The advent of the COVID-19 pandemic thrust messenger RNA (mRNA) vaccine technology into the global consciousness, marking a pivotal moment in public health history with the first mRNA vaccine administered on December 8, 2020, following expedited clinical trials. Modeling later suggested that these pioneering vaccines averted an estimated 14.4 million deaths worldwide within their initial year of deployment, underscoring their profound impact. This success spurred scientific endeavors to adapt mRNA platforms for an array of other infectious diseases, with ongoing trials targeting influenza, Respiratory Syncytial Virus (RSV), HIV, Zika, Epstein-Barr virus, and even tuberculosis bacteria. Concurrently, extensive research into the performance of existing COVID-19 mRNA vaccines began to illuminate certain inherent limitations, thereby highlighting the urgent need for the development of innovative vaccine strategies that could transcend these challenges.
A primary area of concern with current mRNA vaccines pertains to the variability in the immune protection they elicit from one individual to another, alongside the finite duration of this protective shield. This issue is compounded by the relentless evolutionary trajectory of viruses like SARS-CoV-2, which continually generate novel variants capable of partially evading established immune defenses. Consequently, the necessity for frequent vaccine updates becomes a persistent challenge in maintaining robust public health resilience. Beyond immunological considerations, practical hurdles also impede the widespread and cost-effective deployment of mRNA vaccines. The manufacturing processes are inherently complex and resource-intensive, and precise control over the quantity of mRNA molecules encapsulated within lipid nanoparticles remains an intricate technical challenge. Furthermore, these vaccines typically require stringent cold-chain storage, and there exists a potential for unintended off-target immunological effects. Addressing these multifaceted limitations is crucial for enhancing global preparedness and response capabilities against future infectious disease outbreaks.
In response to these identified limitations, a collaborative research initiative involving scientists from the Wyss Institute at Harvard University, the Dana-Farber Cancer Institute (DFCI), and affiliated institutions has explored a fundamentally different approach to vaccine design. This pioneering work centers on a DNA origami nanotechnology platform, christened DoriVac, which is engineered to function simultaneously as both a vaccine delivery vehicle and an adjuvant, a substance that potentiates the immune response. The researchers meticulously designed DoriVac vaccines to specifically target conserved peptide regions, such as the HR2 domain, found within the spike proteins of a diverse range of viruses, including SARS-CoV-2, HIV, and Ebola. Preclinical investigations in murine models utilizing a DoriVac vaccine engineered for SARS-CoV-2 demonstrated the induction of exceptionally potent immune responses. These responses encompassed both antibody-mediated (humoral) immunity and T-cell driven (cellular) immunity, indicating a comprehensive activation of the immune system.
To further validate the potential of this platform in a human context, the research team employed the Wyss Institute’s advanced microfluidic human Organ Chip technology. This sophisticated system, designed to replicate the intricate microenvironment of a human lymph node in vitro, allowed for the assessment of the vaccine’s performance in a simulated human immune setting. Within this advanced in vitro model, the SARS-CoV-2 HR2 DoriVac vaccine successfully elicited robust antigen-specific immune responses from human cells, mirroring the findings observed in animal studies. In a direct comparative analysis against existing SARS-CoV-2 mRNA vaccines formulated with lipid nanoparticles, a DoriVac vaccine encoding the identical spike protein variant demonstrated comparable levels of immune activation in human models. However, the DNA origami-based vaccine exhibited distinct advantages in terms of its inherent stability and simplified requirements for storage and manufacturing, according to findings published in the esteemed journal Nature Biomedical Engineering.
The innovative DoriVac platform, introduced in 2024 by the Wyss Institute and Dana-Farber teams, leverages DNA nanotechnology to create a versatile vaccine architecture with broad applicability. Led by Dr. Yang (Claire) Zeng, the research effort showcased DoriVac’s capacity to precisely present immune-stimulating adjuvant molecules to cells at the nanoscale, offering unprecedented control over vaccine composition. Earlier studies involving tumor-bearing mice had already provided compelling evidence that these DNA origami-based vaccines elicited significantly stronger immune responses compared to antigen and adjuvant formulations lacking the nanoscale structural component. The fundamental building blocks of DoriVac vaccines are minute, self-assembling square DNA nanostructures. One surface of these structures is adorned with adjuvant molecules precisely arranged at controlled nanometer distances, while the opposing surface is functionalized with selected antigens, which can be peptides or proteins derived from pathogens or tumors.
