By Hendra Lukman 
The global landscape of infectious disease defense was irrevocably altered by the COVID-19 pandemic, catapulting messenger RNA (mRNA) vaccine technology into the forefront of public health. On December 8, 2020, the first COVID-19 mRNA vaccine was administered, marking a pivotal moment in modern medicine. Subsequent research, leveraging sophisticated modeling, estimated that these groundbreaking vaccines averted a staggering 14.4 million deaths worldwide within their inaugural year, a testament to their profound impact. This success spurred a wave of research into mRNA vaccines for a spectrum of other infectious agents, with ongoing clinical trials targeting influenza virus, Respiratory Syncytial Virus (RSV), HIV, Zika, Epstein-Barr virus, and even tuberculosis bacteria. However, as the world grappled with the evolving SARS-CoV-2 virus, studies of existing COVID-19 mRNA vaccines also illuminated critical limitations, signaling an urgent need for innovative vaccine strategies and platforms.
Emerging Challenges with mRNA Vaccine Performance and Production
Despite their remarkable efficacy, COVID-19 mRNA vaccines present several significant challenges that researchers are actively seeking to address. A primary concern is the variability in immune protection generated from person to person. Furthermore, the duration of this protection is not indefinite, a factor exacerbated by the relentless evolution of the SARS-CoV-2 virus. The emergence of new variants, capable of partially evading established immune defenses, necessitates frequent vaccine updates, adding complexity and cost to ongoing public health efforts.
Beyond immunological considerations, practical hurdles persist in the manufacturing and deployment of mRNA vaccines. The production process is inherently complex and expensive. A persistent technical challenge lies in precisely controlling the quantity of mRNA molecules encapsulated within lipid nanoparticles (LNPs), the delivery vehicles crucial for vaccine function. These vaccines also require stringent cold-chain storage, limiting their accessibility in resource-limited regions. Moreover, concerns about potential unintended off-target effects, while generally considered minimal, remain an area of ongoing scrutiny. Overcoming these multifaceted limitations is paramount to enhancing global preparedness and response capabilities for future infectious disease threats.
DoriVac: A Novel DNA Origami Vaccine Platform Emerges
In response to these pressing challenges, a multidisciplinary team comprising researchers from the Wyss Institute at Harvard University, the Dana-Farber Cancer Institute (DFCI), and affiliated institutions has explored an alternative paradigm in vaccine development. Their innovative approach centers on a DNA origami nanotechnology platform, dubbed DoriVac, which ingeniously functions as both a vaccine and an adjuvant. This dual-action capability holds significant promise for a more robust and adaptable immune response.
The DoriVac platform is meticulously engineered to target a conserved peptide region, specifically HR2, found within the spike proteins of a diverse range of viruses, including SARS-CoV-2, HIV, and Ebola. This conserved target region offers a strategic advantage, potentially providing broader protection against various viral strains and even different viruses. In preclinical studies conducted in mice, a DoriVac vaccine designed to target the SARS-CoV-2 HR2 peptide elicited powerful immune responses. These responses encompassed both antibody-driven (humoral) immunity and T cell-driven (cellular) immunity, key components of a comprehensive and lasting defense against pathogens.
To further validate the platform’s potential and assess its efficacy in a human context, the researchers employed the Wyss Institute’s advanced microfluidic human Organ Chip technology. This sophisticated system accurately simulates a human lymph node in vitro, providing a more predictive model of immune system interactions than traditional animal models. In this preclinical human model, the SARS-CoV-2 HR2 DoriVac vaccine demonstrated its capacity to generate robust antigen-specific immune responses within human cells, mirroring the findings observed in animal studies.
Crucially, when directly compared with contemporary SARS-CoV-2 mRNA vaccines delivered via lipid nanoparticles, a DoriVac vaccine carrying the same spike protein variant elicited similarly strong immune activation in human models. However, the DNA origami vaccine exhibited distinct advantages in terms of stability, making it easier to store and manufacture. These pivotal findings were recently published in the prestigious journal Nature Biomedical Engineering, marking a significant milestone in the advancement of this novel vaccine technology.
"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 co-corresponding author William Shih, Ph.D., a Core Faculty member at the Wyss Institute and Professor at Harvard Medical School and DFCI, whose research group pioneered this 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."
