.

The scientific community views DoriVac as a testament to the power of interdisciplinary collaboration, bringing together nanotechnology, immunology, and bioengineering. The funding support from diverse sources, 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, the US-Japan CRDF global fund, the National Research Foundation of Korea, the Intramural Research Program of the Korea Institute of Science and Technology (KIST), and the Bill and Melinda Gates Foundation, underscores the broad recognition of its potential and the confidence in its future trajectory.

As the world continues to grapple with emerging infectious diseases and the threat of future pandemics, platforms like DoriVac offer a beacon of hope. The next steps will involve further preclinical optimization and, ultimately, human clinical trials to fully ascertain its safety and efficacy in diverse human populations. If successful, DoriVac could fundamentally reshape how the world prepares for and responds to infectious disease threats, providing a more robust, equitable, and adaptable arsenal against pathogens yet to emerge.

The research involved contributions from a comprehensive team 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.