By Hendra Lukman 
The COVID-19 pandemic, a global health crisis that reshaped societies and economies, thrust messenger RNA (mRNA) vaccines into an unprecedented spotlight. On December 8, 2020, the United Kingdom administered the first authorized COVID-19 mRNA vaccine, marking a pivotal moment in public health history. The impact was profound; researchers later estimated, through sophisticated modeling, that these groundbreaking vaccines averted at least 14.4 million deaths worldwide within their first year of deployment. This remarkable success spurred a fervent wave of scientific inquiry, igniting efforts to harness the potential of mRNA technology for a broader spectrum of infectious diseases. Currently, clinical trials are actively underway, exploring mRNA vaccines against formidable foes such as influenza virus, Respiratory Syncytial Virus (RSV), HIV, Zika, Epstein-Barr virus, and even tuberculosis bacteria.
However, the very successes of COVID-19 mRNA vaccines also illuminated inherent limitations, underscoring the urgent need for innovative vaccine strategies that can overcome existing challenges and enhance global preparedness for future health emergencies.
Navigating the Hurdles of mRNA Vaccine Performance and Production
Despite their life-saving impact, COVID-19 mRNA vaccines present several significant challenges that researchers are actively working to address. A primary concern is the variability in the immune protection they confer. The strength and duration of immune responses can differ substantially from person to person, and importantly, this protection is not permanent. This issue is further complicated by the relentless evolutionary nature of SARS-CoV-2, the virus responsible for COVID-19. As the virus mutates, it generates new variants that can partially evade pre-existing immune defenses, necessitating frequent vaccine updates to maintain efficacy.
Beyond performance, practical and logistical hurdles also impede the widespread and equitable deployment of mRNA vaccines. The manufacturing process for mRNA vaccines is inherently complex and costly. Precisely controlling the quantity of mRNA molecules encapsulated within lipid nanoparticles, a critical step for vaccine stability and delivery, remains a significant technical challenge. Furthermore, these vaccines typically require stringent cold chain storage, a logistical burden that complicates distribution, particularly in resource-limited regions. Potential unintended off-target effects, while generally rare and manageable, also remain an area of ongoing research and development. Overcoming these multifaceted limitations is paramount to improving the global community’s capacity to anticipate, prepare for, and effectively respond to future infectious disease threats.
A Paradigm Shift: The DoriVac DNA Origami Vaccine Platform
In response to these pressing challenges, a multidisciplinary team of researchers from the Wyss Institute at Harvard University, the Dana-Farber Cancer Institute (DFCI), and collaborating institutions embarked on exploring a fundamentally different approach to vaccine design. Their investigation centered on a novel DNA origami nanotechnology platform, aptly named DoriVac, which is engineered to function as both a vaccine antigen delivery system and an adjuvant – a substance that enhances the immune response.
The core innovation of the DoriVac platform lies in its ability to precisely assemble nanoscale structures from DNA. Researchers designed DoriVac vaccines to target specific peptide regions within the spike proteins of various viruses. Notably, they focused on the HR2 (Heptad Repeat 2) region, a conserved structural element found in the spike proteins of several dangerous pathogens, including SARS-CoV-2, HIV, and Ebola. This conserved nature makes the HR2 region a potentially universal target for vaccines against a range of viral infections.
In preclinical studies conducted in mice, a DoriVac vaccine engineered to target the SARS-CoV-2 HR2 peptide elicited robust and comprehensive immune responses. These responses encompassed both antibody-driven (humoral) immunity, which involves the production of antibodies to neutralize the virus, and T cell-driven (cellular) immunity, which includes the activation of immune cells that can directly kill infected cells.
To further validate the platform’s potential in a human context, the team utilized the Wyss Institute’s cutting-edge microfluidic human Organ Chip technology. This advanced system effectively simulates a human lymph node in vitro, providing a more accurate model of human immune responses than traditional animal models. Within this sophisticated human lymph node-on-a-chip system, the SARS-CoV-2 HR2 DoriVac vaccine demonstrated its ability to generate potent antigen-specific immune responses in human cells, mirroring the promising results observed in mice.
A direct head-to-head comparison was then conducted between a DoriVac vaccine carrying a specific SARS-CoV-2 spike protein variant and the mRNA vaccines utilizing lipid nanoparticles that encode the same variant. In human models, the DoriVac vaccine induced a similarly strong immune activation to that of the mRNA vaccines. However, the DNA origami vaccine exhibited distinct advantages in terms of stability and ease of storage and manufacturing, highlighting its potential to overcome some of the key logistical and production challenges associated with mRNA vaccines. These groundbreaking findings were recently published in the prestigious journal Nature Biomedical Engineering, signaling a significant advancement in the field of vaccinology.
Pioneering Precision: The Mechanics of DNA Origami Vaccines
The development of the DoriVac platform represents a culmination of years of research in DNA nanotechnology. In 2024, Dr. William Shih’s team at the Wyss Institute and DFCI introduced DoriVac as a versatile vaccine technology built upon the principles of DNA self-assembly. Dr. Yang (Claire) Zeng, who led the research effort with her collaborators, demonstrated that DoriVac possesses the remarkable ability to precisely present immune-stimulating adjuvant molecules to immune cells at the nanoscale. This level of control at the molecular level is a defining characteristic of the platform.
