The global health landscape was irrevocably altered by the advent of the COVID-19 pandemic, which thrust messenger RNA (mRNA) vaccine technology into the forefront of public consciousness and scientific endeavor. The initial rollout of the first COVID-19 mRNA vaccine on December 8, 2020, marked a pivotal moment, with subsequent modeling estimating that these groundbreaking inoculations averted a staggering 14.4 million fatalities worldwide within their inaugural year of deployment. This profound impact spurred a wave of research and development, prompting scientists to explore the potential of mRNA platforms for combating a spectrum of infectious agents. Consequently, clinical trials are presently underway for vaccines targeting influenza, Respiratory Syncytial Virus (RSV), Human Immunodeficiency Virus (HIV), Zika virus, Epstein-Barr virus, and even the bacteria responsible for tuberculosis. However, parallel investigations into the performance of existing COVID-19 mRNA vaccines have illuminated certain inherent limitations, underscoring the urgent need for innovative vaccine design strategies to bolster global preparedness against future health crises.
One of the primary challenges confronting current mRNA vaccine technology lies in the variability of immune protection conferred upon individuals, with the duration of immunity also proving to be finite. This inherent variability is further compounded by the relentless evolutionary trajectory of viruses like SARS-CoV-2, which continuously generate novel variants capable of partially evading established immune defenses. Such immune escape necessitates the frequent updating of vaccine formulations, a process that can be both time-consuming and resource-intensive. Beyond immunological considerations, practical hurdles also impede the widespread and cost-effective production of mRNA vaccines. The manufacturing processes are intricate and costly, and achieving precise control over the quantity of mRNA molecules encapsulated within lipid nanoparticles, a crucial step for effective delivery, remains a significant technical challenge. Furthermore, these vaccines typically demand stringent cold-chain storage conditions to maintain their efficacy, and there remains a potential for unintended off-target immunological effects. Addressing these multifaceted limitations is paramount to enhancing the world’s capacity to proactively confront and effectively respond to emergent infectious disease threats.
In pursuit of overcoming these challenges, a collaborative effort involving researchers from the Wyss Institute at Harvard University, the Dana-Farber Cancer Institute (DFCI), and affiliated institutions has championed a novel approach leveraging DNA nanotechnology. This innovative platform, christened DoriVac, is designed to function synergistically as both a vaccine and an adjuvant, a substance that amplifies the immune response. The conceptual framework behind DoriVac vaccines involves the strategic targeting of a specific peptide region, designated HR2, which is conserved across the spike proteins of a diverse array of viruses, including SARS-CoV-2, HIV, and Ebola. Preclinical studies conducted in murine models with a SARS-CoV-2 HR2-specific DoriVac vaccine demonstrated the induction of robust immune responses, encompassing both antibody-mediated (humoral) immunity and T cell-mediated (cellular) immunity.
To further validate the translational potential of this technology, the research team employed the Wyss Institute’s advanced microfluidic human Organ Chip technology. This sophisticated system is engineered to replicate the intricate microenvironment of a human lymph node in an in vitro setting, thereby offering a more predictive model of human immune responses. Within this simulated lymph node, the SARS-CoV-2 HR2 DoriVac vaccine successfully elicited potent antigen-specific immune reactions within human cells. A direct comparative analysis between the DoriVac vaccine and established SARS-CoV-2 mRNA vaccines, administered via lipid nanoparticles and carrying the identical spike protein variant, revealed that the DNA origami vaccine induced a comparable level of immune activation in human models. Crucially, the DoriVac platform demonstrated notable advantages in terms of its inherent stability, coupled with enhanced ease of storage and manufacturing, findings that were subsequently published in the prestigious journal Nature Biomedical Engineering.
Dr. William Shih, a co-corresponding author and a core faculty member at the Wyss Institute, whose laboratory pioneered this novel vaccine concept, articulated the significant advantages of the DoriVac platform. He emphasized its exceptional flexibility as a "chassis" that offers unprecedented control over vaccine composition. This control extends to the molecular-level programming of immune recognition within targeted immune cells, a capability that promises to yield superior immunological outcomes. Dr. Shih, who also holds professorships at Harvard Medical School and DFCI, highlighted that their study effectively showcased DoriVac’s versatility and potential by meticulously examining the immune modulations necessary for effective antiviral defense.
The genesis of the DoriVac platform, as introduced by Dr. Shih’s team at the Wyss Institute and Dana-Farber in 2024, lies in the application of DNA nanotechnology to create a vaccine delivery system with broad therapeutic potential. Dr. Yang (Claire) Zeng, who spearheaded this groundbreaking research alongside collaborators, demonstrated DoriVac’s capacity to precisely present immune-stimulating adjuvant molecules to cells at the nanoscale. Earlier investigations in preclinical models of cancer-bearing mice had already established that these DNA origami-based vaccines elicited more potent immune responses compared to antigen and adjuvant combinations lacking the distinct nanostructure. The construction of DoriVac vaccines involves the self-assembly of diminutive, square-shaped DNA nanostructures. One surface of these nanostructures is meticulously adorned with adjuvant molecules arranged at precisely controlled nanometer intervals, while the opposing surface is engineered to display selected antigens, which can include peptides or proteins derived from tumors or infectious pathogens.