Dr. Zeng, a lead and co-corresponding author on the new study and now co-founder and CEO/CTO of DoriNano, a company dedicated to translating this technology into clinical applications, explained that the platform was initially conceived for cancer immunotherapy. However, with the ongoing global impact of the COVID-19 pandemic, the researchers were motivated to explore whether DoriVac’s potent adjuvant capabilities could be effectively repurposed for infectious disease applications. To investigate this hypothesis, Dr. Zeng, alongside co-first author Dr. Olivia Young, a former graduate student in Dr. Shih’s laboratory, collaborated with the research group of Dr. Donald Ingber at the Wyss Institute. Dr. Ingber’s team is renowned for its work in antiviral innovation, utilizing artificial intelligence-driven and multiomics approaches in conjunction with microfluidic human Organ Chip systems. Together, in collaboration with co-first author Dr. Longlong Si, a former postdoctoral researcher in Dr. Ingber’s lab, the integrated research team developed DoriVac vaccines targeting SARS-CoV-2, HIV, and Ebola. These vaccines were designed to present HR2 peptides, recognized as conserved antigenic determinants within the spike proteins of these viruses.
The initial analysis of immune responses elicited by these early DoriVac vaccines in mice yielded highly encouraging results. Dr. Zeng highlighted that the vaccines provoked a significantly greater and broader activation of both humoral and cellular immunity across a spectrum of relevant immune cell types than could be achieved with separate, origami-free antigens and adjuvants. Specifically, the researchers observed substantial increases in the populations of antibody-producing B cells, activated antigen-presenting dendritic cells (DCs), and antigen-specific memory and cytotoxic T cells, all of which are critical for establishing long-term protective immunity. This enhanced immune activation was particularly pronounced in the case of the SARS-CoV-2 HR2 vaccine.
A persistent challenge in the field of vaccine development has been the frequent discrepancy between immune responses observed in mouse models and those that ultimately manifest in humans. This translational gap has unfortunately led to the failure of numerous promising therapeutic candidates during human clinical trials. To mitigate this risk and enhance the predictive accuracy of their findings, the research team rigorously tested the DoriVac vaccines using a specialized human lymph node-on-a-chip (human LN Chip) system. This advanced microfluidic device effectively recapitulates key aspects of the human immune system’s functionality. The human LN Chip experiments, spearheaded by co-first author Min Wen Ku and co-corresponding author Dr. Girija Goyal, Director of Bioinspired Therapeutics at the Wyss Institute, revealed that the SARS-CoV-2-HR2 DoriVac vaccine effectively activated human DCs. Furthermore, it significantly amplified their production of pro-inflammatory cytokines when compared to the effects of origami-free vaccine components. The system also demonstrated an increased abundance of CD4+ and CD8+ T cells exhibiting multiple protective functions, thereby further bolstering the platform’s potential for successful translation to human applications.
Dr. Donald Ingber, a co-corresponding author and a distinguished professor at Harvard Medical School, Boston Children’s Hospital, and the Harvard John A. Paulson School of Engineering and Applied Sciences, emphasized the profound utility of the human LN Chip technology. He stated that its predictive capabilities provided an ideal environment for evaluating DoriVac vaccines and characterizing the induced, antigen-specific immune cell profiles and activities, which are highly likely to mirror those expected in human vaccine recipients. This convergence of cutting-edge technologies, according to Dr. Ingber, dramatically improved the prospects for the success of this novel class of vaccines and established a valuable new testing ground for future vaccine research and development.
In a critical head-to-head comparison, the research team also evaluated 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 vaccine was directly contrasted with commercially available Moderna and Pfizer/BioNTech mRNA lipid nanoparticle (LNP) vaccines, both of which encode the identical spike protein. Employing a standard booster vaccination regimen in mice, both vaccine modalities successfully induced comparable antiviral T cell and antibody-producing B cell responses, indicating a robust level of immunogenicity for both approaches.
Dr. Shih underscored the significant potential of DoriVac as a self-adjuvanted vaccine platform powered by DNA nanotechnology. He elaborated on several key advantages of DoriVac vaccines compared to their mRNA-LNP counterparts. Crucially, DoriVac vaccines do not necessitate the same stringent cold-chain storage requirements, which could facilitate far more effective distribution, particularly in resource-limited regions globally. Additionally, they offer the potential to circumvent some of the substantial manufacturing complexities associated with LNP-formulated vaccines. Recent investigations conducted at DoriNano have also indicated that DoriVac exhibits a promising safety profile. The study benefited from contributions by numerous other authors, 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. Funding for this groundbreaking research was generously provided by 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).
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