Fighting COVID with DNA origami

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Today I look into advances in using DNA origami nanovaccines against viruses. It’s a cool one!

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Fighting COVID with DNA origami

Who could forget 2020? The pandemic changed a lot in everyone’s life, and mRNA vaccines were nothing short of revolutionary in the fight against COVID. And they are also very cool scientifically: I mean, it was even recognized with the Nobel prize in 2023!

But what if we could make better vaccines by exploiting the nanoscale organization of proteins? That’s the idea behind today’s paper, where researchers used DNA origami to create a next-generation COVID-19 vaccine. 

But let’s take a small step back first. Vaccines remain one of our most powerful tools against infectious diseases like SARS-CoV-2. But even with remarkable platforms like mRNA vaccines, challenges remain:

• Adapting to Variants: Viral mutations, like Delta and Omicron, reduce the effectiveness of some vaccines.

• Antigen Display: Traditional vaccines can’t precisely control how antigens (like viral proteins) are presented to the immune system, which impacts their efficacy.

• Durability: Current vaccines don’t always create long-lasting immunity.

To address these challenges, the authors developed a DNA origami-based nanovaccine platform. As we know, DNA origami can fold DNA into precise nanoscale shapes, and offering researchers control on the nanoscale arrangement of antigens to fine-tune immune responses.

Let’s dive more into the design of this COVID vaccine! The researchers created a 90-nm icosahedral DNA origami (ICO) scaffold designed to mimic the size and shape of SARS-CoV-2 virus. This design serves as a platform to display receptor-binding domain (RBD) proteins, which are key antigens for immune recognition. Using a clever engraving-printing strategy based on the SpyTag/SpyCatcher system, the team attached RBD proteins to precise locations on the ICO scaffold. This allowed them to analyze different parameters, trying to maximize immune activation:

•  Antigen spacing: Distances of 10 nm, 20 nm, and higher were evaluated to assess their impact on immune cell engagement.

• Cluster size: Each cluster contained a set number of RBD molecules (e.g., 3, 5, or 7).

• Number of clusters: Different numbers of antigen clusters (e.g., 2 to 12) were arranged across the ICO scaffold.

After testing these designs with engineered B cells, the researchers found the optimal configuration: six clusters of five RBD molecules, spaced 10 nm apart. This arrangement maximized B cell receptor crosslinking, a critical step for strong antibody production. This also showed that the precise spatial arrangement of antigens amplified immune response, and that the DNA origami scaffold enhances immune recognition, probably by mimicking the natural viral antigen presentation.

The optimized nanovaccine wasn’t just tested in cells: it was also evaluated in animal model models, to study its ability to create a robust immune response. And the results were quite impressive (although I am not the right person to judge this). In mouse models:

• The nanovaccine induced significantly higher titers of RBD-specific IgG antibodies compared to monomeric RBD vaccines (not a very high bar, though, since monomeric RBD are not very good antigens alone)

• The neutralizing antibodies were effective against multiple SARS-CoV-2 variants, including Delta and Omicron (remember those?).

• The formation of memory B cell was significantly enhanced, suggesting long-lasting immunity.

• Finally, the vaccine elicited strong activation of CD4+ and CD8+ T cells, providing a balanced adaptive immune response.

They also tested the nanovaccine in Syrian hamsters, a well-established model for SARS-CoV-2 infection. The results were quite promising here as well:

• The hamsters vaccinated with the ICO-RBD nanovaccine showed significantly lower viral loads after being infected with SARS-CoV-2.

• The vaccinated hamsters exhibited reduced lung inflammation and tissue damage, demonstrating the vaccine’s protective efficacy.

So the results are actually quite promising, more or less comparable with the RNA vaccines! Potentially, this could help alleviate some problems with the RNA vaccines, such as the reliance on ultra-cold storage (DNA and protein vaccines requires standard refrigeration) and short shelf life (DNA and protein vaccines tend to have a higher shelf life than RNA vaccines). In addition, the authors also discuss how their DNA origami vaccine has potential for scalability, allowing for large-scale vaccine production. And the DNA origami scaffold can also be adapted to display other antigens for multivalent vaccines or even cancer immunotherapies

So this was a very interesting read into DNA origami vaccines, and I I highly recommend checking out the original paper here!

In other news:

• Exploring Ebola’s structure: Staying with the theme of deadly viruses, this study explores the structure and assembly of filovirus nucleocapsids (e.g., Ebola and Marburg viruses) using cryo-electron tomography. The nucleocapsid condenses vertically during virion assembly, and conserved assembly interfaces present promising targets for broad-spectrum antivirals. Let’s hope!

• Vaccinating against cancer with DNA origami: If you can’t get enough of DNA origami vaccines, but cancer is more your jam, this is the review for you. It highlights the potential of DNA origami as an innovative platform for advanced cancer immunotherapy. By structuring DNA into precise nanoscale forms, DNA origami allows for the controlled arrangement of tumor-specific antigens and adjuvants on its surface. Definitely an interesting read!

• Coupling DNA computing and nanopores: If you are interested in DNA computing, you might find this review compelling! It explores DNA computing, highlighting nanopore technology as a label-free method to decode DNA outputs into human-readable signals, with a focus on medical diagnostics like microRNA detection. The focus on practical applications is quite cool!

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