Dr. Zeng, the first and co-corresponding author of the recent study and now co-founder and CEO/CTO of DoriNano, a company focused on translating this technology into clinical applications, shared her perspective on the platform’s evolution. She explained that during the development of DoriVac for oncological applications, the COVID-19 pandemic was in full swing, prompting an immediate consideration of whether DoriVac’s superior adjuvant properties could be effectively harnessed for infectious disease prevention. This pivotal question guided the subsequent research trajectory.
To explore this hypothesis, Dr. Zeng, in collaboration with co-first author Dr. Olivia Young, a former graduate student in Dr. Shih’s group, joined forces with Dr. Donald Ingber’s research team at the Wyss Institute. Dr. Ingber’s group is a recognized leader in antiviral innovation, employing artificial intelligence-driven and multiomics approaches alongside their pioneering microfluidic human Organ Chip systems. Working in concert with co-first author Dr. Longlong Si, a former postdoctoral researcher in Dr. Ingber’s laboratory, the researchers successfully engineered DoriVac vaccines designed to target SARS-CoV-2, HIV, and Ebola viruses. These vaccines function by presenting conserved HR2 peptides, which act as crucial antigens within the viral spike proteins.
Dr. Zeng further elaborated on the encouraging outcomes of the initial DoriVac vaccine trials in mice. The analysis revealed a significantly greater and more encompassing activation of both humoral and cellular immunity across a spectrum of relevant immune cell types when compared to the efficacy of origami-free antigens and adjuvants. Specifically, she noted an increase in the numbers of antibody-producing B cells, activated antigen-presenting dendritic cells (DCs), and antigen-specific memory and cytotoxic T cells, all of which are vital for establishing long-term protective immunity. This enhancement was particularly pronounced in the case of the SARS-CoV-2 HR2 DoriVac vaccine.
A significant challenge inherent in vaccine development is the frequent discrepancy between immune responses observed in murine models and their replication in human subjects, a gap that has historically led to the failure of many promising therapeutic candidates during clinical trials. To mitigate this predictive gap and enhance the likelihood of successful human translation, the research team rigorously evaluated the DoriVac vaccines using a sophisticated human lymph node-on-a-chip (human LN Chip) system. This advanced microfluidic device is meticulously designed to recapitulate key aspects of the human immune system.
The human LN Chip, developed by co-first author Min Wen Ku and co-corresponding author Dr. Girija Goyal, Director of Bioinspired Therapeutics at the Wyss Institute, provided compelling evidence of DoriVac’s efficacy in human cellular models. The system demonstrated that the SARS-CoV-2 HR2 DoriVac vaccine not only effectively activated human DCs but also significantly augmented their production of inflammatory cytokines, a critical signaling cascade in immune responses, when compared to the effects of origami-free vaccine components. Furthermore, the platform facilitated an increase in CD4+ and CD8+ T cells exhibiting diverse protective functions, thereby strengthening the case for the platform’s potential utility in human vaccination strategies.
Dr. Ingber, a co-corresponding author, Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and Hansjörg Wyss Professor of Biologically Inspired Engineering at the Harvard John A. Paulson School of Engineering and Applied Sciences, underscored the predictive power of the human LN Chip technology. He stated that this system served as an ideal testing ground for DoriVac vaccines, providing insights into the induced, antigen-specific immune cell profiles and activities that are highly likely to mirror those observed in human vaccine recipients. This convergence of cutting-edge technologies, according to Dr. Ingber, has dramatically improved the prospects for success for this novel class of vaccines and established a robust new framework for future vaccine development endeavors.
In a pivotal head-to-head comparison, the research team also assessed a DoriVac vaccine engineered to present the complete SARS-CoV-2 spike protein. Under the leadership of Dr. Zeng and co-author Qiancheng Xiong, this DoriVac formulation was directly juxtaposed against commercially available Moderna and Pfizer/BioNTech mRNA lipid nanoparticle (LNP) vaccines that encode the identical spike protein. Utilizing a standard booster immunization regimen in mice, both vaccine modalities successfully induced comparable antiviral T cell and antibody-producing B cell responses, underscoring the competitive efficacy of the DoriVac platform.
Dr. Shih further highlighted the multifaceted advantages of DoriVac, emphasizing its potential as a self-adjuvanted vaccine platform enabled by DNA nanotechnology. He pointed to several key benefits, including the absence of the stringent cold-chain requirements that burden mRNA-LNP vaccines, thereby facilitating significantly more efficient distribution, particularly in resource-limited regions. Additionally, he noted that DoriVac could circumvent some of the substantial manufacturing complexities associated with LNP-formulated vaccines. Recent preclinical studies conducted by DoriNano have also indicated a promising safety profile for DoriVac. The research was supported by a consortium of 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 study’s authorship also includes 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.
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