Earlier studies, conducted in tumor-bearing mice, had already showcased the superior immune-boosting capabilities of these DNA origami-based vaccines compared to versions that lacked the intricate DNA origami structure. The construction of DoriVac vaccines involves the self-assembly of tiny, square DNA nanostructures. One surface of these nanostructures is meticulously decorated with adjuvant molecules, arranged at precisely controlled nanometer distances. The opposing surface is engineered to display specific antigens – such as peptides or proteins derived from tumors or pathogens – acting as molecular flags that signal to the immune system.
"While we were developing the platform for cancer applications, the COVID-19 pandemic was still moving with full force," explained Dr. Zeng. "So, the question quickly arose whether DoriVac’s superior adjuvant activity could also be leveraged in infectious disease settings." This inquiry led to the expansion of the platform’s application from oncology to infectious disease prevention.
To explore this promising avenue, Dr. Zeng, alongside co-first author Olivia Young, Ph.D., a former graduate student in Dr. Shih’s group, collaborated with the laboratory of Dr. Donald Ingber at the Wyss Institute. Dr. Ingber’s team is at the forefront of antiviral innovation, employing artificial intelligence (AI)-driven approaches, multiomics analysis, and microfluidic human Organ Chip systems to unravel complex biological processes. Together, with co-first author Longlong Si, Ph.D., a former postdoctoral researcher in Dr. Ingber’s lab, the researchers successfully developed DoriVac vaccines targeting SARS-CoV-2, HIV, and Ebola. These vaccines were designed to present conserved HR2 peptides, which are critical components of the viral spike proteins.
"Our analysis of the immune responses provoked by these first DoriVac vaccines in mice led to several encouraging observations," Dr. Zeng stated. "We saw significantly greater and broader activation of both humoral and cellular immunity across a range of relevant immune cell types than what origami-free antigens and adjuvants could produce." Specifically, the researchers observed an increase in antibody-producing B cells, activated antigen-presenting dendritic cells (DCs), and antigen-specific memory and cytotoxic T cell types – all of which are vital for establishing long-term protection against viral infections. This enhanced immune activation was particularly pronounced in the case of the SARS-CoV-2 HR2 targeting vaccine.
Bridging the Gap: From Preclinical Animal Models to Human-Centric Systems
A persistent challenge in vaccine development is the imperfect translation of immune responses observed in animal models, particularly mice, to human outcomes. This translational gap has historically led to the failure of many promising experimental treatments during clinical trials. To mitigate this risk and provide more accurate predictions of human efficacy, the research team rigorously tested the DoriVac vaccines using a sophisticated human lymph node-on-a-chip (human LN Chip) system. This advanced microfluidic device is meticulously engineered to mimic key aspects of the human immune system.
The human LN Chip, 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, proved to be an invaluable tool. This system demonstrated that the SARS-CoV-2 HR2 DoriVac vaccine effectively activated human dendritic cells (DCs) and significantly amplified their production of inflammatory cytokines, which are crucial signaling molecules in immune responses. Furthermore, the DoriVac vaccine increased the numbers of CD4+ and CD8+ T cells possessing multiple protective functions, providing compelling evidence for the platform’s potential to elicit beneficial immune responses in humans.
"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 Dr. Donald Ingber. "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." Dr. Ingber is also 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.
A Direct Confrontation: DoriVac vs. mRNA Vaccines
To provide a definitive assessment of DoriVac’s competitive standing, the researchers conducted a critical "head-to-head" comparison. They evaluated a DoriVac vaccine engineered to present the full SARS-CoV-2 spike protein, mirroring the target of current mRNA vaccines. Led by Dr. Zeng and co-author Qiancheng Xiong, the team directly compared this DoriVac vaccine with the commercially available Moderna and Pfizer/BioNTech mRNA lipid nanoparticle (LNP) vaccines, both of which encode the same spike protein.
In a standard booster immunization approach in mice, both vaccine types – DoriVac and the mRNA-LNP vaccines – elicited similarly potent antiviral T cell and antibody-producing B cell responses. This finding underscores DoriVac’s potential as a self-adjuvanted vaccine platform powered by DNA nanotechnology.
However, the advantages of DoriVac extend beyond comparable efficacy. "DoriVac vaccines have a number of other advantages," explained Dr. Shih. "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. Moreover, they could overcome some of the enormous manufacturing complexities of LNP-formulated vaccines, to name two major ones." Recent safety assessments conducted at DoriNano, a company co-founded by Dr. Zeng to advance this technology, have also indicated a promising safety profile for DoriVac vaccines.
The research was supported by significant funding from various institutions, 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 extensive list of contributing authors highlights the collaborative and international nature of this pioneering research.
The implications of the DoriVac platform are far-reaching. Its inherent stability, simplified manufacturing, and reduced reliance on cold chain logistics could democratize vaccine access globally, particularly in regions where such infrastructure is limited. The platform’s modular design also allows for rapid adaptation to new or emerging pathogens, offering a flexible and robust tool for future pandemic preparedness. As scientific inquiry continues to push the boundaries of what is possible in vaccinology, DNA origami technology, as exemplified by DoriVac, stands poised to play a critical role in safeguarding global health.