A team of researchers from the Massachusetts Institute of Technology (MIT) has pioneered a groundbreaking approach to vaccine development, utilizing a DNA-based scaffold carrying viral proteins to provoke a robust antibody response against SARS-CoV-2. This innovative technique, tested successfully in mice, offers a potential game-changer in the fight against not only COVID-19 but also other challenging viruses like HIV and influenza.
MIT Professor Mark Bathe, along with Harvard Medical School’s Daniel Lingwood and Aaron Schmidt, spearheads this transformative research, which has significant implications for future vaccine development. The project was funded by major organizations, including the National Institutes of Health, the National Science Foundation, and the Fast Grants program.
Other senior authors of the study published in Nature Communications include lead authors Eike-Christian Wamhoff, Larance Ronsard, Jared Feldman, Grant Knappe, and Blake Hauser.
A Potential Solution for Challenging Viruses
Immunology has focused on peptide vaccines because of their potent humoral immune response and ability to replicate the structure of the virus. Unfortunately, earlier attempts to use protein scaffolds frequently resulted in unneeded immune responses that took focus away from the target antigen. The MIT researchers found that their DNA scaffold, unlike protein scaffolds, did not induce distracting immune responses.
“DNA, we found in this work, does not elicit antibodies that may distract away from the protein of interest,” explains Professor Bathe. “Your immune system is being fully trained by that target antigen, and that’s what you want – for your immune system to be laser-focused on the antigen of interest.”
The study suggests that this approach, which strongly stimulates B cells responsible for antibody production, could simplify the development of vaccines against viruses notoriously challenging to target, such as HIV, influenza, and SARS-CoV-2. Unlike T-cell-based immunity triggered by other vaccines, the B cells activated by this DNA scaffold approach can persist for decades, providing long-term protection.
Daniel Lingwood, an associate professor at Harvard Medical School, emphasizes the potential of this technique in overcoming conventional vaccine limitations. “This idea of decoupling the response against the target antigen from the platform itself is a potentially powerful immunological trick,” Lingwood notes.
DNA Origami: Precision in Vaccine Design
MIT’s innovative approach involves using DNA origami, providing precise control over the synthetic DNA’s structure. In a 2020 study, the researchers demonstrated the efficacy of a DNA scaffold carrying 30 copies of an HIV antigen in generating a strong antibody response. The structure closely mimics nano-sized viruses, displaying multiple copies of viral proteins on their surfaces.
When testing the SARS-CoV-2 vaccine in mice, the researchers observed high levels of antibodies to the spike protein while avoiding immune responses to the DNA scaffold itself. In contrast, a vaccine based on a traditional protein scaffold generated antibodies against both the scaffold protein and SARS-CoV-2, complicating repeated usage.
“The DNA nanoparticle itself is immunologically silent,” remarks Lingwood. This silence minimizes off-target effects and holds promise for developing a vaccine inducing broadly neutralizing antibodies against various SARS-CoV-2 variants.
Nevertheless, in the future, the researchers are exploring whether a DNA scaffold with multiple viral antigens attached could induce broadly neutralizing antibodies against not only SARS-CoV-2 but also related viruses within the sarbeco subgenus, including those responsible for SARS and MERS.
