DNA Origami Vaccine: A Stable Alternative to mRNA for Infectious Diseases

The COVID-19 pandemic spurred unprecedented innovation in vaccine technology, most notably with the rapid development and deployment of messenger RNA (mRNA) vaccines. These vaccines, first administered in December 2020, are estimated to have prevented at least 14.4 million deaths worldwide in their first year of use. But even with this success, scientists are already looking ahead, recognizing both the limitations of current mRNA technology and the need for more versatile vaccine platforms to address future infectious disease threats. A promising new contender is emerging: DNA origami vaccines.

Beyond mRNA: Addressing Current Vaccine Challenges

Whereas mRNA vaccines proved remarkably effective against initial strains of SARS-CoV-2, their performance isn’t uniform. Immune protection varies significantly between individuals, and the protection isn’t permanent. This is compounded by the virus’s ongoing evolution, with new variants constantly emerging that can partially evade the immune response triggered by existing vaccines, necessitating frequent updates. Manufacturing mRNA vaccines also presents hurdles. The process is complex and costly, and controlling the packaging of mRNA molecules into lipid nanoparticles – the protective bubbles that deliver the mRNA into cells – remains a challenge. These vaccines require ultra-cold storage, limiting accessibility in some regions, and there’s a potential for unintended off-target effects.

Introducing DoriVac: A DNA Nanotechnology Platform

Researchers at the Wyss Institute at Harvard University, the Dana-Farber Cancer Institute, and collaborating institutions are exploring an alternative approach using DNA origami nanotechnology. Their platform, called DoriVac, functions as both a vaccine and an adjuvant – a substance that enhances the immune response. Unlike mRNA vaccines, which deliver genetic instructions for cells to produce a viral protein, DoriVac directly presents viral components to the immune system in a highly controlled manner. The team designed DoriVac vaccines to target a specific region of the spike proteins found in viruses like SARS-CoV-2, HIV, and Ebola, known as HR2. In mouse studies, the SARS-CoV-2 HR2 vaccine generated robust immune responses, activating both antibody-mediated (humoral) and T cell-mediated (cellular) immunity.

Human-Relevant Testing with Organ Chips

To further assess DoriVac’s potential, the researchers utilized a cutting-edge technology: the Wyss Institute’s microfluidic human Organ Chip technology. These “organs-on-chips” simulate human lymph nodes in vitro, providing a more realistic environment than traditional cell cultures. Testing in this system confirmed that the SARS-CoV-2 HR2 vaccine generated strong antigen-specific immune responses in human cells. Importantly, when compared directly to mRNA vaccines delivering the same spike protein variant, DoriVac demonstrated comparable immune activation in these human models. However, the DNA origami vaccine exhibited superior stability and easier storage and manufacturing requirements. These findings were published in Nature Biomedical Engineering.

How DoriVac is Constructed: Precision at the Nanoscale

DoriVac vaccines are built from tiny, self-assembling square DNA nanostructures. One side of this structure displays adjuvant molecules arranged at precise nanometer distances, while the opposite side presents selected antigens – peptides or proteins from pathogens or tumors. This precise arrangement is key to maximizing the immune response. Yang (Claire) Zeng, M.D., Ph.D., who led the effort, explained that DoriVac can precisely deliver immune-stimulating molecules to cells at the nanoscale. Earlier studies showed that vaccines with the DNA origami structure elicited stronger immune responses than those without it. The platform’s versatility was highlighted by its successful application to SARS-CoV-2, HIV, and Ebola, demonstrating its potential to target a wide range of infectious diseases.

Head-to-Head Comparison: DoriVac vs. MRNA Vaccines

The researchers directly compared a DoriVac vaccine presenting the full SARS-CoV-2 spike protein with the Moderna and Pfizer/BioNTech mRNA vaccines, which also encode the same spike protein. Using a booster approach in mice, both vaccine types induced similar antiviral T cell and antibody-producing B cell responses. However, DoriVac offers several logistical advantages. It doesn’t require the same stringent cold-chain storage as mRNA vaccines, making it potentially more accessible in resource-limited settings. The manufacturing process is less complex, potentially reducing costs and increasing production capacity. DoriNano, a company founded by Zeng, is currently working to translate this technology into clinical applications, and recent studies have indicated a promising safety profile.

Predicting Human Responses: The Role of Human Lymph Node Chips

A significant challenge in vaccine development is the often-limited correlation between immune responses observed in animal models (like mice) and those seen in humans. This discrepancy has led to the failure of many promising treatments during clinical trials. To address this, the researchers employed a human lymph node-on-a-chip (human LN Chip), which mimics aspects of the human immune system. This system demonstrated that the SARS-CoV-2-HR2 DoriVac vaccine activated human dendritic cells (DCs) and significantly increased their production of inflammatory cytokines – signaling molecules that help orchestrate the immune response. It also boosted the number of CD4+ and CD8+ T cells, which play crucial roles in long-term protection. According to co-corresponding author Donald Ingber, M.D., Ph.D., the predictive capabilities of these human LN Chips provide a valuable testing ground for DoriVac vaccines and increase the likelihood of success in human trials.

What Comes Next: From Preclinical Studies to Clinical Trials

The research team is now focused on advancing DoriVac towards clinical trials. This will involve rigorous testing to evaluate its safety and efficacy in humans. Further studies will also explore the potential of DoriVac to target other infectious diseases and to combine multiple antigens into a single vaccine, offering broader protection. The funding for this research came from a variety of sources, including the Wyss Institute’s Director’s Fund and Validation Project program, the Claudia Adams Barr Program at DFCI, and grants from the National Institutes of Health and the Bill and Melinda Gates Foundation. The development of DoriVac represents a significant step forward in vaccine technology, offering a potentially more stable, accessible, and versatile platform for combating current and future infectious disease threats. For more information on vaccine development and clinical trials, you can visit the Centers for Disease Control and Prevention website.

You can also find more information about mRNA vaccines from the FDA.