The Architecture of DNA Origami Vaccines: Precision at the Nanoscale
The genesis of the DoriVac platform lies in the sophisticated application of DNA nanotechnology. In 2024, Shih’s team at the Wyss Institute and Dana-Farber introduced DoriVac as a vaccine platform with extensive potential applications, fundamentally rooted in DNA self-assembly. Yang (Claire) Zeng, M.D., Ph.D., who spearheaded this transformative effort alongside collaborators, demonstrated DoriVac’s remarkable ability to precisely present immune-stimulating adjuvant molecules to cells at the nanoscale, a level of control previously unattainable.
Prior investigations in tumor-bearing mice had already revealed that these DNA origami-based vaccines induced significantly stronger immune responses compared to versions lacking the intricate DNA origami structure. The construction of DoriVac vaccines involves the precise assembly of minuscule, self-folding square DNA nanostructures. One facet of these nanostructures is engineered to display adjuvant molecules arranged at meticulously controlled nanometer distances. The opposing side of the structure is then functionalized to present selected antigens, such as 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," explained Zeng, the first and co-corresponding author on the new study, who is now also a co-founder and CEO/CTO of DoriNano, driving 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."
This pivotal question spurred further research. Zeng, in collaboration with co-first author Olivia Young, Ph.D., a former graduate student in Shih’s group, joined forces with Donald Ingber’s team at the Wyss Institute. Ingber’s group is renowned for its pioneering work in antiviral innovation, integrating artificial intelligence-driven and multiomics approaches with microfluidic human Organ Chip systems. Together, with co-first author Longlong Si, Ph.D., a former postdoctoral researcher in Ingber’s lab, the researchers embarked on the development of DoriVac vaccines specifically targeting SARS-CoV-2, HIV, and Ebola. These vaccines were engineered to present HR2 peptides, which serve as conserved antigens within the spike proteins of these formidable viruses.
"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," 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," she further explained.
Bridging the Gap: From Mouse Studies to Human Organoid Models
A persistent challenge in vaccine development has been the often-unpredictable translation of immune responses observed in mouse models to human physiology. This translational gap has unfortunately led to the failure of numerous promising vaccine candidates during clinical trials. To mitigate this risk and improve the predictive accuracy of their findings, the research team strategically employed human lymph node-on-a-chip (human LN Chip) systems. These advanced microfluidic devices are designed to meticulously mimic key aspects of the human immune system, offering a more robust preclinical assessment.
This sophisticated system, further developed by co-first author Min Wen Ku and co-corresponding author Girija Goyal, Ph.D., Director of Bioinspired Therapeutics at the Wyss Institute, provided compelling evidence of DoriVac’s efficacy in a human context. The SARS-CoV-2-HR2 DoriVac vaccine demonstrated its ability to activate human dendritic cells (DCs) and significantly amplify their production of inflammatory cytokines when compared to standalone origami-free components. Moreover, it led to an increased population of CD4+ and CD8+ T cells exhibiting multiple protective functions, thereby bolstering 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 co-corresponding author Donald Ingber, M.D., Ph.D. Professor Ingber, who also holds distinguished positions as 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, underscored the significance of this convergence of technologies. "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."
Head-to-Head Comparison: DoriVac vs. mRNA Vaccines
In a critical head-to-head comparison, the researchers evaluated a DoriVac vaccine designed to present the full SARS-CoV-2 spike protein. Under the leadership of Zeng and co-author Qiancheng Xiong, the team pitted this DoriVac candidate against widely used Moderna and Pfizer/BioNTech mRNA lipid nanoparticle (LNP) vaccines, both of which encode the same spike protein. This rigorous comparative analysis was conducted using a standard booster approach in mice.
The results revealed that both vaccine types – DoriVac and the mRNA-LNPs – elicited similarly potent antiviral T cell and antibody-producing B cell responses. This parity in immune activation underscores DoriVac’s significant potential as a self-adjuvanted vaccine platform enabled by DNA nanotechnology.
"This underscored DoriVac’s potential as a DNA nanotechnology-enabled, self-adjuvanted vaccine platform," Professor Shih reiterated. "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." Furthermore, recent studies conducted at DoriNano, the company co-founded by Zeng to advance this technology, have indicated that DoriVac exhibits a promising safety profile, an essential consideration for any new vaccine candidate.
The groundbreaking research involved a broad spectrum of dedicated scientists. Other authors contributing to this seminal study include 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 extensive research was made possible through the generous support of several prominent funding bodies, 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 collective effort and diverse funding streams highlight the global recognition of the importance and potential of this innovative vaccine technology.
